term 1

Copy of arrows ? ? ? ? ? ?
Practical things and counseling about ADR
general for dx to know, CAUSE, GOALS OF THERAPYMichael Linares pharmacology psychiatic in youtube
(dr. najeeb lect- basal ganglia in youtube)
ftplectures TCA in youtube
pain by Dr. John Campbell in youtube
types of pain MjSylvesterMD youtube

Practical things -Dr still prescribe rx that is relative CI. Its ok. Document that u counsel pt about problem and management since its in the package insert.
ADR- tell symptoms and how to manage itGen- definition, etiology, classification (primary and secondary dx, acute and chronic dx), pathophysiology, symptoms, complications, diagnosis, staging, tx goals, tx guidelines, non pharm tx ( lifestyle modification, diet, excersise,. Edu and psyc support), rx ( prevention, tx of acute and chronic disease).
CAUSE – drugs (rx and OTC), disease, lifestyle
GOALS OF THERAPY-tx the cause, relif of symptom, prevent progression & complication, and relapse or exacerbation

IV bag in mg/ml (ref %w/v = g/dl. )
PCA pump in ml/hr
dose of a drug in *mg/kg/hr*

(GFR 125ml/*min*. CO- 5L/*min*, Creatine clearance – 120 ml/min, ).
UOP – 0.5-1 ml/kg/*hr* or 1.2 l/day or 500- 1200 *ml/day*
polyurea ->2500 ml/day . when hydration given for the tx of rhabdo UOP is maintained >3ml/kg
if rate of pump is 1*ml/hr* its slow (equal to UOP), >3ml/kg/day its fast.
percentage (%) w/v is the g of solid in dl (100ml) of solution.ie, 80% w/v is 80g in 100ml.

quick
*nerve* has K, ca at the axone TIP. presynaptic ACh release is based on K or ca in axone. K inside the cell depolarize cell which opens voltage gated Ca to open and get inside the cell. ( ACh released with can on heart cause depression. ref insulin dr najeeb)
K lost from the presynaptic cell hyperpolaize it. (no ca, no Ach release and relaxaton). *too much K in the blood,* too much on the axone also and don’t go out it due to high blood conc. now ach release. act on heart to cause arrhythmia.postsynaptic ach increase CAMP and Ca inside the muscle cells and increase K inside cell by activating Na/K pump (ex SA node cells, BB). then release K from the cell due to high K conc. (repolarize).
M 2 receptor on heart is a Gi on postsynaptic, atropine inhibit inhibitory and thus stimulate HR.
when u give low dose atropine only bind to presynaptic Gi, no more inhibition and release too much ach. ach act on postsynaptic Gi cause inhibitory action. thus low heart rateNm receptor are ionic receptor opens calcium chanel

know resting and repolarization state.
No autoregulation in RF
low BV/perfusion *(cause) *? ? GFR (body try to conserve BV. but low GFR is not good, cause RF) ? RAAS (hormonal compensation ? ?BV or edema with oligurea/ ?BP or hypertension/ azotemia *(result/symptom)*.
hypotension is the cause of RF but hypertension is the result of RF. bodies natural method to deal/solve with the result/hypertension is PG. NSAID cause hypertension *(aggravating the symptom/result. supposed to tx the symptom* and reduce GFR).
ACEI help in step 2-4 but ?BV/ BP is method to adapt or compensate which is lost by ACEI ( ACEI is used to tx symptom but it will *aggravate the cause of AKI. it also increase K further aggrevate symptom. pt don’t need it unless pt has high BP or microalbumin urea* (goal Bp < 130/80 for +ve albuminuria. *ACEI need a higher dose that that is needed for BP*)

Na/K pump put K inside the cell. (know insulin release najeebyoutube and digoxin mechanism in muscle cell ftplectures hyperkalemia) the beta 2 agonist act on Na/K pump by downstream effect of cAMP and ca which activate pump.

HHM= Humoral Hypercalcemia of Malignancy
HHS= hyperglycemic, hyperosmolar syndrome. seen in DM. thus hyperkalemia
HH- hyporenin, hypoaldosterone disease seen in DM. thus hyperkalemia
exceesive tissue release of K in DM. high glucose (hyperosmolar) outside the cell and inside the blood (high K inside the cell than outside). glucose cause shink of cell and release water from the cell. which further increase the conc of K inside the cell higher.. release K form the cell due to conc change to even higher inside the cell. inulin put K back in to cell (high K inside the cell depoarise cell to release insulin. DM high K inside the cell leakout early and no release of insulin. or lack of insulin in DM).
aldosterone (adrenal gland) is responsible for K dumping. ACEI cause hypercalemia.

hyperkalemia due to increased intake, decreased output in RF or adrenal failure (aldosterone), excessive tissue release in DM or hemolysis or muscle death/necrosis or acidosis. other reasons are leukocytosis, thrombocytosis. distribution issue AIDS (ADME) acidosis (too much H+ in blood which goes inside the cell death. leak K out. on the cell Na K pump put K inside the cell), insulin deficeinecy, drugs -digitalis, succinyl choline and BB (Gs receptor activation cAMP high ca high thus acitate Na/K pump. BB donot activate this pump thus K stay outside the cell.)

hypoxia and acidosis though co2.

Short codes of expansions

Class 1 antiarrhythmics rx, rx for htn urgency
2 Beta blockers (nonselective ?B, selctive ?1B),
GAD rx, thiazide diuretic rx, adr of phenytoin, rx used for partial and generalized siezure.

ethosuximide (Zarontin), zaroxolyn is metolazone (thiazide like diuretic),
metaxalone is skelaxin (musle relaxant)

Class 1 antiarrhythmics- PF Chang ML jolly DQPitous ulcer
Class Ia (prolong ERP but do have antimuscarinic effect, hypotension) – Quinidine, procainamide, disopyramide (not dipyridamole)
Class Ib-Lidocaine, mexiletine
Class Ic-Flecainide PO (tambocor), propafenone PO (rhythmol)labetolol, captopril, clonidine (lcc) for htn urgency
2 Beta blockers (nonselective ?B- stppn, selctive ?1B- baame),
(baame)- Beta 1 antagonist 2nd generation-atenolol, metoprolol, bisoprolol, esmolol, acebutolol

(stppn)- Beta 1 & 2 antagonist – 1st generation-propranolol, sotolol, timolol, nadolol, pindolol

BB with ISA activity- pindolol, penbutolol, acebutolol (ppa no propranolol). NOT recommended in IHD since it increase HR.
Alpha/beta agonist- epinephrine
Alpha/beta blockers- carvedilol, labetalol

GAD rx- LOT

thiazide (IMCH- HCTZ, chlorthalidone, indapamide, metolazone or zaroxolyn)

Light and MMoPPS- adr of phenytoin. lympadenopathy, induction of P450, gingival hyperplacia, hirsuitism, teratogenecity, ataxia, nystagmus, diplopia, megalobalstic anemia, malignant hyperthermia, o is empty, peripheral neuropathy, SJS, sedation.

*partial seizures – lamb top gave funny carb. *
Lamb (also for depression) top (also for migrain) gave (gabapentine) funny (phenytoin, Na or funny current MOA) carb (also for trigerminal neuralgia)

GTS rx * (barbara val suck good- pam *( diazepam)

Short codes of expansions

large intestine, Small intestine parts, cholinergic and anticholenergic ADR. causes of Metabolic acidosis with positive anion gap. cloting cascade and Thrombus formation steps, Indications for dialysis,

large intestine or cecum (Colon and rectum)
Small intestine – DJI (Duodenum, Jejunum, Ileum)• SLUD- cholinergic ADR. Salivation, lacrymaiton, urination, defecation (increased GI motility)
• Anti SLUD (“dry, red, mad”)- flushed skin, dry mouth, blurred vision, urinay retension, constipation, bloating, drowsiness, HA, suppression of lactation (not recommended for nursing mothers), high HR (anti SLUD)

• MUDPILES -Methanol, Uremia, Diabetic ketoacidosis, Propylene glycol, Isoniazid/Iron, Lactic Acidosis (anaerobic metabolism in sepsis), Ethylene glycol/ Ethanol,Salicylates /Starvation (catabolism of protein). – Metabolic acidosis with positive anion gap. catabolism of CHO, protein and fat cause/starvation Co2 raise. Seen in CKD. AKI (ATN) cause normal aniongap acidosis

Unstable atherosclerotic plaque rupture easily and starts the process of ACS. Plaque spews thrombogenic vasoactive substances by AAAA (Adherence, Activation, Aggregation of platelet and Activation cloting cascade) thus Thrombus formation (Platelets and fibrin attached to plaque)

• Indications for dialysis – Acute and chronically in ESRD, AEIOU.
– A – acidosis
– E – electrolyte abnormalities ( primary indication. high K, Mg)
– I – intoxications- Toxic Alcohols (Methanol, Ethylene glycol), Drugs (Lithium, Salicylates,Theophylline)
– O – volume overload ( primary indication. ultrafiltration)
– U – Uremia (not a primary indication)

*Trimethoprim (TMP*) is an antibiotic, It works by blocking folate metabolism via dihydrofolate reductase in some bacteria. given with With sulfamethoxazole TMP/SMX ( 1: 5 part. combination has *synergic effect*). Sulfamethoxazole, a sulfonamide, induces its therapeutic effects by interfering with the de novo (that is, from within the cell) synthesis of folate inside microbial organisms such as protozoa, fungi and bacteria. It does this by competing with p-aminobenzoic acid (PABA) in the biosynthesis of dihydrofolate.
The effects of trimethoprim causes a backlog of dihydrofolate (DHF) and this backlog can work against the inhibitory effect the drug has on tetrahydrofolate biosynthesis; this is where the sulfamethoxazole comes in, its role is in depleting the excess DHF by preventing it from being synthesised in the first place
Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate. (*triamcinolone* is a steroid)

*Tromethamine THAM or Tris* (hydroxymethyl)aminomethane is an organic compound and contains a primary amine *(not used in acidosis due to uremia* (MUDPILES)- ammonia (basic) and urea (acidic) come form aminoacids/proteins), widely used as a component of* buffer solutions*, such as in TAE and TBE buffer, especially for solutions of nucleic acids, (*toradol inj* is ketorolac tromethamine). Tris is used to increase membrane permeability of cell membranes, used as alternative to sodium bicarbonate (IV, natural buffer by kidney) in the treatment of *metabolic acidosis* when pt has Na overlaod .

*Triamterene* (Dyrenium), Amiloride- Epithelial sodium channel blockers, *Potassium-sparing diuretics*, Spironolactone, Eplerenone – Aldosterone antagonists, *Potassium-sparing diuretics*. *Maxzide and Dyazide* is combination of dyrenium with HCTZ. (triamcinolone is a steroid)

EPS (extrapyramidal side effects due to D2 receptor blockade resulting in involuntary motor acions)
*EPSPs* or excitatory post synaptic potential by AMPA glutamate receptor (neurone at the EPSP can reach threshold and generate its own AP spike).
*IPSP* inhibitory post synaptic potential by GABA receptors.

Acids and alcohol cause acidosis and can be removed by dialysis
Alcohol and NSAIDs inhibit mucus production and no more mucosal protection of GI cells.
*Nondigestable sugars and alcohols used for tx of constipation are -lactulose, sorbitol, and mannitol*

Sympathetic nervous system stimulation causes vasoconstriction of most blood vessels, including many of those in the skin, the digestive tract (constipation), and the kidneys.
cholenergic increase everything including motility and fluid except depression of heart rate.

Purines (GA)
Pyrimidines (CTU)

define Etioloty, risk factor,comorbidity, Morbidity and Mortality, Mortality rate, first degree relative, second degree relative, third degree relative, Primary & secondary Prevention, disorder, disease and syndrom
• Etiology- A cause is the reason you have a disease.
• A risk factor increases your chance for acquiring a disease.
• In medicine, comorbidity is the presence of one or more additional disorders (or diseases) co-occurring with a primary disease or occurring in the same person.
• Morbidity and Mortality are used to calculate the prevalence of a disease.
Morbidity refers to the unhealthy state of an individual
mortality refers to the state of being mortal. a morbidity rate looks at the incidence of a disease across a population and/or geographic location during a single year. Mortality rate is the rate of death in a population ie, how likely that disease is to be deadly, particularly for certain demographics.• The “degree of relationship” describes the proportion of genes shared by two blood relatives. A person’s first degree relative is a parent, sibling, or child. A first degree relative shares about half of their genes with the person. A second degree relative of a person is an uncle, aunt, nephew, niece, grandparent, grandchild or half- sibling. A second degree relative shares about one quarter of their genes with the person. A third degree relative of a person is a first cousin, great-grandparent or great-grandchild. A third degree relative shares one eighth of their genes with the person.

• Primary Prevention-Prevention of the development or progression of dx in a patient without clinical manifestations
• Secondary Prevention-Prevention of further cardiovascular events in a patient with a history of clinical manifestations of dx

A Disorder is any abnormality of function. Disorder is a disturbance of structure or function
or both due to a genetic or embryological failure in
development or as the result of exogenous factors,
such as certain chemical substances, injury, or disease.
It may be inborn or acquired. disorder cannot be cured.

A Disease is an illness with a recognizable set of signs and symptoms. Disease is an acquired
morbid change in any tissue or tissue of an organism,
or in an organism as a whole, of specific microorganismal
causation with characteristic symptoms.

Syndrome- characterized by the consortium of a group of signs and symptoms that occur together in a disease

define cardiac cycle, heart rate

Serum prolactin levels, CRP- (C-reactive protein), CPK- creatinine phosphokinase, CK-MB

• cardiac cycle refers to a complete heartbeat from its generation to the beginning of the next beat, and so includes the diastole, the systole, and the intervening pause. Each beat of the heart involves five major stages. The first two stages, often considered together as the “ventricular filling” stage, involve the movement of blood from the atria into the ventricles. The next three stages involve the movement of blood from the ventricles to the pulmonary artery (in the case of the right ventricle) and the aorta (in the case of the left ventricle)
• The frequency of the cardiac cycle is described by the heart rate, which is typically expressed as beats per minute.A dromotropic agent is one which affects the conduction speed in the* AV node*, and subsequently the rate of electrical impulses in the heart. they often (but not always) inotropic and chronotropic. ex. ach ( act on SA and AV node, but not on cardiac muscles, non DHP
Ionotrops -increase the force of cardiac muscle contraction through Ca

chronotrops increase HR through *SA node*. but CCB change heart rate through ca channels. Vasodilators like CCB and nitro cause reflex tachycardia through its action on the alpha.

• tachyphylaxis -rapidly diminishing response to successive doses of a drug, rendering it less effective. The effect is common with drugs acting on the nervous system. Ex metochorpromide (not resistance) Used in motility disorders like postoperative paralytic ileus, for gastric atony, gastroparesis, adynamic ileus. The PDE3 inhibitors, milrinone and inamrinone, are used to substitute for dobutamine when tachyphylaxis develops to the ? receptor agonist.

• Endothelium is the lining of body cavities
• Endothelin- is a peptide. cause vasoconstriction antagonist are used in tx of pulmonary htn
• Endorphins- endogenous opioids and is a peptide released to alleviate pain
• Ecosanoids – are prodused from the arachidonic acid pathway (TX, PG. LT etc)(endorphine and enkephalins are endogenous morphine. autocoids are local hormones, cytokinins, nuclear receptors)

epithelium- is a tissue
•* Endothelium* is the lining of body cavities and artery. ref in pathophysiology of atherosclerosis
• *Endothelin*- is a peptide. cause vasoconstriction antagonist are used in tx of pulmonary htn. NO cause vasodilation.
• *Endorphins*- endogenous opioids and is a peptide released to alleviate pain
•* Ecosanoids* – are prodused from the arachidonic acid pathway (TX, PG. LT etc) of phospholipids.Priapism is a potentially painful medical condition in which the erect penis does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. Priapism is considered a medical emergency, which should receive proper treatment by a qualified medical practitioner.
Erection by ACH vs ejaculation NE. Erectile dysfunction is – inability to erect.

Arteries carry oxygenated blood (with the exception of the pulmonary artery and umbilical artery). Anatomy Thick, elastic muscle layer. Disease artherogenesis- myocardial ischemia. Thickest layer Tunica media. Location Deeper in the body

Veins carry deoxygenated blood. Thin, elastic smooth muscle layer with semilunar valves that prevent the blood from flowing in the opposite direction. dx of vein is DVT. thickest layer-Tunica adventitia. seen Closer to the skin.

ER- *endoplasmic reticulum*- There are two types of ER, rough and smooth ER. The outer (cytosolic) face of the rough endoplasmic reticulum is studded with ribosomes that are the sites of *protein synthesis*. mainly seen in hepatocytes. The smooth endoplasmic reticulum lacks ribosomes and functions in* lipid manufacture* and metabolism, the production of steroid hormones, and detoxification seen mainly in liver and gonad cells.
*sarcoplasmic reticulum* is the endoplasmic reticulum of a striated muscle fiber that *regulates the concentration of calcium ions in the cell cytoplasm*

States of high adrenergic tone, vagal tone
States of high adrenergic tone in AF- Excessive physical activity, Sepsis, Thyrotoxicosis, Alcohol withdroal
state of high cholinergic tone in AF- after meals or during sleep when vagal tone is high
Vagal maneuvers may terminate PSVT: carotid massage and Valsalva maneuver (most common), squatting, deep breathing, coughing.protein binding interactions imp when 80-90% protein bound.change in pk or CL total less 20% is not clinically significant.
XR means drug absorbed slower but half-life same. after 5 half life drug is completely eliminated from the body.

• DASH- (Dietary Approaches to Stop Hypertension) diet
• GFR ; 60 mL/min/1.73 m2. Avoid high protein intake (; 1.3 g/kg/day) in ? risk of CKD progression ( RF kidney cannot remove nitrogen waste formed from protein)
– GFR ; 30 mL/min unless ? risk for malnutrition as in dialysis (loose nitrogen waste or protein. so take protein) or elderly , Low-protein diet 0.8 g/kg/day
• In chronic pancreatitis Decrease fat intake 0.5 g/kg/day
• For TPN Protein: 1.5 g/kg/day ssential and Nonessential amino acids (approx. 50% ratio of each)
• PATIENT ACUITY total calorie or harris benedict eqn
o – Acute Care: 25 – 30 Total Kcals/Kg
o – Critical Care: ; 25 Total Kcals/Kg
• Non-protein Kcals: = total cal- protein calerie. NPC:N ratio method. 125: 1
Dextrose 65 – 85% of kcals
Lipids 15 – 35% of kcals. 4% calorie must be form EFA
• Fluid: 25 mL/kg/day (1 kcal/mL or 1 oz/kg/day)• visceral proteins
• somatic proteins -skeletal muscle proteins
• Hypercatabolism: . NB= Nitrogen intake – ntrogen out. N out is measured using urea N excretion. When more protein is broken down by a person’s body than taken in, negative nitrogen balance occurs. Protein breakdown occurs more quickly than protein synthesis and creates the imbalance.
• Hypermetabolism: An increase in energy expenditure above normal. Treat by replacing calories. Use REE or BEE or IBW method to calculate it. Pt acuity method Replace calories with CHO, and fat. Hypermetabolic state result in hypercatabolism and loss of immune funtcion. Seen in malnutrition
• metabolic syndrome

DM Portion control- use a 9 in plate. 1/2 plate is vegitable (fiber), ¼ meat, ¼ carbohydrate.
for CHO counting- CHO (22g),Fibre (9gm). fiber is a CHO but it does not increase BS. So CHO count/serving is 22-9=13gm of CHO, or 1 serving of CHO. Combine CHO with a *protein (don’t increase BS but help to secrete insulin like CHO)*
1 CHO serving = 15 gm of CHO, (will ? BG 50 mg/dL over 40 min.)
3-4 CHO servings per meal for females
4-5 CHO servings per meal for males*general correction BS rule for long/fast acting insulin-1 unit of insulin (fast or long acting) lowers BG, (FBS and Pre-PBS) by 30 mg/dL*
* general ICR or intented carbohydrate rule- 1 unit of (fast acting) insulin per 15 gm of CHO*

• DASH- (Dietary Approaches to Stop Hypertension). DASH diet ( lots fruits and vegies, whole grain and low fat. 60% CHO, 30% fat, 10% protein /day, fiber -10-25 gm/day, 20% in low fat, 5-6 % saturated fat and in TPN 4% essential fA )
Dietary Fiber Sources – goal in tx of constipation is 20-25gm.
• GFR ; 60 mL/min/1.73 m2. Avoid high protein intake (; 1.3 g/kg/day) in ? risk of CKD progression ( RF kidney cannot remove nitrogen waste formed from protein)
– GFR ; 30 mL/min unless ? risk for malnutrition as in dialysis (loose nitrogen waste or protein. so take protein) or elderly , Low-protein diet 0.8 g/kg/day
• In chronic pancreatitis Decrease fat intake 0.5 g/kg/day
• For TPN Protein: 1.5 g/kg/day ssential and Nonessential amino acids (approx. 50% ratio of each)
• PATIENT ACUITY total calorie or harris benedict eqn
o – Acute Care: 25 – 30 Total Kcals/Kg
o – Critical Care: ; 25 Total Kcals/Kg • Non-protein Kcals: = total cal- protein calerie. NPC:N ratio method. 125: 1 Dextrose 65 – 85% of kcals Lipids 15 – 35% of kcals. 4% calorie must be form EFA • Fluid: 25 mL/kg/day (1 kcal/mL or 1 oz/kg/day) • visceral proteins- proteins other than muscle tissue; for example, internal organs and blood (LBM) • somatic proteins -skeletal muscle proteins • Hypercatabolism: An increase in protein losses above normal (usually via urinary excretion of urea nitrogen). Negative nitrogen balance need nutrition. NB= Nitrogen intake – ntrogen out. N out is measured using urea N excretion. When more protein is broken down by a person’s body than taken in, negative nitrogen balance occurs. Protein breakdown occurs more quickly than protein synthesis and creates the imbalance. • Hypermetabolism: An increase in energy expenditure above normal. Treat by replacing calories. Use REE or BEE or IBW method to calculate it. Pt acuity method Replace calories with CHO, and fat. Hypermetabolic state result in hypercatabolism and loss of immune funtcion. Seen in malnutrition • metabolic syndrome- Any three of the following: Abdominal obesity (pear not apples), Atherogenic dyslipidemia Elevated TG (> 150), Low HDL (M < 40; F < 50), pre Hypertension (> 130/ >85 mmHg), pre Diabetes (> 110mg/dL/100)

• Nephrotic syndrome – symptoms of Proteinuria (>3.5g/d)- problem with nutrition, fatigue, Foamy or frothy urine
Hypoproteinemia – edema, Weight gain
Hyperlipidemia
Causes: DM, lupus, amyloidosis, preeclampsia, or a primary glomerular disease
• Nephritic syndrome- Hematuria- Pus, cellular and granular casts
Proteinuria (up to 3g/d)- Edema with declining renal function
Hypertension- with declining renal function
Causes: glomerulonephritis
• Ultrafiltration -movement of water across a membrane
• Parecentisis – remove excessfluid from peritoneum to tx acitis
• Plasmapharesis – to remove antibody in Glomerulonephritis (GN) due to autoimmune disease
• TIPS
• Nephrotic syndrome – symptoms of Proteinuria (>3.5g/d)- problem with nutrition, fatigue, Foamy or frothy urine
Hypoproteinemia – edema, Weight gain
Hyperlipidemia
Causes: DM, lupus, amyloidosis, preeclampsia, or a primary glomerular disease
• Nephritic syndrome- Hematuria- Pus, cellular and granular casts
Proteinuria (up to 3g/d)- Edema with declining renal function
Hypertension- with declining renal function
Causes: glomerulonephritis
• Ultrafiltration -movement of water across a membrane
• Parecentisis – remove excess fluid from peritoneum to tx acitis
• Plasmapharesis – to remove antibody in Glomerulonephritis (GN) due to autoimmune disease ex SLE
• TIPS- it is a surgical procedure to bypass liver by connecting portal vein to systemic hepatic vein. used to tx acitis, Portal hypertension. not curative but reduse symptoms when rx don’t work well. It give time . It is a to settle the complication. shunt procedure, to *bypass *fibrotic area of liver done between systemic hepatic vein and portal vein. *It shunt albumin back to systemic circulation bypassing liver to maintain oncotic pressure. decrease pressure and volume.
*Limitation- restenosis after a yr.* risk encephalopathy* because the organ loses its ability to remove brain-poisoning toxins from the circulation.A sinusoid is a small blood vessel that is a type of capillary similar to a fenestrated endothelium. The level of permeability is such as to allow small and medium-sized proteins such as albumin to readily enter and leave the blood stream. Sinusoids are found in the liver, lymphoid tissue, endocrine organs, placenta and hematopoietic organs such as the bone marrow and the spleen.

copy

Blood from *portal vein* (gastric vein, mesenteric (small and large intestine) vein, splenic vein ; pancreatic vein) goes to *systemic hepatic vein* to join venecava . *Hepatic portal system * ( the hepatic artery (from splanchnic artery), the hepatic portal vein) goes to sinusoidal then goes to inferial venecava.

• Splanchnic circulation from aeorta to gut (except gut) include hepatic artery, celiac artery (and artery to stomach, spleen, pancreas) and mesenteric artery (intestinal and pancrease Artery). celicac and mesentic vein join to form portal vein. portal vein and hepatic artery (thus the whole gut or splanchnic circulation) join to go back to venecava.
*Hepatic portal triad* (is an area at the liver named after its triangular shape and its three major components: the hepatic artery (from splanchnic artery), the hepatic portal vein, and the hepatic ducts, or bile ducts)

Distribution of CO (5 l of blood the body)- lung get 100% (pulmonary circulation). 20% of CO goes to kidney, muscle, brain and whole GIT (splanchnic circulation. from there 5% to liver). 5 % to heart, bone and skin

TIPS- it is a surgical procedure to bypass liver by connecting portal vein to *systemic hepatic vein.*

*Common Bile Duct-carries pancreatic fluid and bile from liver and gall baldder to duodenum. it has digestive enzymes and bile salts (emulsify fat), and can erode protective mucus in the intestine* and increase ph of the small intesinal secretions. The sphincter of Oddi is a muscular valve that controls the flow of digestive juices (bile and pancreatic juice) through ducts from the liver and pancreas into the first part of the small intestine

enterohepatic circulation – process by which bile is reabsorbed in the small intestine (94%) and returned to the liver via the portal vein in order to be reused. Common bile duct secrete bile to intestine.

Blood containing medications = first pass metabolism Modify medications (prodrug to active, vise versa, affect BA) prior to entering circulation ( blood from the intestine reaches liver before reaching systemic circulation)

•* Enteric nervous system (ENS, a part of ANS or vagal nerves) in GI tract* (parts are mucosa, submucosa, muscle, and advetecia) organized into 2 connected networks of neurons:
o The myenteric plexus -Responsible for motor control of longitudinal and circular muscle layers GIT through Ach and NO. (mesentric artery supply blood to intestine and part of portal vein ref slide 1 set 14 cirrhosis)
o The submucosal plexus -Regulates secretion, fluid transport and vascular flow though 5 HT.
o Numerous neurotransmitters; the most important are *ACh, 5-HT, DA*

four main tissues in the body – epithelium, muscle (sk mus., smooth mus, cardiac mus.), connective tissue (bone, cartilage, blood and adipose tissue) and nervous tissue.
Collagen type I is found in B*one*, collagen type 2 is found in Car*two*lage, type 3 all over the body, type Four under the floor (basement membrane of lungs and glomorulous.)

• Smooth muscle – blood vessel, artery and veins. These are involuntary muscles unlike sk. Muscle. Cardiac muscle is a sk. Muscle but it is involuntary muscle (AP is different).

tendons help muscle tissue to bind to bones. *muscle cell is called myofiber.* its bundled together inside facicle (a connective tissue). bundle of facicle is seen inside the muscle tissue called epimycium.
outer membrane of the muscle cell (myofiber) is called *sarcolemma. myofibrils* are tubes with in the muscle cells with strations of protein actin and myocin (myofibrils has lots of *sarcomere* repetition. inside sarcomere protein called actin and myocin for contraction).
All muscle cells produce (ATP) molecules to power the movement of the myosin heads. Muscles have a short-term store of energy in the form of *creatine phosphate which is generated from ATP* and can regenerate ATP when needed with creatine kinase. Muscles also keep a storage form of glucose in the form of glcogen for sustained, powerful contractions. (glucose metabolized anaerobically in a process called glycolysis to produce and pyruvate or lactate anaerobic conditions thus ATP). fat in the Muscle cells are used for energy during aerobic exercise which take longer to produce the ATP. Cardiac muscle on the other hand, can readily consume any of the three macronutrients (protein, glucose and fat) aerobically without a ‘warm up’ period and always extracts the maximum ATP yield from any molecule involved.
during strong reps cells compensate by hypertrophy of the sarcoplasmic or myofibril (myofiber is muscle cell). in the sarcoplasmic hypertrophy body try to make more more space inside the sarcoplam to store glycogen to keep up with the exercise, thus *hypertrophy (bigger) of the cell with out increasing the no. of cells. *myofibril hypertrophy body increase the no. of cells to compensate for the need of energy during exercise. in cardiac hypertrophy, cardiac muscles are constantly contracting and relaxing, normally there is compensatory hypertrophy but when the compensation not happening, cardiac muscles *increased the size and become thick and cardiomyopathy. result in decreased size of blood holding chambers and increased pressure.*

perfusion is blood flow. low perfusion cause ischemia and infraction (necrosis) and, hypoxia. one of the reason is low *central perfusion (CO)* or local tissue perfusion ( the volume that reaches the tissue. vessels are not patent ( think or *leaky capillary*), clot). blood thinners help with local perfusion if u have clot, lipid lower drugs, vasodilators.

tissue injury/inflamation *repaired* by regenartion or fibrosis (well in epithelial and connective tissue. poor in muscle and nerve tissue). 1st step of repair process in skin is vascular change like vasodilation, fluid leak into the space of tissue along with inflammatory substance and fibrinogen (clotting occure due to stasis of blood due to loss of fluid) then cellular events of inflammation occurs at the end tissue repaired and replaced by fibous tissue or scar tissue.

ref Nervous system -CNS, PNS ANS, sensory, motor and somatic nerves, (*voluntary and involuntary nerves and muscles* so AP generation is different in nerves, muscles and cardiac muscles) cranial (vagal nerve and trigerminal nerves) and cervical nerves, interneuron or connector neurons. cranial and spinal nerves from brain and spinal cord origin, so CNS. but can be a part of peripheral nervous system and ANS. ex. *parasypathetic supply is by vagus nerve and sympathetic supply by splanchnic nerves. *

• Enteric nervous system (ENS) or intrinsic nervous system – A division of the ANS whose component neurons lie within the walls of the digestive organs (GIT) (esophagus, stomach, intestines, pancreas, gall bladder and pancreato-biliary ducts). The enteric nervous system contains entire nerve circuits for digestive organ control, and can function autonomously. ENS is now usually referred to as separate from the autonomic nervous system since it has its own independent reflex activity.

• Enteric neuron- A neuron whose cell body is in a ganglion within the wall of the digestive tract, biliary system or pancreas. Most enteric neurons make connections with other enteric neurons or with gastrointestinal tissues, such as its muscle coats, intrinsic blood vessels and glands.
• Myenteric plexus- A plexus of small groups of nerve cells (ganglia) and connecting nerve fibre bundles that lies between the longitudinal and circular muscle layers of the gut wall and forms a continuous network from the upper esophagus to the internal anal sphincter.
• Submucosal plexus- A plexus of small ganglia and connecting nerve fibre bundles that lies within the submucosal layer, between the external musculature and the mucosa of the small and large intestines, forming a continuous network from the duodenum to the internal
anal sphincter.

*Intrinsic* means Of or relating to the essential nature of a thing; inherent. in Anatomy Situated within or belonging solely to the organ or body part on which it acts. Used of certain nerves and muscles. ENS is intrinsic and can act with out ANS control as well.

A *valve* is a structure in a hollow organ (like the heart) with a flap to insure one-way flow of fluid through it whereas a *sphincter* is an opening of skin and surrounded by muscle that physically restricts and controls the passage of substances through the digestive tract. There are three main sphincters in the digestive tract: the esophageal sphincter, the pyloric sphincter and of course the anal sphincter.

Brain and nervous system and central neurotransmitters, action potential of the nerve, muscle relaxant and anesthetics (dr. najeeb lect- basal ganglia in youtube)
Brain and nervous system and central neurotransmitters, action potential of the nerve, muscle relaxant and anesthetics (dr. najeeb lect- basal ganglia in youtube)
*Nervous system 2 kind* – *CNS* (brain and spinal cord) and* PNS.* CNS uses PNS to sent and receive signals from the periphery. Autonomic and somatic nervous system in CNS (brain and spinal cord) connect with PNS (consist of cranial and spinal nerves). both CNS and PNS has afferent and efferent neurons.* sensory* (afferent nerves) conduct impuses from receptors on the skin to the PNS then to CNS.* Motor nerves* (efferent nerve cause effect on the effector cells) conduct impulse back to the effectors through ANS (involuntary impulse for the smooth muscle and gland. Include parasympathetic and sympathic nervers) or *somatic* nervous system (voluntary impulse for *smooth muscles (ref sk. muslces)*). Motor neurons are 2 kind one for voluntary movements *(somatic *nervous) and for involuntary movements *ANS*. ANS made of sympathetic (throraco lumbar origin) and parasympathetic (*cranio* sacral origin) neurons. brain has 12 pairs of cranial nerves (include trigeminal nerve an vagal nerve- for digestion and HR) and spinal cord has 31 pairs of spinal nerves, one on each side of the vertebral column. These are grouped into the corresponding *cervical*, thoracic, lumbar, sacral and coccygeal regions of the spine. There are eight pairs of cervical nerves, twelve pairs of thoracic nerves, five pairs of lumbar nerves, five pairs of sacral nerves, and one pair of coccygeal nerves. The *spinal nerves* are part of the peripheral nervous system along with *ANS* with cranio scaral *(parasympathetic- ex vagus nerve*) or thraco lumbar *(sympatheic – ex.splanchnic nerves*) origins. main NTs in ANS are Ach and epi/NE sympathetic nervous Promotes a *fight-or-flight response*, corresponds with arousal and *energy* generation, and *inhibits digestion*. The parasympathetic nervous system promote a *”rest and digest” response*, promotes calming of the nerves return to regular function, and enhancing digestion (include *depressing HR*).
• Enteric nervous system *(ENS)* or intrinsic nervous system – A division of the* ANS *whose component neurons lie within the walls of the digestive organs (GIT) (esophagus, stomach, intestines, pancreas, gall bladder and pancreato-biliary ducts). The enteric nervous system contains entire nerve circuits for digestive organ control, and can function autonomously. ENS is now usually referred to as separate from the autonomic nervous system since it has its own independent reflex activity.CNS is developed from *neural tube in embryo*. it develop to spinal cord and brain (fore brain, mid brain and hind brain). in adult brain, hind brain develop to *cerebellum (muscle coordination*) and *brain stem* (relay information between periphery and higher brain center). brain stem has 3 areas – mid brain (carries higher brain functions), ponds and *medulla* oblangata. Fore brain develop to 2 cerebral hemispheres and inter-brain along with *limbic system, basal ganglia,* and ventricle (filled with CSF). inter-brain has 4 areas *thalamus (relay station)*, hypothalamus (HPA axis -hypothalamus -pituitary adrenal ), epithalamus and mamilary bodies. interbrain maintain homeostasis. cerebrum has higher functions and has 4 lobes – *frontal lobs,* temporal, occipital, parital lobes. Prefrontal cortex/ *PFC* -involved in *complex cognitive functions*, decision making, expression of personality and appropriate social behavior.

*brain stem* provides the main motor and sensory innervation to the face and neck via 10 of 12 pair of cranial nerves. This includes the *cortico-spinal tract (motor),* the posterior column-medial lemniscus pathway (fine touch, vibration sensation, and proprioception), and the *spinothalamic tract (pain*, temperature, itch, and crude touch). The* raphe nuclei* are nuclei found in the brain stem and release *serotonin* to the rest of the brain.
The *midbrain* consists of:
1.*Periaqueductal gray PAG*: with neurons involved in the *pain desensitization* pathway with lots of* opioid receptors*. Neurons synapse here and, when stimulated, cause activation of neurons in the nucleus raphe magnus, which then project down into the posterior grey column of the spinal cord and prevent pain sensation transmission.
2. Oculomotor nerve nucleus or *3rd cranial *nerve nucleus.
3. Trochlear nerve nucleus or *4th cranial* nerve.
4. Red nucleus: motor nucleus that sends a descending tract to the lower motor neurons.
5. *Substantia nigra pars compacta: uses dopamine* as its neurotransmitter and is involved in both motor function and emotion. Its dysfunction is implicated in Parkinson’s disease.
6. Central tegmental tract:this is a pathway by which many tracts project up to the cortex and down to the spinal cord.
7. Ventral tegmental area *VTA: A dopaminergic* nucleus in midbrain, deals with *reward pathway of dependence*
8. Tail of VTA: A GABAergic nucleus
9. Reticular formation: *large area.* it contains lower motor neurons, is involved in the pain desensitization pathway, is involved in the arousal and consciousness systems, and contains the *locus coeruleus (with NE for fright or flight response) * involved with physiological responses to *stress, GAD and panic*.

*Limbic system (reward system)* has *amygdala (emotions*/fear-sexual and social behavior) and *hippocampus (short term memory and traumatic memory in PD )* involved with *depression, and anxiety disorders*. amygdala connect with PFC, hippocampus, hypothalamus, Neucleus accumbuens (in basal ganglia, and its called *pleasure center*, causing habits) and insuli. limbic system and PFC has lots of *serotonin and NE *neurons (but *reward/pleasure NT is dopamine* and pathway start at VTA in midbrain and connect with PFC, striatum & Neucleus accumbuens in basal ganglia (dopamine) and limbic system). Neurtrophins are protein that help with *neural growth or neuroplasticity* and is low in *depression*.

*basal ganglia* (or basal nuclei) comprise multiple subcortical nuclei, situated in forebrain regulate *movement *. basal ganglia parts are *Straitum* [the dorsal striatum (caudate nucleus and putamen), ventral striatum *(nucleus accumbens* and olfactory tubercle)], globus pallidus, ventral pallidum, *substantia nigra (lots of dopamine),* and subthalamic nucleus. *muscle movements are regulated by direct and indirect pathway, striato nigral pathway. * nucleus accumbens (habits formed with out conscious/ pleasure center)* and *PFC(concious planning planning).*) has lots of *dopamine and cause reward.* basal ganglia has GABA, glutamate, dopamine and Ach.

*Direct pathway or stimulatory* pathway of basal ganglia- cortex-stratum -thalamus loop back to cortex:
motor Cortex get stimulated or with movements (stimulates release *glutamate)* ?* Striatum* (inhibits, due to release *GABA* and substane P) ? globus pallidus internal”SNr-GPi” complex (less inhibition of thalamus. normally release GABA, but since its doble _ve action *on movement,* no GABA release and stimulate thalamus. but *at rest* too much GABA inhibit thalamus) ? Thalamus (stimulates. release glutamate) ? Cortex (stimulates) ? Muscles, etc. ? *(hyperkinetic* state)

*indirect pathway or inhibitory* pathway with an *(extra loop)* of basal ganglia- cortex- straitum – hypothalamus- thalamus and loop back to cortex:
Cortex (stimulates though *glutamate*) ? *Striatum *(inhibits due to *GABA *release) ? *globus pallidus external *GPe ( GABA neuron. less inhibition of STN due to doble inhibition) ? *subthalamic nucleus *STN (stimulates. no more inhibition and release its normal glutamate) ?*globus pallidus internal* “SN-GPi” complex (stimulates to release normal GABA. inhibits thalamus) ? Thalamus (is stimulating less or no more release of glutamate due to GABA inhibition) ? Cortex (is stimulating less) ? Muscles, etc. ? *(hypokinetic* state on movement for balance)

*Straito nigral *pathway from substantia nigra is the *kick starter* for movement *through dopamine*. it gets the impulse from the cortex. nigra should *stimulate the the direct pathway* thus increase movement (through *D1 stimulaory* receptors just like glutamate form the thalamus) and *inhibit indirect pathway* thus less inhibitory movement (throgh *D2 inhibitory* receptor unlike glutamate from the thalamus in the indirect pathway due to change in net potetintal). In the presence of dopamine, D2-receptors in the basal ganglia inhibit these GABAergic neurons, which reduces the indirect pathways inhibitory effect (preventing full inhibition of movement). Through these mechanisms the body is able to maintain *balance between excitation and inhibition of motion.* Lack of balance in this delicate system leads to pathologies such as *Parkinson’s disease.* Parkinson’s disease involves the *loss of dopamine* which means the *direct pathway* is less able to function (so no movement is initiated by Straito nigral pathway) and the *indirect pathway is in overdrive* (causing too much inhibition of movement by Straito nigral pathway).

Remember direct pathway get stimulation from cortex (glutamate) and substantia nigra (stimulatory D1 dopamine) at the straitum and thus activated since net potential is stimulatoy. But in the indirect pathway get glutaminergic stimulation from the cortex and inhibitory dopamine (D2) from the substantia nigra and the net potential determine indirect pathway effect. *Ach* has exact opposite actions of dopamin in direct and indirect pathway of muscle movements (skeletal muslce end plates stimulated by Ach).

when PNS sense *pain*, signal not always goes up to brain. sometimes spinal cord sent messages to motor neurons to fix it. through *reflex arc. 5 steps pain signaling* are 1. *receptors* on the periphery senses the stimuli, 2. *sensory neurone* transmit the signal to CNS, 3. *intergration* of signal in spinal cord, 4. *motor neuron *sent directions back to the site of stimuli, 5. *effector* cells respond by contracting or secreting. each kind of sensory receptors responds to different stimuli, thermoreceptor, mechanoreceptors, chemoreceptors (responds to chemical stimuli), photoreceptors (responds to pressure), *nociceptors (only for pain). *inter-neurons* are used to sent messages from spinal cord to Brain.

body as a whole is electrically neutral. nerves build potential or difference in charge inside and outside of the nerve by keeping the charges seperate like in battery. neurons have -ve membrane potential. nerves hates electrochemical gradient. it uses ATP to open and close Na/K pump to balance electrochemical gradient. channels are voltage gated channel, ligand gated channel or mechanically gated channel to respond to electrochemical gradient. nerve are like wires, and communicate via NTs in synapse. nerves use* electrical voltage potential and chemical (NTs) to transmit a signal.*

Brain and nervous system and central neurotransmitters, action potential of the nerve, muscle relaxant and anesthetics (dr. najeeb lect- basal ganglia in youtube).

know neuroadaptive changes in brain (abuse), neuro plasticity (depression), long term potentiation and long term depression of glutamate receptors (epilepsy), neuroleptic foci, synaptogenesis.

Important *NTs* in central nerous system include glutamate, GABA, monoamine NTs (dopamine, serotonin, NE) ach, endorphine.

NE and adrenalin cause *energy, fright or flight response.* lot in *locus coeruleus* of the midbrain.
Ach in basal ganglia (basal ganglia also have dopamine, gaba and glutamate).
*dopamine is reward/ euphoria/ pleasure/sex pleasure/ social activity/ food/appetite* NT. seen in *VTA *of midbrain, *basal ganglia (striatum, Neucleus accumbuens). reward pathway is limibic system* with NE and SE. relay station is the thalamus.
*serotonin* is (pleasure NT like dopamine) for *mood/anxiety, *pain, appitite, sleep (serotonin melatonin balance), sex (sex issue when its high). serotonin receptor found in CNS, GIT, platelet (5-HT2A- cause platelet agreegation) . *serotonin seen in raphe nuclei *found in the brain stem and in *limbic system. amygdala (emotions*/fear-sexual and social behavior) in limbic system.
endorphine are inhibitoy and help with *coping pain.*
*glutamate* is imp in *memory formation, long term potentiation* and long term inhibition. (ketamine are blockers).
GABA is inhibitory neurotransmitter.

Drugs used to increase (or reduce) the effect of monoamine may be used to treat patients with psychiatric disorders, including depression, anxiety, and schizophrenia, mania

*mania or bipolar* has high NE in synapse, but *MDD* low NE/SE. when antidepressants are used for tx of bipolar depression, rx should be combined with mood stabliser. *schizophrenia *has high dopamine use neurleptics to tx. 5HT2 serotonin receptor antagonist are atypical antispychotics and trazodone.

in anxiety -GAD and PD- NE & ANS are hypersensitive & overreacts to various stimuli. Give rx that decrease LC firing (BDZs, SSRIs, SNRIs). *5 HT/serotonin is excess* in raphe nuclei of brain due to Dysfunction of serotonin receptor subtypes 5HT1A. (depression has deficiency in serotonin and NE and rx to tx raise the serotonin levels). increased SE activity *decreases* (is not going to worsen pathophysiology)* NE* activity in the LC (SSRIs, SNRIs).
*GABA* is an inhibitory neurotransmitter. Give agonist rx to decreased anxiety & cause sedation or to treat somatic and autonomic symptoms but not phsychologic symptoms. only antidepresents are used in PD tx (no antipsychotic).

*OCD and PTSD* are both associated with *reduced levels of serotonin* and severe anxiety. OCD associated *Abnormalities dopamine* transmission in: Orbitofrontal cortex, *Basal ganglia,* Thalamus. PTSD Abnormal and constant (not turned off) Flight or flight response, HPA axis is suppressed due to Lower cortisol levels
*Abnormal NE, SE and glutamate levels*.

*Epilepsy* has too much *glutamate* and long term potenciation of glutamate receptors. and low IPSP or *GABA.*

in *parkinsonism* imbalance with high ACH and low dopa). *Dementia of Alzheimer* type (neurodegerative disease, loss of synapse. low Ach and glutamate.). tx of dementia with Cholinesterase inhibitors such as donepezil (Aricept. aripitrazole- abilify anti psychotic, Aprepitant (Emend) and antimetic), Rivastigmine (Exelon), Galantamine (Razadyne),
N-methyl-D-aspartate (NMDA) receptor blockers such as memantine (nemenda)

amygdala *responsible for emotions, sex and social behavior.*
serotonin receptors are *functionally redundant* so action depends on target nerve. serotonin is a pleasure NT (like dopamine) for mood, *pain, appitite*, sleep. serotonin 5HT2 cause* anxiety, sex problem and sleep issue (imbalance with melatonin)*. serotonin receptors
5-HT1A is inhibitory (buspiron anxiolytic is agonist), 5-HT1B- D (Triptan ex sumatriptan for migrain & is agonist),
5-HT2A receptor (Trazodone, mirtazepine antidepressant, atypical anti-psychotic, cloxapine and cyproheptadine for the serotonin syndrome tx, are antagonist),
5-HT3 cause emesis (reglan, ondansetron antiemetic is antagonist. reglan is dopamine antagonist),
5-HT4 (cisapride a gastrokinetic agent is agonist),
5-HT5, 5-HT6 ,5-HT7

LSD (a psychedelic) is nonselective 5-HT receptor agonist.

( 5-HT1 (inhibitory) cause antianxiety so agonist ex buspirone is used as an anxiolytic 5-HT2 (exicitatory) cause sleep problem, anxiety, sexual problem. so antagonist like trazone used as a antidepresent with no sexual problem, and for sleep. remember depression is due to low 5HT, NE, dopa. unless it block reuptake (presynaptic blok) or degradation enzyme, conc of NT (pathophysiology) in the synaptic junction is not going to increase eventhough it block the receptor (no NT comming from presynaptic neuron, whats the point of blocking the receptor). high serotonin in the synapse cause sexual problem (think of SSRI)
sleep and pain (low dose and effect in 1 week when compaired with std use of antidepresent), antidepresent action take 6 weeks due to receptor downregulation. OCD need high dose than std antidepresent action.

serotonin is a pleasure NT (like dopamine) for mood, pain, appitite, sleep (serotonin melatonin balance). and is funcunctioanally redundant so action depends on target nerve. smoothmuscle receptor vasoconstriction, endothelial receptor vasodilation. serotonin receptor found in CNS, GIT, platelet (5-HT2A- cause platelet agreegation) . 5-HT1is inhibitory and cause vasoconstiction.

amphitamine and coccain are dopamine agonist. caffine affects *dopamine (pleasure NT or reward).*
atypical antipsychotics are 5 HT2 antagonist. but too much dopamine in psychosis pathophysiology. like depakeote (DR), bupropion (IR) also SR and SL avilable)
plant based narcotics are opium (Heroin), cocca, cannabis.
Opium and alcohol are CNS depressants while, amphetamine and cocca are stimulant, cannabis (less stimulant and some depressant action.

rx that cause serotonin syndrome- cyclobenzaprine has TCA str. zyvox MAOI str. cocain and amphetamine block dopamine reuptake and MAOI increase synaptic dopamine and NE. opioids (meperidine/demerol, *tramadol*, fentanyl (short half life so not much of a probem), NMDA blocker (dextromethorphan, ketamine),

diphenoxylate has meperidine str. Wellbutrin has amphetamine str.

classificaion of pain and terms and dorsal pathway

diffuse (distribution)- the spreading of something or dispersing more widely.

Etiology- Tumor related (presses on soft tissues and nerves) or Treatment related
1. *Nociceptive*
a. Somatic – *sharp, localized,* throbbing, pressure-like due to *tissue damage* in the skin if superficial. if deep somatic pain it is from muscle or bone/connective tissue pain and feels like a visceral pain can be a referred pain
b. Visceral – *diffuse,* irritating, cramping, difficult to locate (organs or viscera), *radiating or referred pain* pain due to stretch or lack of oxygen or inflammation to an organ.
2. *Neuropathic*- burning, tingling, “electrical”, *pins and needles, sharp or shooting, numbness*. Ex. Hitting the “funny bone” in your arm. due to nerve damage or affecting the *somatosensory nervous* system (not motor sensory or ANS sensory). it is associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli *(allodynia). *can be peripheral (ex shingles, diabetic neurological) or central (parkinsons, stroke)

Pain may be musculoskeletal pain, bone and neuropathic pain. Pain can be adaptive (a protective signal) or pathological pain. adaptive can be Nociceptive or inflammatory (inflamated tissue are kept at a lower threshold). Nocieptive can be somatic or visceral. pathological pain can be neuropathic or dysfunctional (ex. fibromyalgia, IBS) with no neuronal damage, have an amplification of norma sensory signal in these nerves.
*Chronic (>3 months)* vs. Acute pain (a week)

gray matter- collection of neuronal cell bodies. also glial cells, synapses, and capillaries. also *small no.* of neuropil (dendrites and myelinated as well as unmyelinated axons)
white matter -collection of axon *CNS* (brain and spinal cord). myelinated axon tracts.
nucleus- is a cluster of densely packed cell bodies/gray matter of neurons in brain mainly cerebral hemispheres and brainstem.
ganglia- a cluster of cell bodies/gray matter of neurons in PNS
*Tract* is a bundle of axon/white matter connecting *brain and spinal cord* going up or down. these have same origin and termination. can be *ascending or descending tracts*.
association *fiber* – bundles of axons/white matter within the *brain* that unite different parts of the same cerebral hemisphere (anterior and posterior connection)
The *commissural fibers* or transverse fibers are bundle axon/white-matter structures that connect the two hemispheres of the *brain* (right and left connection of brain). ex. corpus collosum.
spinal *trunk *- place where both dorsal and ventral *route* from the spinal cord join together out side of the spinal cord at the trunk. trunks have both motor and sensory nerve. trunk to peripheral connection is called ramus and plexus which are also mixed motor and sensory nerves.
An *interneuron* (also called relay neuron, association neuron, *connector neuron* or local circuit neuron)enabling communication between sensory or motor neurons and CNS. found to function in reflex arc, neuronal oscillations, and neurogenesis

stimuli actives peripheral receptor (ex nociceptor for pain) which convert this stimuli to electrochemical AP then goes to brain through afferent/sensory neurons. afferent pathway can be a dorsal pathway for fine touch, locomotor stimuli (highly myelinated for fast stimuli) or antrerio lateral pathway for pain, temp, visual stimuli, crude touch (unmyelinated for slow stimuli) . efferent pathway can be efferent neutons/motor neuron from the brain passes the response to effector (muscle or gland).

1st order nerves- neuron that are 1st in the sensory process. start from the sensory receptor up to CNS either up to brain if its dorsal pathway (for fine touch, locomotor stimuli) or up to spinal cord if its antrerio lateral pathway (pain, temp, visual stimuli, crude touch). 1st order neuron have central and peripheral process. cell body (ganglia) of the 1 st order neuron are seen in the peripheral process near the dorsal horn has only sensory neuron (no motor nerve).
2nd order nerves- neuron that are 2nd in the sensory process.
3rd order nerves- neuron that are 3 rd in the sensory process.

spinal cord anatomy
gray matter of the spinal spinal cord has a dorsal horn or a posterior horn, ventral horn or anterior horn, and lateral horn. all sensory stimuli that goes to CNS, enter in to the dorsal route of the spinal cord and all motor stimuli that goes out to the effect tissue exit through ventral route. dorsal and ventral join together at the trunk of the spinal nerve.
white mater of the spinal cord has all the tracts are divided into dorsal/posterior column, ventral/anterior column, and lateral column.
*anteriolateral pathway tracts* have both sensory and motor nerves ie, goes up and down. sex, pain, temp, visual, crude touch path way uses these tracts.
*tract * (fasciculus gracilis, fasciculus cuneate) in the *dorsal pathway or discriminating touch and pressure and kinesthesia pathways * are fast by myelination for locomotor sensations. dorsal tract is made of different bundle of *sensory neurons only*. dorsal pathway makes conscious awareness/*discrimination of body position* and movement is called the kinesthetic sense and even the level of muscle tone. sides of the 1st order neurons don’t cross or it goes ipsilateral.

In the dorsal pathway for fine touch (pin prick touch) and locomotor stimuli, 1st order neuron (ganglia in the peripheral process of the spinal cord), move ipsilaterally up to medulla of the brain stem and terminates. However, not all of these signals from the medulla reach the conscious level of cortex and some goes through cerebellum for subconscious evaluation and integration. 2nd order neuron cross over (right side neuronal bundle has connection with left side of the body and vise versa) connect nucleus (cell body of the 2nd order neuron) of the medulla (lots of pyramids and nucleus) and terminates at the thalamus. VPL/ ventral posterior lateral nucleus of the thalamus has the cell body for the 3rd order neuron and it terminates at the cerebrum.

pain and thermal pathway (anterio lateral pathway). also visual stimuli and crude touch pathway. analgesia pathway.

pain stimuli activates nociceptors and AP reaches spinal cord through dorsal route. ( all sensory stimuli goes though here just like in dorsal pathway). cell body (ganglia near the dorsal route) for the 1st order neuron is in the periphery just like in dorsal pathway. but in the pain pathway, 1st order neuron terminates in the spinal cord near dorsal horn at substancia gelatinosa. and the 2nd order neuron (cell body in spinal cord at substancia gelatinosa) start and , cross over in the spinal cord then goes up to thalamus through lateral spinothalmic tract. before it terminate 1st order neuorns makes a upper and lower dorsolateral tract of lessure, from where 2nd order neurons originates. three 2 order neurons, lateral spinothalmic tract (for pain/temp) antero spinothalmic tract (for crude touch) and spino tectal tract (for the visual stimuli. tectum part in the mid brain.) cross over (pain modulation occurs here) goes up to the thalamus, but these 3 bundles at the medulla to form spinal laminus. the visual AP goes up to tectum of the mid brain. fast pain goes up to VPL of the thalamus, slow pain goes up to intra-laminar nucleus of the thalamus, or reticular formation (main switch of the cerebrum which connect with both crearal hemispers) of the whole brain stem. 3rd order neuron originates in thalamus and connect to the cerebrum.

pain can be fast pain or dull pain. fast pain stimuli can be a mechanical or thermal stimuli. dull pain can be mainly a chemical stimuli, or mechanical or thermal stimuli. mediators of slow chemical pain can be 5HT (serotonin), histamine, bradykinin, acids and potassium. substance that reduce the pain threshold in the inflammatory pain mediators are prostaglandin and substance P. pain fiber, in the 1st order neuron can go through A delta fiber (lightly myelinated for fast pricking pain from the skin) or C fiber (unmyelinated for dull pain/visceral pain). C fibers are slow because it has so many connection from the end of 1st order neuron up to the cross over of the second neuron unlike A delta fiber.

Gate theory says that, pain pathway can be modified by other overstimulation pathways like a massage. glutamate is released at the pain path ways. other neuronal pathways when stimulated can produce collateral *connector neurons (interneurons)* whcih can sent a *inhibitory NTs* to the 2nd order neurons in the spinal cord of the pain pathway and can modulate the pain or reduce pain.

2 different pain pathways and structures are involved in the pain pathway? define modulation, transduction, transformation and transmission of pain signals?

explain *ascending (afferent) pain pathway* or pain *perception * process or 4 elements of The pain process?

{The brainstem is the region of the brain that connects the cerebrum with the spinal cord. It consists of the midbrain, medulla oblongata, and the pons.} ref slide 12,13,19 of this set. pain pathway, chemical stimuli in set terms, pain and temperature pathway is ventero (anterio) lateral pathway. AP is transmitted via electrochemical method. chemical (NT) for pain signal transmission is glutamate.

The *ascending pain pathway* transmits sensory pain signals from the periphery to the *spinal cord, *brain stem, *thalamus, cerebral cortex* and other regions of the brain
The *descending pain pathway* conveys pain *modulating* signals to the periphery/*effectors*. Modulation: neural activity controls transmission of pain signal/AP by *either inhibiting or enhancing*• Peripheral *nociceptors* are activated by painful *stimuli*. Signal transduction: A basic process in molecular cell biology involving the conversion of a signal from outside the cell to a functional change within the cell.
• Signal/AP is transmitted to *dorsal horn of spinal cord* (all sensory signals of afferent pathway ie, ventero (anterio) lateral pathway and dorsal pathway) via 1st order neuron, A-delta and C fiber.
• Then interpretation/perception of pain in CNS pain centers in *brain stem (reticular fibers, PAG) and cerebral cortex.*

1. Transduction: *Pain receptors* (nociceptors, *one target of analgesic rx ex. local anesthetics*. 1st order neurons originate here) is a sensory nerve ending in peripheral tissues and are simple mechanoreceptors usually with high thresholds. And it recognize stimuli of tissue damage or pain and modify membrane potential. *Conversion of membrane potentials to action potentials is called transformation* (at the nociceptors). Inflamatory autocoids such as 5HT, histamine, bradykinin, etc from the chemical (dull pain) stimuli can sensitize nociceptors to pain stimuli. *PGs, substance P* (released as a response to pain) are pain modulators to reduce AP threshold (modulate pain by enhance pain).

2. Transmission: pain stimulus is transmitted via two types of *1st order* sensory neurons, *sensory nerve fibres: A-? nerve fibres (fast *pain, surrounded by thin layer of myelin) and *C nerve fibres (slower pain*, non-myelinated, for *chronic pain).* The first order neuron enters the dorsal horn of the spinal cord where it transmits the pain signal to a second order neuron utilizing the NT, substance P (It is a neuropeptide, acting as a NT and as a neuromodulator) and glutamate. These *second order *neurons *cross* the midline of the *spinal cord* or goes through *spinothalamic tract (lateral)* and synapses with a *third order neuron in the thalamus* which then carries the pain signal to higher brain areas. Cells of the *dorsal horn of the spinal cord or nucleus of the 2nd order neuron are first processing* level for pain stimuli *(one target of analgesic rx).* Here, direct activation of *motor neurons* can result in restrictive and thus protective movement (reflex).

3. Modulation: neural activity controls transmission of pain signal/AP by *either inhibiting or enhancing it. Peripheral modulation* of pain occurs at the nociceptor level. *Central modulation* can either facilitate or inhibit pain as well.

4. Pain perception: perception of the pain stimulus is processed in the Specific areas within the brain stem (the periaqueductal gray *(PAG) region of midbrain- lots of opioid receptors to desensitize the pain)* and interpret the pain. somatosensory region of the *cerebral cortex*, is also involves in the interpretation activity. *(The thalamus with nucleus of 3rd order neuron acts as a relay station:* dissemination of the signals to the cerebral cortex.* limbic cortex* is a regulation centre of the pain threshold and of *emotional reaction*. Some ascending fibres reach the hypothalamus where* endocrine response* is triggered (e.g.,* endorphin release from the pituitary gland for pain desensitization)*.

Descending (efferent) Pain Control Pathway, explain Cortical and subcortical response and Inhibitory synapses response to pain stimuli

By *sending responses* back to the periphery, the *CNS can induce the release of neurotransmitters* which reduce the transmission of pain signals (feedback loop).

*central modulation (one target of analgesic rx)* – Neuronal centres of the *cortex* and subcortical areas of the brain respond to incoming (ascended) pain signals and can modulate pain signals by *activating inhibitory descending pathways.*
the periaquaeductal grey *(PAG) in brain stem* (has high affinity *binding sites for opiate drugs),* receives pain signal and initiates inhibitory nerve impulses which descend the CNS in two different tract systems.
a• The medial tract is triggered by the so-called *Raphé nuclei* and is mainly influenced by the neurotransmitter *serotonin* which can execute pain inhibitory as well as pain facilitating activity.
b• The lateral tract starts in the *Locus coeruleus.* In this pathway, the neurotransmitter *noradrenaline* plays a central role. (help with pain)

Inhibitory impulses descend to the *dorsal horn of the spinal cord* segment (one target of analgesic rx) where respective painful stimuli are transmitted to the second order neuron. Activated *inhibitory interneurons* release inhibitory NTs such as *endorphins, noradrenaline and serotonin* (dopamine agonist help to tx respiratory depression, dopa antagonist help with nausea. glutamate increase pain, opioid agonist reduse pain)

terms hallucination, psychosis, delerium
reward/pleasure/euphoria, craving
agitationNarcotics – a *legal term for many abused drugs.* Narcotics from natural plants* opium, cocca (not codeine) and cannabis*. Dope- A slang term for cocaine, marijuana (weed is less potent CNS stimulant than coccaine for smoking), opium, heroin, methamphetamine (speed, ice or meth), and/or other illegal narcotics

Opium is made from the latex of the opium poppy’s (Papaver somniferum) and are *CNS depresent*. Opium poppy juice Contains at least 20 distinct alkaloids but major is *Morphine (10%), *Codeine (0.5%)* – a methylated morphine, Thebaine (0.2%), Papaverine (1.0%), Heroin (acetylated morphine are called *Brown Sugar.*

Cocacaine or *crack* is an Alkaloid obtained from the coca plant. It interferes with the transport of the neuro-transmitter *dopamine.* (dope is cannabis from opium). It has a potent *CNS stimulant*, producing a sense of *Euphoria,* excitement & increase in energy. Excessive dosage of cocaine can cause *hallucinations.*

Natural cannabinoids are obtained from inflorescences of the plant Cannabis sativa (hemp) used to produce *marijuana (weed),* hashish/hash, charas, *Dope,* & ganja. Its active ingredient is *tetrahydrocannabinol* (THC), which has a variety of effects, some *stimulant,* some depressant, and some *hallucinogenic. *

A hallucinogen is a psychoactive agent which can cause hallucinations, *perceptual* anomalies (alter the perception of reality), and other substantial subjective changes in thoughts, emotion, and consciousness. criteria for establishing that a drug is hallucinogenic are as follows:
in proportion to other effects, changes in thought, perception, and mood should *predominate;*
addictive craving should be *absent.*
intellectual or memory impairment should be minimal;
stupor, narcosis, or excessive stimulation should not be an integral effect;
autonomic nervous system side effects should be minimal;
cause effects by initially disrupting the interaction of nerve cells and the neurotransmitter *serotonin, (perceptual changes),* glutamate.

Pharmacological classes of hallucinogens
Psychedelics (drug with perception-altering effects ). ex. 5-HT2A receptor agonist (Tryptamine), LSD, Cannabinoids (CB-1 receptor agonists)
Dissociatives (produce analgesia, amnesia and catalepsy at anesthetic doses). ex. NMDA receptor antagonists (ketamine, dextromethorphan), ?-Opioid receptor agonists
Deliriants (cause extreme confusion and an inability to control one’s actions like in agitation) ex. Anticholinergics (atropine, belladonna)

amphetamines are *CNS stimulants (Euphoria)* not considered (often amphetamine psychosis), as they are not a primary effect of the drugs themselves unless abuseing

SSRI affect serotonin but not abusive. cause withdral symptoms.
LSD- nonselective serotonin agonist
tobaco has nicotine, a cholinergic NT agonist. cause CNS stimulation.
caffine affects *dopamine (pleasure NT or reward).*

Drug diversion involving the transfer of any legally prescribed controlled substance from the individual for whom it was prescribed to another person for any illicit
use (without a prescription)

agonist- mimic action of NTs.
full agonist- it can bind to all the receptors and exert full action just like NT (efficious)
partial agonist- do not produce full effect (like NT), even if it binds to all the receptors
allosteric agonist- bind to place other than agonist and make conformational changes to increase the effect of agonist NTs.
antagonist- antagonize action of NTs by blocking receptors.

(suboxone- A mu receptor partial-agonist and an antagonist at kappa receptor. High *affinity* for the mu receptor but low *efficacy* and *efficiency*). High affinity for mu may displace other opioids from the receptor and can precipitate withdrawal sx. DOA is long due to high affinity. 16 mg = coverage of 95% of opioid receptors. due to partial agonism no ceiling effect. SL (30-50%). * Safety* profile: buprenorphine/naloxone is better than methadone.
*Methadone superior efficacy* vs buprenorphine but studies.but not safe at high dose of addiction due to QT prolongation.
naltrexone- Efficacy- Patients dropped out at high rates due to lack of effect.

Cross-tolerance is a phenomenon that occurs when someone who is tolerant to the effects of a certain drug also develops a tolerance to another drug. It often happens between two drugs with similar functions or effects – for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. BDZ is used for alcohol withdrwal due to cross-tolerance

due to incomplete cross tolerance for receptors, dose of opioids need to reduce % when switching from one effective opioid to another due to ADR

substance Abuse- adv and disadv and ex.
*drugs of abuse /Narcotics* (legal term)* are *Psychoactive* substances are abused for their mood and perception altering effects *(use vs Abuse*). drugs, including hallucinogens (*LSD (act on serotonin)*, mescaline, psilocybin), CNS stimulants (Cocaine, amphetamines, MDMA, “bath salts”) , *caffeine (act on dopamine)*, tobacco/*nicotine (act on Ach)*; CNS depresents (sedatives, hypnotics, and anxiolytics/ *BDZ (act on GABA)*, barbiturate; alcohol; opioids), cannabis; abusive (vs use) rx are *misused* cause drug diversion, and harm by intoxication (tolerance, and overdose), dependence (physical or psychological dependence and harm). Drugs of abuse are not *fatal unless overdose* or intoxication. Many drugs of abuse, but *not all of them are addictive (psychological dependence* or cause dependence but just improve mood and percepton altering effect. Those can *stop any time. Ex. Hallucinogen* (LSD, mescaline, psilocybin).Drugs of abuse can cause 1. make you believe that you need the rx to feel good or function normally. 2. developing a chemical need for drugs. Drugs of abuse cause *psychological dependence/addiction ex. CNS stimulants* (Cocaine, amphetamines, MDMA, “bath salts”) or *physical dependence. ex.CNS depressant (opiates, alcohol, barbiturates, some BDZ)*. drugs of abuse/addiction increase in any specific neurotransmitter or imitate the natural NT (endorphin imitation by opiates, nicotine act like Ach) .

normally synapse has some amount NTs produced normally by the body to communicate the signal with other neurons.
Reward Circute in the brain- reward system reinforces important behaviors for survival (eating, sex, social interaction) through pleasure impulse transmission. it start with dopamine in VTA of midbrain which connect to limbic system (reward center is limbic system, pleasure NT is dopamine) and PFC (conscious planning and memory), and nucleus accumbens (pleasure center for habitual memory). reward system make activity pleasurable/rewarding (transmit pleasure impluse by excitatory dopamin) and memorable to do it again and again and craving for reward ex. eating. craving can stimulate reward as well. when dopamine goes up serotonin goes down.
Reward in the neuronal level- but when you take a the *excitatory (dopamine) drug/food* multiply the effect of that specific *NT (flood and reward/ high euphoria)*. when you abuse it, there is always a lot of NT and body adapt/compensate by slowing down the production of NT naturally (leads to *desensitize and delplete and * the post synaptic receptors or change wireing ), later do not get the effect without the presence of the drug/food/chemical (since brain stoped producing NTs naturally). they need take drug just to feel normal (not for euphoria), leads to *addiction/psychological dependence for reward*. and later even drugs cant stimulate reward and leads to *tolerance *. ie too much excitation, body compensate by not responding to drug. same anount of rx don’t stimulate much, then need moore rx thus tolerance. at the neural level, when body don’t have rx cause depression, agitation and withdrwal sympotms since body is used to the drug. now aiming just to feel normal not for euphoria. ,sex addicts have low dopamine and try to get the dopamine and reward of sex. once they get the pleasure they get the *anticipation and carving *for more.
when you take* alcohol acting on inhibitory GABA*, initially feel good, calm and no more social anxiety, sedation. but on chronic use too much inhibition, body try to compensate the signal transmission by excitation. when u stop taking alcohol body overfire exicitatory transmitters with nothing to calming down (body not geting GABA) and shaking and physical dependence (to calm down and avoid withdrawal). alcohol indirectly act on reward system dopamine.

* addiction or psychological dependence*- compulsive craving, *seeking* and use that persist even in the face of negative consequences due to strong feeling of *euphoria and reward.* Chronic rx administration induces *neuroadaptive changes* ? alterations in transcription factors and gens affects regional brain function ? which may underlie drug taking behaviors, “craving” and relapse. users may become addicted after only a *few exposures* to cocaine.

* physical dependence* – is a state caused by chronic use resulting in* tolerance and withdrawal symptoms.* Chronic drug exposure ? adaptive changes in the brain ? withdrawal symptoms *when the drug is discontinued.*

Tolerance: on *repeated use* 1. need for *increased amount/dose of EtOH* for desired effect* (euphoria or even just to feel normal) or 2. markedly *diminished effect* with same amount/dose of alcohol. think of graph with dose of on the x axis and effect on the y axis. causes of tolerance can be receptor up or down regulation.
receptor down regulation happen with CNS stimulant rx like cocaine. too much stimulation, body balance by reducing the number of healthy receptors. now we need more drug to get effect ie, tolerance (due receptor desensitization). if pt stop taking the drug feels bad (not feeling normal, not euphoria) due to less healthy no. of receptors.
receptor up regulation happen with CNS depressant rx like opioids. pain is a normal phenomenon and there is healthy no. of receptors to pass pain signals. when opioids block these receptors, body knows its not normal and try to upregulate it increasing the healthy no. of receptors. now we need more drug to get effect/pain relief ie, tolerance.

Tolerance and withdrawal can happen with physical and psychological dependence.
Withdrawal- if patient has characteristic withdrawal symptom or need to take the same or related drug has to be taken to relieve withdrawal symptoms. craving is the withdrawal symptom in psychologic dependence (CNS stimulants) and delirium tremens (alcohol). flu like symptom (heroin) in physical withdrawal (CNS depressants).
addiction – compulsive drug take, and ignore consequences even after negative results.

*Alcoholism is a disease* manifested by a Characteristic set of symptoms and is not about how long or how much (don’t have to be a chronic user or don’t need to be intoxicated).

Alcohol, the Drug MOA: dose dependent CNS depression. Influencing opiate and neurotransmitter systems GABA, glutamate and dopamine. during intoxication GABA the inhibitory neurotransmitter is increased (more sedation), glutamate the excitatory neurotransmitter, Inhibits excitatory function at lower doses (initial euphoria, more sedation), stimulate endogenous opitates and increase craving and reward. Also stimulates mesolimbic dopamine system and DA release leading to reward & reinforcing effects of consumption.
This dopamine pathway originates in the ventral tegmental area (VTA), and projects to the nucleus accumbens (NAc) and *prefrontal cortex ( concious planning planning).* DA are released in the NAc and the prefrontal cortex. As a general rule, all addictive drugs activate the mesolimbic dopamine system

with heavy chronic abuse, GABA and glutamate dysregulation. Decrease in GABAA receptors with chronic intake (less sedation, more tolerance and cross tolerance with BDZ and OH), Glutamate Up-regulation higher doses to compensate (less sedation) and people are more functional. abrupt withdrawal may lead to seizures due to sudden hyperactivity for receptors that are accustomed to being inhibited

plant based narcotics are opium (Heroin), cocca, cannabis.
Opium and alcohol are CNS depressants while, amphetamine and cocca are stimulant, cannabis (less stimulant and some depressant action.

Brain and nervous system and central neurotransmitters, action potential of the nerve, muscle relaxant and anesthetics (dr. najeeb lect- basal ganglia in youtube)
muscle relaxants are *centrally action (spasmolytic)*acting on spinal cord throgh GABA receptors by hyperpolarising the nerons (ex baclofen, diazepam Tizanidine ) or *directly* acting on the muscle acting through ACH (*neuromuscular blockers or peripherally acting)*. neuromuscular blockers can be *depolarizing or non depolarizing* drugs. these are also used in surgery to medically induce coma using general anestetic. skeletal muscle will contract only when a somatic motor neuron is stimulated.
*-anticholin estrases* increase Ach by bing to both sub-unit of the nicotinic receptors and depolarises the axone at first and eventually desensitise the end plate since it dont allow binding of more ach to the end plate due to the 1st ach still occupyng the receptors and thus muscle relaxant. ex succinyl choline is used for rapid intubation (last only 5-10min)
-Non depolarisers are compatative *antagonist of ach* recptors and prevent deprolarzation and thus relaxation of muscle.ex curarium and dantrolin (an agent that acts on the sarcoplasmic reticulum of skeletal muscle)agents for *chronic muscle spasm* and act on spinal cord.
baclofen- GABA b receptor agonist inhibit glutamate release CNS/spinal cord
diazepam- gaba A presynaptic inhibitor
tizanidine-a congener of clonidine, (?2) agonist in the spinal cord thus no glutamate.

agents for *acute muscle spasm* resulting from muscle injury. Most of these drugs are sedatives or act in the *brain stem* and antimuscarinic actions
cyclobenzaprine, (carisoprodol), metaxalone (skelaxin), methocarbamol (robaxin), orphenadrine (norflex. norfloxacin is a like Cipro)

goals of general anesthetic are relaxation of motor reflexes *(musle relaxation),* autonomic relaxation and loss of conciousness *(sleep)*. thus it provide *analgesia.* single anesthtic dont give all 3 goals so give preanesthics includs skeletal muscle relaxant, analgesic and anti anuausea rx, induction and maintenece anesthetics, nuromucular reversal agents. 4 stages of anesthsia include 1. anagesia, 2. excitement 3. surgecal anesthcia 4. death. in each stage watch muslce relaxation, respiration, and eye movements. monitor vital sings by ECG, BP monitor, pulse oxygen meter. Anesthetic that act on the cns/spinal cord is general anesthtic. can be inducing agents (propofol, *etomidate*), slow acting ketamine, opiods, benzo, alpha 2 agonist (*dexmetomidine* and clonidine). anesthetic act of peripheral nervous sysem (somatic or autonomic nerve) is local anesthetic. ex lidocain.

Short codes of expansions

pain asessesment, Strategies for smoking cesation: 5As (willing to quit) vs 5Rs (unwilling to quit) 5 A’s. what is ABC in cardiac rescitation, If asthma control worsens, first check what, Diagnosis for depression

PQRST or (PQRRSTLA) – in pain asessesment (ref slide 1 set pain) also angina chest pain (ref slide 9 set IHD 8)

Strategies for smoking cesation: 5As (willing to quit) vs 5Rs (unwilling to quit) 5 A’s – Ask, advise, assess if they are ready to quit, assist, and arrange
Are willing to quit (5 As)- Ask about tobacco use, Advise tobacco users to Quit, Assess readiness to make a quit attempt, Assist with the quit attempt (e.g., prescribe cessation medication), Arrange follow up care
Are unwilling to quit (5 Rs -methods for enhancing motivation to quit)- Relevance, Risks associated with tobacco use, Rewards related to quitting, Roadblocks to quitting, Repetition

ABC – airway, breathing, circulation

If asthma control worsens, first check “ICE”
• Inhaler technique
• Compliance
• Environment issues that trigger asthma

“SIG E CAPS” Diagnosis for depression (Sleep, Interest, Guilt, Energy, Concentration, Appetite , Psychomotor, Suicide)

• osteoclasts (chew bone and get ca out). the tearing down/destruction of bone
• osteoblast- the building/production of new bone
• osteocyte is a bone cells
• Osteopenia- reduced bone mass of lesser severity than osteoporosis.
• Osteomalacia is a condition of defective bone mineralization or soft bone, with sufficient or even excessive matrix. It results from vitamin D deficiency or phosphate depletion. undecalcified bone in which the mineralized areas are black, and the unmineralized osteoid is pink. Normally, very narrow seams of unmineralized osteoid are found in growing bone. The degree of unmineralized osteoid material found in this section is excessive.
• If it occurs in children it is called rickets. One hallmark of rickets is a characteristic deformity of the chest wall composed of knobby costochondral lesions which are referred to as the rachitic rosary.
• In histology, osteoid is the unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue or osteocyte. Osteoblasts begin the process of forming bone tissue by secreting the osteoid as several specific proteins.
• Osteoid osteoma and osteoblastoma are commonly seen benign osteogenic bone neoplasms.
• In CKD-MBD
• osteoclasts (chew bone and get ca out). the tearing down/destruction of bone. these are bone macrophages (monocyte moved to tissue)
• osteoblast- the building/production of new bone. PTH receptor on this, which can make a protein that stimulate osteoclast
• osteocyte is a bone cells
• Osteopenia- reduced bone mass of lesser severity than osteoporosis.
• Osteomalacia is a condition of defective bone mineralization or soft bone, with sufficient or even excessive matrix. It results from vitamin D deficiency or phosphate depletion. undecalcified bone in which the mineralized areas are black, and the unmineralized osteoid is pink. Normally, very narrow seams of unmineralized osteoid are found in growing bone. The degree of unmineralized osteoid material found in this section is excessive.
• If it occurs in children it is called rickets. One hallmark of rickets is a characteristic deformity of the chest wall composed of knobby costochondral lesions which are referred to as the rachitic rosary.
• In histology, osteoid is the unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue or osteocyte. Osteoblasts begin the process of forming bone tissue by secreting the osteoid as several specific proteins.
• Osteoid osteoma and osteoblastoma are commonly seen benign osteogenic bone neoplasms.
• In CKD, Vit D deficiency, no bone mineralization and osteomalacia). when ca is low, high PTH (hyperparathyroidism) cause bone demineralization (high blood Ca PO4) along with RF (no uncoupling of minerals or no reabsorption. renal dystrophy- bones show signs of both osteomalacia or soft bone due to vitamin D or PO4 deficiency and osteitis fibrosa due to high PTH and high ? bone metabolism due to high osteoclast) result in settling of Ca and PO4 on vasculature (low Ca and PO4). but fibroblast increase PO4 level (ultimate result in high PO4 and low Ca in blood).normally when ca is low, PTH cause bone demineralization (raise the couple in the blood 1st but don’t like PO4 so excrete in kideny and reabsorb Ca from the kidney) and increase Vit D (bone mineralization) with act on GIT to increase the couple in blood. now calcitonin come to bring blood ca to deposit back into bone (bone mineralization), result in low blood ca and PO4.

• Apathy- lack of interest, enthusiasm, or concern
• Akathisia- “inability to sit”) is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. Akathisia is fundamentally a subjective disorder characterized by a desire to be in constant motion resulting in an inability to sit still and a compulsion to move.
• Chorea is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias.
• Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Tardive dyskinesia is an involuntary movement disorder characterized by repetitive purposeless movements which typically involve the buccolingual masticatory areas but which can include choreoathetoid limb movement.
• Dystonia is a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures.[1] The movements may resemble a tremor. Dystonia is often initiated or worsened by voluntary movements, and symptoms may “overflow” into adjacent muscles.
• Cachexia-weakness and wasting of the body due to severe chronic illness.
• Ataxia describes a lack of muscle control during voluntary movements, such as walking or picking up objects.or loss of balance
• An atonic seizure is a sudden loss of muscle tone in the muscle
• Clonus is a series of involuntary, rhythmic, muscular contractions and relaxations
• Tonic- involuntary contractions
• Asterixis ( flapping tremor, or liver flap) is a tremor of the hand when the wrist is extended, sometimes said to resemble a bird flapping its wings.characterized by an inability to actively maintain a position and involuntary control, when the outstretched hands. Due too much ammonia causing encephalopathy in cirrhosis
• Paroxysmal – sudden
• Prodrome- premonitoring symptom

Extrapyramidal symptoms (EPS) are drug-induced ex Antipsychotics, movement disorders that include acute and tardive symptoms. These symptoms include dystonia (continuous spasms and muscle contractions), akathisia (motor restlessness), parkinsonism (characteristic symptoms such as rigidity, bradykinesia, and tremor), and tardive dyskinesia (irregular, jerky movements). rating scales to assess the severity of movement disorders are Abnormal Involuntary Movement Scale (AIMS), and Extrapyramidal Symptom Rating Scale (ESRS).

* (allodynia)*- pain from normally non-painful stimuli. can be peripheral (ex shingles, diabetic neurological) or central (parkinsons, stroke). due to nerve damage or affecting the somatosensory nervous system (not motor sensory or ANS sensory).
dysesthesia (opposite of anesthesia)- unpleasant, abnormal sense of touch/pain.

*Anhedonia -*inability to experience pleasure from activities usually found enjoyable, e.g. exercise, hobbies, music, sexual activities or social interactions. also motivation or desire to engage in activities.
•* Apathy*- lack of interest, enthusiasm, or concern
• Akathisia- “inability to sit” is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. Akathisia is fundamentally a subjective disorder characterized by a desire to be in constant motion resulting in an inability to sit still and a compulsion to move.
• Chorea is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias.
• Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Tardive dyskinesia is an involuntary movement disorder characterized by repetitive purposeless movements which typically involve the buccolingual masticatory areas but which can include choreoathetoid limb movement.
• Dystonia is a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures.[1] The movements may resemble a tremor. Dystonia is often initiated or worsened by voluntary movements, and symptoms may “overflow” into adjacent muscles.
• Cachexia-weakness and wasting of the body due to severe chronic illness.
• Ataxia describes a lack of muscle control during voluntary movements, such as walking or picking up objects.or loss of balance
• An atonic seizure is a sudden loss of muscle tone in the muscle
• Clonus is a series of involuntary, rhythmic, muscular contractions and relaxations. jerky or convulsion
• Tonic- . muscle stiffens and tense. involuntary contractions
• Asterixis ( flapping tremor, or liver flap) is a tremor of the hand when the wrist is extended, sometimes said to resemble a bird flapping its wings.characterized by an inability to actively maintain a position and involuntary control, when the outstretched hands. Due too much ammonia causing encephalopathy in cirrhosis
• Paroxysmal – sudden
• Prodrome- premonitoring symptom
dysthymia – chronic low level dipression

TERMS
• Enteric nervous system- A division of the ANS whose component neurons lie within the walls of the digestive organs (esophagus, stomach, intestines, pancreas, gall bladder and pancreato-biliary ducts). The enteric nervous system contains entire nerve circuits for digestive organ control, and can function autonomously.
• Enteric neuron- A neuron whose cell body is in a ganglion within the wall of the digestive tract, biliary system or pancreas. Most enteric neurons make connections with other enteric neurons or with gastrointestinal tissues, such as its muscle coats, intrinsic blood vessels and glands.
• Myenteric plexus- A plexus of small groups of nerve cells (ganglia) and connecting nerve fibre bundles that lies between the longitudinal and circular muscle layers of the gut wall and forms a continuous network from the upper esophagus to the internal anal sphincter.
• Submucosal plexus- A plexus of small ganglia and connecting nerve fibre bundles that lies within the submucosal layer, between the external musculature and the mucosa of the small and large intestines, forming a continuous network from the duodenum to the internal anal sphincter.
• tenesmus (straining to empty an already empty bowel)
• varices
• A hernia
• Fistula-
• anal fissure
• Aneurysm
• Stenosis- narrowing of blood vessel due to thinkening
• Strictures- narrowing and scarring can cause obstruction/ perforation
• Ischemia- due to reduced blood supply, result in lack of oxygen supply to the tissue.
• Thrombus or clot-
• Thrombosis- clot stays wherever it is formed.( sodium citrate an anticoagulant in diaysis, since it binds to Ca in cloting cascade and also used in the treatment of acidosis. Other anticoagulants are EDTA (chelation), heparin. tPA is used to throbolytics.
• hematoma
• Embolus
• Embolism
• gastroparesis (delayed gastric emptying)
• tenesmus (straining to empty an already empty bowel). a feeling of constantly needing to pass stools, despite an empty colon or even after passing a stool.
• varices – Enlarged collateral blood vessels of the lower esophagus and stomach . abnormally dilated veins of the esophagus. They are native veins that serve as collaterals to the central venous circulation when flow through the portal venous system or superior vena cava (SVC) is obstructed. they are prone to hemorrhage.
• A hernia occurs when an organ or fatty tissue squeezes through a weak spot in a surrounding muscle or connective tissue called fascia (layer of abdominal cavity wall and peritonium is weakened). natural normal hernia is testis coming from ingunal canal (also have blood supply). ofter ingunal cannal make colone protrude as well.
• Fistula- the connection of two body cavities or as the connection of a body cavity to the skin. It may form is from an abscess, breaks through to the skin, another body cavity, or an organ.common in Crohns or UC.
arterio venous fisutula/graft is used to get blood for HD.
• anal fissure is a tear in the lining of the lower rectum (anal canal) that causes pain during bowel movements.
• gastroparesis (delayed gastric emptying)
hemorrhoids – straining (siting in toilet for long time) cause pressure in the veins (hemorrhoid plexus) of anus and rectum, lack of blood supply to that vein, causing it to bulge (lack pain receptors). warm water (sitz bath), improve blood supply, other tx include band ligation, sclerotherapy, surgery. It can be internal or external (after healing forms skin tag outside anus. thrombotic once are painful) hemorrhoid.
Short forms
CI is cardiac index,
CI-contraindication.
MOA- mechanism of action
MOD – mechanism of disease
MODS -multiple organ dysfunction syndrome
DOC- drug of choice
DOA- duration of action
TOD- target organ damage in BP
NT- neurotransmitters
OD- overdose
SERT- 5HT (serotonin) transporter blocker (presynaptically to increase NT level in synaptic cleft)
NET – norepinephrine transporter blocker (presynaptically to increase NT level in synaptic cleft)
DSM-V (Psychiatry Guidelines) – Diagnostic & Statistical Manual of Mental Disorders, 5th edition
AAP- atypical antipsychotic rx
PHN- Post Herpetic Neuralgia (due to herpes zoster virus)
RRT, HD, PD, IHD, SLED, Anti-SLUDGE
EPO, ESA, HTN, HLD, RAAS, RAS, ACR, TIPS, GN, SPS, SBP, PR, BA, AST, ALT, GGT, DI, HBS, ALS, GBS, myasthenia gravis, MS, RTA, ATN
RRT- renal replacement therapy. It include dialysis (HD, PD) and renal transplant
CRRT-continuous renal replacement therapy. 24 hr HD
SLED- slow low efficiency daily dialysis
Anti- SLUDGE- ADR of anticholenergics
IHD- intermittent HD
IHD- ischemic heart desease
IHD= Coronary Artery Disease (CAD) = Coronary Heart Disease (CHD)
IHD include Stable angina and ACS.
CVD due to atherosclerosis = IHD or CAD or CHD + Cerebrovascular disease +PAD
ACS include STEMI, NSTEMI, Unstable angina.heart block- can be ACS since it is the occlusion of coronary artery due to thrombus. need reperfusion or PCI
primary and secondary heart block- is due to AV node bradyarrhythmia. tx by using pacemaker

PSVT- paroxysmal supraventricular tachycardia due to reenty in atrium
PVC- premature ventricular contractions. ventricular arrhythmia due to ectopic beat

USES
• pacemake -used to increase HR in sinus bradycardia and heart block
• ICD- is implanted defibrillator used in VT and VF
• DCC -direct cardio current or defibrillator in AF/VT. need sedation and analgesic. Manual defibrillator in hospital. It help to restore normal sinus rhythm.
• AED- commom non hospital shock machine or defibrilator, no need of sedation.
• AED- antiepileptic drugs.
• Cardiovertion in AF help to restore sinus rhythm through drugs or DCC.
• CPR- help heart to pump.
• holter monitor to watch arrhythmia in PCV
• telemetry unit – for monitoring people after MI 24-72 hrs.Neurokinin 1 antagonists are rx with unique antidepressant, anxiolytic, and antiemetic properties.
Neuropeptides are small protein-like molecules (peptides) used by neurons to communicate with each other. They are neuronal signaling molecules that influence the activity of the brain including analgesia, reward, food intake, metabolism, reproduction, social behaviors, learning and memory. ex is substance P in pain.
Neurotrophins are a family of proteins that induce neuronal growth by secteting GF that are capable of signaling particular cells/neurons. ex CREB, BDNF in depression
cytokinins – small signaling proteins (~5-20 kDa), released by cells and affect the behavior of other cells. Cytokines can also be involved in *autocrine* signaling.
eicosanoids are signaling molecules made by oxidation of 20-carbon fatty acids. for growth during and after physical activity, inflammation or immunity. some are hormones.
know neuroadaptive changes in brain (abuse), neuro plasticity (depression), long term potentiation and long term depression of glutamate receptors (epilepsy), neuroleptic foci, synaptogenesis. receptor up/down regulation

Mechanism
Roflumilast (Daliresp) MOA- Phosphodieasterase-4 inhibitor (PDE4) (Specific for lung smooth muscle). Inhibition of cyclic AMP breakdown in lung cells. Bronchodilation and Reduction in inflammation in COPD
Theophylin- MOA- Multiple. Non sective PDEI, increase cAMP in copd
Viagra is a PDE5I blocking breakdown of cGMP bronchodilation via cGMP)
ADR- palpitation and tachycardia (only at high dose/frequency)
PDE 3 I or dipyrine class rx is* milirinone* (shock slide 12 pic). Ionotropic inhibitor.
PDE3 inhibitor- increases cAMP class, cause vasodilation-dypyridamol and other antiplatets in stroke. Also used in pharmacologic stress testing.
ADP inhibitor is Plavix and other antiplatelet
(DPP-4 I) Dipeptidyl-peptidase-4 inhibitors , bloks hydrolysis of incretin in DM.clozapine, loxapine- antipsychotic
amoxapine- antidepresent . Amoxapine is a metabolite of the antipsychotic drug loxapine
atomoxetin (stratera)- for ADHD tx

dextroamphitamin- respiratory stimulant
dextromethorphan- NMDA-receptor blockers can suppress this central sensitization. ex- Dextromethorphan, Ketamine (Ketalar), Amantadine (Symmetrel), Memantine (Nemenda), d-Methadone
dexmeditomidine(Precedex and Dexdor)-anxiolytic, sedative, and analgesic medication. sedation without risk of respiratory depression (unlike other commonly used sedatives such as propofol, fentanyl, and midazolam) and can provide cooperative or semi-arousable sedationMOA clonidine, it is an agonist of ?2-adrenergic receptors in certain parts of the brain.

*Minoxidil*- venodilator
Nesiritide – BNP analogue

hydralazine vasodilator antihypertensive rx
Hydroxazine (vistaril- pamoate salt) for GAD tx
Hydroxazine HCL salt- (atarax)- antihistamine.

• *tramadol* is not str. similar to opioids but has agonist action on the mu receptors.
(demerol is meperidine) opioid ananlgesic. also effect on lowering seizure potential (like tramadol)

HCl secretion by chief cells, and synthesis is activated by gastin, H2, M3 receptors to activate H/K ATP ase to produce HCL.

Stimulant laxatives (senna, bisacodyl) have direct effects on enterocytes, *enteric neurons (EN) *and GI smooth *muscle* ? accumulation of water and electrolytes and stimulation of intestinal motility. Proposed mechanisms: activation of PG-cAMP pathway, activation of NO-cGMP pathway, inhibition of Na+, K+-ATPase

H+/K+ ATPase proton pump of parietal cells in PPI action (in ulcer slide 11 set ulcer)
Na+/K+ ATPase inhibitor is digoxin,
• aldosterone Na K exchange in kidney
• Ethosuximide (Zarontin)- absence seizure
• Metolazone is a thiazide-like diuretic. Zaroxolyn,
• morphine – for refractory angina.( increase catecholamine further aggravate ischemia. Can be treated with morphine which blocks sympathetic efferent form CNS and thus decrease vasoconstriction, decrease oxygen demand and symptomatic improvement. it causes vasodilation through histamine as well). reduce BP
morphine also is extremely helpful in *controlling shortness of breath* due to Congestive Heart Failure (CHF) or to Chronic Obstructive Lung Disease (COPD) or Emphysema. It relaxes the muscles in the bronchial/breathing tubes, making the work of breathing easier; and, it helps to control the anxiety associated with a “suffocating” feeling which may occur. It can be taken by mouth or by injection, and is usually started at a low dose (e.g. 3mg every 3?4 hrs) and increased as needed. (There has been no significant advantage to giving it through a nebulizer/breathing treatment.). *Dose dependent * laboured breath/* respiratory center depression is an ADR/toxicity of morphine*. so goal is to only titrate to symptom relief/ dyspena, rather than a specific respiratory rate. Patients can be tachypneic or appear to have labored breathing, yet they say their breathing now feels comfortable. if pt has pain it is a respiratory stimulant and cant supress respiratory center. reduce dose if sedation is increased.

• Opioid receptor *antagonists* such as methylnatrexone (Relistor®), alvimopan (Entereg®)
• • MOA: Methylnatrexone and alvimopan inhibit peripheral ? receptors Mediated through intestinal ? receptors *without crossing the BBB*. Thus *antagonize effect of opoids*. Opioid therapy decreases intestinal motility and causes constipation.
Opiod antagonist has limited use due to *risk of opoid withdrawl effect. *
• • Used -treatment of opioid-induced constipation in patients receiving palliative care (methylnatrexone) and post-operative ileus (alvimopan). Not for GERD. But used in tx of constipation. senna S is also good for *prevension* opioid induced constipation.
• Opioids are antidiarrheal loperamide, diphenoxylate and difenoxin. diphenoxylate/atropine (lomotil) are structurally related to meperidine (ref slide 19 set 14cirrhosis). no effect on sphicture of oddi.
Difenoxin is an active metabolite of diphenoxylate
ADR: At higher doses both can produce* CNS effects and seizure* ? so they have a *potential for abuse and addiction*
loperamide (immodium OTC) -*Peripherally acting* Opioid , to *inhibit peristalsis and prolong transit time, (antisecretory activity), increases tone on the anal sphincter* In therapeutic doses it does not cross the BBB, therefore, *no potential for abuse.* In cases of overdose, it causes* CNS depression*

Naltrexone (ReVia & Vivitrol) Indication: craving. Decrease heavy drinking but do not cause abstinence
MOA: opioid antagonist.
Naloxone- opiod antagonist
(buprenorphine and naloxone)- suboxone

Buprenophrine (used in addiction in acute withdrawal and maintenance phase)
Butorphanol Nasal spray is management of migraine, IV for pain, general anesthesia, pain during labor (selctive Kappa agonist activity with no respiratory depression).
Bupropion (Wellbutrin) antidepressant

tx causeing constipations- *(anticholinergic, oxybutynin, TCA, phenothiazine, H1 antihistamine, non DPH, opiods, fe, Ca, Al, Bismuth).* (Mg, PO4, Cl-, cause diarrhea)
Synthetic fibers* (polycarbophil*-for tx of constipation, also act as a adsorbent antidiarrhea agent)
• Antisecretory agents- bismuth sub salicylate. antidiarrheal. Also a mucosal protectant in PUD
secretory laxative -Lubiprostone, Linaclotide. used for constipation tx
• Prokinetic agents in GERD increases GI motility and decrease transit time include cholenomemimitic agents. Antispasmodic in IBS are anticholinergics. anticholenergic are used for tx for urinary incotinence.
b. *Prokinetic agents (improve motility* giving less time for the food to irritate mucosa.)
1• *Cholinomimetic agents- betanechol and neostigmine (high acidity but affect LES)*
2• D2 receptor *antagonists*- Metoclopramide
3• 5-HT4 receptors* agonist-* Cisapride (ref slide 14, set 17 GERD in IBS)
4• Opioid receptor antagonists- methylnatrexone and alvimopan (not used for GERD)

Most severe forms IBS- 5HT3 *antagonists* (Alosetron – Lotronex) or 5HT4 *agonists* (Tegaserod) (cisapride is a prokineti agent in GERD)

More persistent disease IBS- *Anti-spasmodics or anticholinergic*/ antimuscarinic agents (dicyclomine and hyoscyamine. Peppermint oil. used also in PUD), Antidiarrheals (Loperamide)

*Augmentation of antidepressant (AD) efficacy, if pt has a partial response without discontinuation distress*. Agents: stimulants (methylphenidate), *modafinil*, buspirone, levothyroxine, lithium.
*Antiseizure Lamotrigine* (Lamictal)

Stool surfactant agents (like bile that emulsify fat, simethicone or gas X- an anti-foaming agent that decreases the surface tension of gas bubbles used for abdminal distention) or softners or emolient, lubricant- Docusate (*for prevention opoid, fe induced constipation not for tx)*
docusate salts are anionic surfactants that lower the surface tension of the stool to allow mixing of aqueous and fatty substances, softening the stool. not efficient in treatment of opoid induced constipation. use sennna S (senna +docusate)
indigetion or dyspepsia ref GERD
• Colesevelam (Welchol) -Bile-acid sequestrant used in cholesterol. DM agent
• Antidiarrheal agents-Bile-salt-binding resins: cholestyramine, colestipol and colesevelam
• Bromocriptine (Cycloset) Dopamine agonist, DM agent
• Sevelamer carbonate (renvela) or HCl (renagel)- PO4 binder

Lotrel (amlodipine and benazepril) is used to treat high blood pressure (hypertension).
loperamide (immodium OTC)- peripherally aciting opioid antidiarrheal agents. It is an opioid with no significant absorption from the gut and does not cross the blood brain barrier when used at normal doses.

diphenoxylate/atropine (lomotil) are structurally related to meperidine- opioid antidiarrheal agents
LOTRONEX or * Alosetron *is a medicine for female sufferers of (IBS) with diarrhea
• Used -treatment of opioid-induced constipation in patients receiving palliative care (methylnatrexone) and post-operative ileus *(alvimopan). *
clotrimazole (Lotrimin, Mycelex, Lotrimin-AF, Gyne-Lotrimin) antifungal for vaginal yeast infections, thrush, jock itch, athlete …
Lotrisone cream ( clotrimazole and betamethasone)

Reflux and reflex
Reflux most often used in reference to GERD, a very common condition. GERD results from the relaxation of the muscles around the entrance to the stomach, which allows a back flow of food, stomach acid and digestive enzymes up into the esophagus. This is called acid reflux. Reflux refers to the stomach acid rising up the “wrong way” back up the esophagus and sometimes into the mouth. Pain from reflux is called heartburn. Chronic reflux that reoccurs or persists may be caused by GERD. See also heartburn and indigestion for similar complaints. reflux is used in chemistry to supply energy to reactions over a long period of time.

A reflex (when we talk about nerve) action, differently known as a *reflex, is an involuntary and nearly instantaneous movement* in response to a stimulus. reflex is an action performed without conscious thought as an automatic response to a stimulus (motor neuron reaction to a sensory stimulus).
Scientific use of the term “reflex” refers to a behavior that is mediated via the reflex arc;

mechanism

. in sepsis infection, Blood: transfuse if Hgb ; 7g/dL

IV fe Ppn- fe dextran ( IV OR IM. Infed, dexferrum not interchangable. cause anaphylaxis), fe sucorse (IV), sodium feric gluconate (IV ferrlecit), fermoxytol (IV, ADR anaphylaxis and hypotension).
• Iron antidot – desferroxamine (desferal)
• deferasirox (exjade) if iron overload due to blood transfusion.
dextrose and icodextin are osmotic substance in Peritonial dialysis.
fluid replacement with Colloids- albumin , hetastarch, dextran. Larger molecules ; Increases oncotic pressure in vascular spaces, pulling water from 3rd space (cirrhosis) or extravascular compartments into intravascular compartment. Less volume necessary for similar increase in intravascular volume, since it don’t move out of vasculature and no fluid overload since it just pull water from 3rd space.
• Monoclonal Antibody-Omalizumab (Xolair)- in asthma

SABA Agents-levalbuterol (xopenox) in COPd,asthma
• Phosphodieasterase type 4 inhibitor- Roflumilast (Daliresp) in COPD
• Sevelamer carbonate (renvela) or HCl (renagel)- ca phosphate binder in CKD
• Ranolazine or renexa reduces MVO2 (demand). Inhibit late sodium influx (lowers intracellular sodium) and prevent contractile dysfunction therefore delays ischemia lower intracellular calcium leads to decreased wall tension,
ADR- increased QT interval and torsades CI- renal impairment.
BENEFIT . No change in BP or HR Found to lower HbA1C by 0.5-0.7%
• *CALCITROL* – active vitamin D produced in kindney to increase Ca when its level are low
• *CALCITONIN*- hormone from thyroid gland it decrease Ca and PO4 when its levels are high.
• Turning off parietal acid secretion when too much H+ conc. by releasings somatostatin and inhibits further gastrin release.

Pancreatic delta cells produce somatostatin (GH).
its target tissue is alpha and beta cells. Response is inhibition of insulin and glucagon secretion. (The opioid receptors are ~40% *identical to somatostatin* receptors.)

Incontinence means lack of control/ undiciplined life

tolterodine (Detrol) and oxybutynin (Ditropan™) are anticholenergic (act on detrusor muscle of bladder) used to tx urinary incontinence/urgency. ADR is urinary retension.

Fecal incontinence- involuntary discharge of rectal content due to neuromuscular or structural problem.
tx causeing constipations- *(anticholinergic, oxybutynin, TCA, phenothiazine, H1 antihistamine, non DPH, opiods, fe, Ca, Al, Bismuth).* (Mg, PO4, Cl-, cause diarrhea)

dandtrolin sodium- skeletal muscle relaxant helps to tx neuroleptic manlignanant syndrom, malignant hyperthermia and spasticity.

prazosin, doxazosin, tamsulosin are alpha blockers used for BPH or BP. enlaged prostate cause obstucion of urethra in male.

H2 antagonist is used – in tx of PUD, GERD, Prevention of stress-related mucosal bleeding or* SRMB* in critically ill patients due to mucosal ischemia. ( but not for varices bleeding)

(Antispasmodic in IBS are anticholinergics. anticholenergic are used for tx for urinary incotinence. 5 HT or serotonin and dopamine a precursor of norepi, are monoamine neurotransmittors work as an antidepesent)

(Antisecretory agents- bismuth sub salicylate, antidiarrheal. Also a mucosal protectant in PUD.
cystic fibrosis (due chloride ion transporter protein defect. too much thick fluid, if it thickens bile get trapped, inflammation.
prokinetic agents are used for tx of GERD and opioid induced constipation.
opioid antagonist for tx constipation and GERD
opioid agonist for tx of diarrhea due to reduced motility.
antispasmodics are used for IBS pain)
ref slide 10 set 17GERD

ADR of SSRI-*sexual dysfunction:* Decreased sex drive, erectile dysfunction, anorgasmia due to Spinal cord 5-HT2 receptor activation. tx
*Add Dopamine agonist: bupropion (Wellbutin) or called wellzac when add prozac*
*5HT antagonist: cyproheptadine (Periactin), may reverse antidepressant effect*
*Cholinergic agonist*: bethanecol (Urecholine)
Yohimbine: alpha2 antagonist may cause panic attack due too much NE
Sildenafil (Viagra) or other agents in class: improve nitric oxide metabolism
Gingko Biloba: vasodilator effect
*Drug holidays;* issue- patient may forget to resume

elemental Fe and Ca.

Must know relation between gm, mol and meq from maolarity and molality in term 2)
take away pt. (mol/mmol is small and eq/meq are bigger and just multiply the small with valance to get bigger. 1 mole = molecular wt in gm not in 1gm m.wt).
1 *mole* of cacl2 and ca gluconate is same *conc.* but since the *molecular wt* is different (ca gluconate has lots of atoms so higher wt.. cacl2 is 110, ca gluconate is 3 times higher, so* low potency*), 1 molar conc of cacl2 has low wt. so 110 gm cacl = 290 gm of ca gluconate (less potent or only 9% calcium eventhough high molecular wt. need to get same conc.).

10% of conc of cacl2 and 10% ca gluconate are same *conc. by wt *because 10gm/100ml. but molar conc ration is 1 gm cacl= 3 gm ca gluconate. so 1gm of cacl and 1 gm of ca gluconate is not same conc per mole, but 1gm of ca gluconate give you a diluted solution or 1/3rd dilution per mole (higher molecular wt substance in % conc give you a low conc solution). Treat acute, symptomatic hypocalcemia with 10% calcium gluconate or 10% CaCl2 (3 X more potent than Ca. gluconate. 1.0 gram CaCl2 = ~2.92 grams Calcium Gluc. .
1 gram (10ml) of Cacl = 273 mg elemental calcium = 13.6 mEq = 6.8 mmol. 1 gram (10ml) of ca gluconate = 93 mg elemental calcium = 4.65 mEq = 2.325 mmol.

dose of Ca is given in meq/Kg/hr (not in % since exact Ca conc is imp if low Ca and in emergy tx of K toxicity. based on the *potency* of ca supplement used (% of ca in the comound), we may need use more* volume* of calcium gluconate (low conc by in 1gm) than cacl to get the same rise in conc by meq or mmol

*acid* is a proton doner, *base is a proton acceptor or hydroxide doner*. anions are -ve chaged and *cation are +ve charged* in chem 8 (cat has paws so potisitive charge). acids AH in gastric acidic environment are *unionised so lipid soluble*. *ionised forms* are watersoluble but does not cross lipid membrane. bases used in acidosis tx is sodium/k/ca *bicarbonate (40% elemental ca), citrate (21% elemental ca), acetate (25% elemental ca) lactate (13% elemental ca) .* (hydroxides are not used due to less absorption into the blood. OH and protone makes water not CO2/gas. Cacl and ca gluconate IV available but these are not bases to tx acidosis). Ca citrate is a anticoagulant due to Ca. With oral administration, *onset of action* of drugs are 20 minutes to over an hour. (transit time affect drug absorption as well). ref acetazolamide in diuretics terms 2 (acid trap base and vice versa).
common cations are Na, K, Ca, Mg, Al. cations are PO4, Cl, CO3 in bicarbobate. acids produced in the body are ammonia, urea, co2. (DMTI channel for Fe also for other divalent ions like co, cu, Zn, Mn). other divalent Ca2+ and Mg2+ and Al3+. Fe3+ (ferric) form of fe is absorbed from the food in small intestine. but it need to be oxidized to Fe2+ (ferrous) by vitamin C. Proper vitamin D is need for Ca absorption, vitamin D is converted to a hormone in the body to induce calcium absorption. *Calcium carbonate (40%* elemental ca. absorption similar to milk) should be taken with food, and depends on low pH levels (acidic) for proper absorption in the intestine. (but Ca can release gastrin and thus acidity. highest acid level in stomach after food and at night time. so PPI is given before food to control it). *Calcium citrate (21% *elemental calcium) can be taken without food and is the supplement of choice for individuals with achlorhydria or who are taking H-2 blockers or PPI. calcium phosphate in the form of Hydroxyapatite (same form as in bone) is about 40% calcium. Calcium lactate (13% elemental Ca) and calcium gluconate (9%) are less concentrated. arrythmia due K toxicity give CaCl, NaHCO3 to tx acidosis. Treat acute, symptomatic hypocalcemia with 10% calcium gluconate or 10% CaCl2 (3 X more potent than Ca. gluconate. 1.0 gram CaCl2 = ~2.92 grams Calcium Gluc. cacl cause acidosis like Nacl?). dose of Ca is given in meq/Kg/hr (not in % since exact Ca conc is imp if low Ca and in emergy tx of K toxicity. and 10% IV solution is used. conc of 1 solution is expressed as molarity= no of moles of solute/litter of slolution or number/conc of solute/L). 20mg of elemental calcium per mEq. 0.5 mmol of elemental calcium = 1.0 mEq. 1 gram (10ml) of Cacl = 273 mg elemental calcium = 13.6 mEq = 6.8 mmol. 1 gram (10ml) of ca gluconate = 93 mg elemental calcium = 4.65 mEq = 2.325 mmol. CaCo3 has 40% calcium but but can cause alkalosis and not available IV. (when *making TPN* dose/conc limits of electrolytes minerals inj are given in meq/mmol. remember 2mg of ca citrate and cacl inj provide different no. of meq of elemental ca. make sure elemental ca is not over the limit) Ca is available in the body as free ionized ca and bound ca. when you blood, you get only total Ca of free and bound ca. inoised ca/free Ca (50%, biologically active) or as Ca complexed with anions (10%. CaPO4 (bone), SO4, Ca citrate (anticoagulant). ferrous sulphate (20% fe), ferrous fumorate (33%), ferrous gluconate (12%), polysaccaride iron (100% fe complex) and carbonyl (heme) iron (100%).
• Risk classification in CVD, stroke, MI,dyslipidemia

• Framingham risk category for primary/secondary prevention tx of *IHD/ CVD and in stroke* tell u if you need aspirin or not and also goal BP .

Low risk – 0-1 risk factor with risk score <10%. • *1o prevention of stroke.* add *Aspirin (75-162)* if patient has 10-yr risk of CV events of ?6% in Framingham *Stroke *Risk Profile Moderate risk -2+ risk factor or with risk score 10-20%- give* aspirin (75-162)* for *primary prevention of IHD* if age >50. If warf is used instead of aspirin in IHD INR less than 1.5. Keep INR 2-3 if warfarin used ACS pts who are intolarent to aspirin.
• per AHA goal BP for pts with CAD-130/80 if >10% risk (moderate) (ref slide 14 set HTN 1). remeber IHD goal bp is less than 140/90

High risk- ACEI for* secondary prevention of IHD*. CHD OR CHD equivalent AND 2+ risk factor with risk score >20%. for secondary prevention of ACS use BB.

Very high risk -established CHD PLUS poorly controlled or multiple major risk factor ( DM, Metabolic syndrome).

• CHADS2 scoring system will estimate the risk of clinical stroke among patients with AF but no CVD, tells u if you need *anticoagualation (moderate risk) *for *primary/secondary prevention of stroke.* low risk for stroke patient, 0 point: No therapy or *ASA 325 mg/d*

• TIMI risk score – high risk pts need immediate reperfusion or PCI in NSTMI

The Pooled Cohort Risk calculator is used to determine the 10-year ASCVD risk and life time risk in hyperlipidemia. Cut off to guide therapy on 10-year ASCVD risk score is >7.5 or < 7.5.

VALUE LIMITS
• Reduce dietary Na in HTN- No more than 1.5gm Na in severe restriction (normal<2.3gm Na) or 6gm NaCl per day- 1tsp salt)
• fluid restriction(<2L fluid,<2gm of Na) in CHF.
• CKD – <2gm of Na
• Cirrhosis and ascitis Sodium restriction (long term), <2 gm sodium per day. since fluid leake make body think that no BV and stimulate RAAS,
• restriction of fluid to 1000-1200ml/day give negative UOP (N-1500ml/day). needed in hyper/euvolemic hypernatremia. (negative Nitrogen balance in malnutrition and hypermetabolic states which needs TPN)
• Fluid overload(edema), Cardiac failure, Renal failure(low GFR), SIADH (water increased not sodium) need fluid restriction
• Fluid in TPN: 25 mL/kg/day (1 kcal/mL or 1 oz/kg/day)• HTN life style modification – Increase moderate level aerobic exercise 30-45mit/day most days of the week. Start with 20-30mins
• In IHD, life style modification -moderate intensity exercise for 30-60 minutes/d for 5-7 days/wkin
• stroke Physical activity -Engage in ?30 minutes of moderate-intense activity daily.
exersise is advised in stable HF not in uncompensated case

physical activity- Aerobic and resistance training. It helps the body use insulin to convert eaten food into energy
*In Type 2, Aerobic training more imp. Than resistance training. help with wt loss.* Accumulate at least 150 min/wk of moderate-intensity aerobic activity (50-70% of maximal HR) – ideally 30 min/day daily
Resistance training also improves glycemic control , at least 2-times per week
*In Type 1, Aerobic and resistance training. exercise can be dangereous, but reduce CV risk*

Lab values
• In IHD, CKD, Diabetes- Tx Goal Hb1c < 7%
• Primary prevention in Stroke Goals -FBS 70-130 mg/dL
PPBS <180 mg/Dl
HgbA1C <7% • Metabolic syndrome -Diabetes (> 110mg/dL/100)• In stroke thrombolysis contraindicatd if Pt is on anticoagulant or If INR >1.7
• For primary prevention of IHD keep INR 1.5 if warf used insead of low dose aspirin.
• For stent in MI keep INR 2-3.
• Acute stroke after thrombolytic INR 2-3
Normal INR if not on warf: 0.8-1.2

DM lab
*Pre-Diabetes* with any one of the folowing
• Impaired fasting glucose (IFG). FBG 100-125 mg/dL
• Impaired glucose tolerance (IGT). 2-hr OGTT of 140- 199 mg/dL
*• Hemoglobin A1C.5.7-6.4%*DM- a positive value should be confirmed unless values are clearly high.
Fasting blood glucose ? 126 mg/dL OR
Symptoms of diabetes with a random glucose ? 200 mg/dL OR
75 gm OGTT with a 2 hr glucose ?200 mg/dL
Hemoglobin A1C ? 6.5%

monitoring
1. Glucose monitoring
• Blood glucose- goal per ADA
Fasting/pre-prandial-70-130
1-2 hrs post-prandial-<180
• Urine glucose- Renal threshold generally corresponds to a blood glucose level of ~200 mg/dL. Not accurate
• Self-Monitoring of Blood Glucose- Measuring glycemic control and impact of rx changes. Test bid for type 2, tid/qid for type 1.
2. Hemoglobin A1C (HbA1C) A.K.A. glycohemoglobin, glycosylated. Reflects mean glucose control over 2 to 3 months (Estimated average glucose is reported. Incorporate pre and PPBS). direct relationship between HbA1C and microvascular complications. Even if BS not in goal if A1c in goal no complications.Goal < 7% Individualize based on patient factors. Gold std of monitoring
3. Fructosamine- Measure of glycated serum proteins. Reflects mean glucose control over 2 to 3 weeks .NOT equivalent to HbA1C Not related to risk of complications. Used when anemia or Hb problems
4. Ketones- dipstic or special glucometer (mild, moderate or severe). Presence of ketones + high blood glucose levels = Diabetic Ketoacidosis (DKA). Recommended for Type 1 DM (no insulin, body use FFA as fuel then ketone spill in to urine) and pregnancy (ketone hurt fetus) with DM

5. C-peptide- released with insulin from beta cells. Indirect measure of insulin secretion. Can be used to help distinguish between Type 1 and Type 2 diabetes (Type 1: no to low levels Type 2: normal to high levels). Can be used to determine need for insulin in a Type 2 diabetic

goals of therapy in *type 1*
1. Maintain euglycemia FBG < 130, HbA1C < 6-7%
*Type 2 Diabetes*- Goals of therapy
Maintain euglycemia FBG < 130, HbA1C < 7% (Individualize goals based on length of deasease) Glucose metabolism monitoring goal in tpn. FSBG – qid x 3-4 days prn; goal 140 – 180 mg/dL. *(need insulin)* Wounds that don’t heal ( BS ;200 surgens don’t do surgery)

Htn
• HTN definition or diagnosis if BP <140/90
• CVD (IHD, cholesterol) risk, Hypertension-140/90 or taking BP Rx,
• Goal BP in tx to prevent TOD= 1. <150/90 in pt >60yr. (JNC-8),
<140/90 in pt <60, DM,CKD (JNC 8)
2. <140/80 in pts with DM (ADA)
3. <140/90 in CKD without protein urea (KDIGO)
<130/80 with proteinurea (KDIGO)
4. <140/90 in general people (AHA)
<130/80 in pts with DM, CKD, CAD (Framingham risk score >10%), <120/80 mmHg LVH (AHA), • Hypertensive emergency is Severe elevation in BP > 180/120 with acute TOD
• HTN Severaity classification
mild or stage 1 HTN – 140-159/90-99
moderate HTN or stage 2 -160-179/100-109
severe HTN or stage 3 – >180/>110
• In STMI- Thrombolytic CI- if severe bp 180/110
• In stroke thrombolysis ,CI if BP >185/110
• In IHD, HTN tx-Goal < 140/80
• Acute *ischemic stroke – not receiving fibrinolytics*: ?220/120 mmHg
• Acute *ischemic stroke -Prior to fibrinolytic initiation*:?185/110 mmHg
•* Hemorrhagic stroke / ischemic stroke after fibrinolytic treatment*:<180/105 mmHg. • Metabolic syndrome -Hypertension (> 130/ >85 mmHg)
• Erythropoetin ADR Hypertension (associated with rate of in Hgb. CI if uncontrolled BP ( > 180/100 mmHg)
• Just CKD (ACR normal) goal is < 140/90.
• CKD + albuminuria – goal is Stringent BP < 130/80.
• CKD + DM (ACR normal) goal is < 140/80.
• CKD + DM + ACR high – goal is < 130/80
• Dialysis BP goal: predialysis < 140/90 ( before take off BV. Keep high to make sure pt is not going to go low after dialysis. Some time we hold BP rx before dialysis and give it after dialysis if BP is still high).
• postdialysis < 130/80 • (HVPG) Hepatic venous pressure gradient (Normal = 3-5 mmHg).Complication like Ascites when HVPG is >5 mmHg, Esophageal and gastric Varices when HVPG is >10 mmHg, spleenomegaly.
AGE
• HTN risk- Family history of premature CVD (men under age 55 or women under age 65)
• HTN risk -Age (older than 55 for men, 65 for women)
• CVD (IHD, cholesterol), risk- Age ( M> 45y, F>55y)
• Risk Factors in AKD Age > 65 yrs
• Susceptibility Factors in CKD Age > 60 yrs
• Stroke risk age >55
• Goal BP in tx to prevent TOD= <150/90 in pt >60yr. (JNC-8), <140/90 in pt <60, DM,CKD (JNC 8) • Framingham score age ( 55 & 65 for female) for IHD or angina • CHADS2 score age >75 in AF to prevent stoke
• age > 65 yo per TIMI risk score in NSTMI in ACS
• IHD prevention give aspirn after the age of 50 and moderate risk in Framingham score
• Relative CI to thrombolytics after 75 yrs in MI
• In stroke if AGE >80 thromolytics may be contraindicatd if time is 3-4.5
• PaO2 normal value in ABG -Subtract 1 mm Hg from the minimal 80 mm Hg level for every year over 60 years of age.Not applicable for age over 90
• Alarm symptoms of PUD Age > 55 years with new-onset dyspepsia
• Test and treat” for H. Pylory < 55 yrs and no alarm symptoms • High dose NSAID and concurrent steroid or anticoagulants or antiplatelet, complicated ulcer, age >65 are in risk of NSAID indused PUD, need prophylaxis or tx depending on the severaity of riskLipid- Existing ASCVD event Age <75High-intensity statins and Age >75
moderate-intensity statins .
• No ASCVD o DM on no DM patients age 40 to 75, LDL 70-189 statin based on the risk score

Alarm symptoms of PUD-
Age > 55 years with new-onset dyspepsia
moderate GI risk if High dose NSAID and concurrent steroid or anticoagulants or antiplatelet, complicated ulcer, age >65 and need prophylactic therapy with misoprostol or PPI.

• *Genetic predisposition tp COPD (alpha1 antitrypsin deficiency*- cannot maintain elastin)- Screening: all patients less than 45 years of age who develop COPD AND have a strong family history of COPD.
Age < 3 yr is ppt factor of asthma. screening of DM- Children: OGTT or HbA1C every 3 years • *at age 10 or onset of puberty *(autoantibody takes 10 ys to destruct beta cells) Type 2- OGTT or HbA1C every 3 years in… •*Adults > 45 yo* OR Overweight individuals (BMI ? 25) with at least 1 of the following risk factors:

time period
ACS -Door to needle time 30 min, 90 in PCI
In stroke thrombolysis Door to needle 1 hr.In stroke thrombolysis <4.5 or 3 preffered. If ischemic,< 4.5 hrs since symptom onset, fibrinolytics, then find out if cardioembolic or noncardioembolic stroke before starting *PO* antiplatelet/anticoagulant. a. If non- cardio start Antiplatelet > 24 hrs after fibrinolytic
b. If cardio embolic start* PO anticoagulants *>48h after fibrinolytic
3. If ischemic, >4.5 hrs since symptom onset, no fibrinolytics, start antiplatelet within 48 hours. Try non pharmacologic methods, start on antiplatelet/ anticoagulants based on type of ischemia.
a. If non cardioembolic continue antiplatelet
b. If cardioembolic d/c and begin anticoagulant.

In ACS- Thrombolytic used if symptoms <12 thrombolytics, but pci preferred for ACS. Continue anticoagulants for 24 hrs in IHD. in NSTMI Continued *IV anticoagulant* for at least 48 hours or until end of angiography or PCI. in STMI, if given before PCI and continued for 24 hrs, if given after thrombolytics continued for 24 hrs. In stroke thrombolysis contraindicatd, if Pt is on anticoagulants for >48 hrs or INR >1.7
Class I recommendation in patients less than 75 yo with Chest Pain, ST segment elevation ACS who present within 12 hrs of CP.These need to be evaluated very quickly!!

3-4 wks of anticoagulant warf, before cardiovert if pt has AF for more than 48 hrs
need 6 wks of anticoagulation after pt is cardioverted. When used class 1 or 3 rx for cardioverting AF/ arrhythmia monitor 48-72 hours.

Alcoholism is a Disease, when there is Any deviation from normal body function manifested by a Characteristic set of symptoms. clinically significant impairment occurring in 12 months with min of 2 symptom for diagnosis. 2 – 3 symptoms for mild, 4-5 symptoms for moderate and >6 symptom for severe alcoholism. After successful detoxification/ treating the patient’s withdrawal symptoms (based on CIWA scale), medication to take to help pt remain abstinent and craving/addiction once he leaves the hospital. Drugs treatment for alcohol use disorder is indicated if Moderate – Severe alcohol use disorder symptom (4 or more symptoms for 12 months per DSM V) along with Current, heavy use, Motivated and Willing to rx and No contraindications to rx.

Withdrawal = ? 2 of the symptoms within hours-days (96hrs) of discontinuation of (or reduction in) chronic, heavy EtOH use.
CIWA-Ar: tool or protocol used to assess withdrawal symptoms in uncomplicated case ; determine if therapy should be given. Administer therapy when symptoms moderate-severe or ;10

Per DSM-5 Opioid Use Disorder occurs over past 12 months, Used larger amounts and longer, Unsuccessful in cutting back, Craving, Use continues despite physical or psych problems secondary opiates.

Clinical opioid withdrawal scale (COWS)- Used to follow course of sx as well as effectiveness of medications. 5-12 = mild; 13-24 moderate; 25-36 mod. severe; ; 36 severe.

-Brown Obsessive Compulsive Scale: Y-BOCS to Measures severity of symptoms.
Remission = score of 8 or less, (Scores 25 shows a severe OCD).
Response = minimum 25% reduction in Y-BOCS score
Reduce anxiety

alcohol deterrence tx
when to start- once pt is abstinent (all 3 rx). Disulfiram (wait 12 hours *after alcohol* otherwise severe rx. rx in the system for 14 days even after D/c so no alcohol). Naltrexone (wait 7-10 days after last *opioid use* otherwise severe withdrawal symptom)
How long is tx- continued for months to years.

opioid deterrence tx
when to start- Addicted with heroin with a history of ; 1 yr. pt don’t need to be abstinent since it can prevent withdrawal symptom through opioid agonism.

Duration: days to 6 months for methadone. Maximum time allowed in OTP is 180 days. *prevent withdrawal sx and drug craving* (clonidine don’t take care of craving). not for pts with substance use disorder. not safe due to QT prolongation.
buprenorphine -High affinity for mu may displace other opioids from the receptor and can precipitate withdrawal sx (not fatal). so better for longterm use up to 2yrs unlike methadone.Stabilization lasts 2-3 months at lowest dose. Length of treatment (maintenance) = at least 6 months but can last up to 2 yrs. Some times cant get off . not for pts with substance use disorder. efficient in displaceing other opiods, low efficacy and high affinity for receptors.
naltrexone-Use -to treat and prevent relapse after patients with opioid dependence who have undergone detoxification treatment. Abstinent from opioids 5-7 days. Confirm with a test dose of 0.8mg IM (naloxone challenge test must be failed). not very efficient.

Kidney lab

Definitions of Azotemea, uremea, gout, urine and blood PH, s. osmolality, polyurea, diuresis ,natriuresis, Oliguria, Anuria, dysuria, incontinence/urine urgency, urinary retention

normal values of BUN, s. ablumin, albumin urea, ACR, S.Cr. CrCl, GFR ( ml/min ; litter/day),UOP, CO, blood volume,reanl blood flow, renal plasma flow

Azotemia -accumulation of nitrogenous wastes (urea, ammonia and uric acid) in blood, both BUN and S. Cr are increased, normaly seen when GTR is ;60, in early AKI. but pt has no symptoms
uremia -increased urea in blood.(blood urea ;1 g/day). Uria is normally present in urine . Urea is then filtered and up to 50% reabsorbed at the kidney. seen in later stages of RF, and has symptoms of fatigue, N/V, anorexia etc.it is an indication of dialysis hyperuricemia- high uric acid, level over about 6.8 mg/dL. high uric acid is tumor lysis syndrome. This does not equate with gout until, in fact, crystals precipitate; at that point you have developed gout. gout- disease state resulting from the deposition of mono sodium urate crystals in tissues BUN ( shows fluid status)-10-20 mg/dl s. albumin- 3.5-5 (av-4) help to findout normal anion gap in a person. It produce oncotic pressure in blood. In PD dextrose is used to provide oncotic pressure. albumin urea- ;30 mg/dl
ACR (albumin Cr. ratio)- ;30 mg/dl
S Cr- 0.3-1.5 mg/dl, no cut off, look for increase from baseline. ;0.3. if ; 4 severe RF in stagingurine PH Normal: 4.6-8.01
Blood Ph- 7.35-7.45)
serum osmolrity – 275-295 mosm/kg
UOP – 0.5-1ml/kg/ hr or 1.2 l/day or 500- 1200 ml/day
polyurea -;2500 ml/day
Diuresis- increased urine output , due to inihibition of Na channels or water transporter in kidney
natriuresis– process of excretion of Na in the urine (aldosterone cause Na retention. Aldosterone Increases number and activity of Na+ transporters in nephrons. Results in increased reabsorption of Na+ from kidney. K excretion. Diuretics inhibit sodium trasporters to result in less water reabsorption and thus more urine.ACEI decrease ANG 2 thus prevention of aldosterone and ADH thus less Na and water retention thus low BP and more urine. Diuretics work differently.
ADH Increases number of water channels in nephrons. Results in increased reabsorption of water from kidney. Water follows sodium passively but has limitations in the absence of ADH. BNP also regulate BV)
Oliguria – ;500ml urine/day. Little urine
Anuria – ;50ml urine/day. No urine
dysurea – Painful urination
Incontinence -high urgency and frequency. sudden urge to urinate or leaky bladder. Loss or decrease in voluntary control of bladder and cannot hold pee. Too much contraction and increased frequencyof urination TX- anticholingergic Ex: tolterodine (Detrol™), oxybutynin (Ditropan™)
Urinary retention is caused by anticholinergic drugs.

Glomerular Filtration Rate (GFR)= 125 ml/min = 180 L/day (filtrate)
Creatine clearance – 120 ml / min, below 60 use GFR eqn
CO – 4-6 l/min
blood volume – 5 l
Normal FVC (forced vital capacity)- Normal M-5-6l, normal F-4-5 . Restrictive diseases limit volume.

Kidney receive 20% cardiac out put. so renal blood flow is 1200ml/min or 1500 l/day.
renal plasma flow is 55% renal blood flow (650 ml/min).
GFR is 19% of plasma flow (125 ml/min or 180 l/day).
0.8% GFR makes up UOP ( 0.5-1 ml/min or 1.2 l/day or 1200ml/day)

Distribution of CO (5 l of blood the body)- lung get 100%. 20% of CO goes to kidney, muscle, brain and whole GIT (5% to liver). 5 % of CO goes to heart, bone and skin.

whole Blood ( 5l in body) = formed elements (RBC (99% of formed element), WBC, platelet) + plasma 60 % of whole blood (or 5 % of Bwt) {H2O (92 % of plasma) plasma proteins (or albumin 7%) and 1% of plasma is electrolyte (Na, Cl, K, Ca), nitrogenous waste (NH3,Urea, Uric Acid), Carbs, Lipids, A.A.s. H+, HCO3-}

FVC – force vital capacity (meaure volume)
FEV1- forced expitroy volume (measure flow rate) of the predicted or postbronchodilator- 80% is normal
FEV1/FVC-(normal actual value (not predicted value) -0.7
FEF (forced expiratory flow ),
PEFR (peak expiratory flow rate- can be measured through peak flow meter)

urine test and hydration status

Urine Dipsticks -pH, Specific gravity, Protein, Glucose, Ketones, Blood, Bilirubin, Urobilinogen, Nitrite, Leukocyte esterase

Urine analysis – UOP, ph, sp.gravity, glucose, protein, formed elements, casts (hyaline, cellular, granular/ waxy), crystals, *FeNa.

UOP- hydration status of patient for qualitative indication of renal function. *Kidneys ability to handle fluid, help in deciding whether impaired kidney function is due to dehydration or actual kidney damage/ prerenal dx.* ( osmolaity eqn has BUN, glucose and Na from Chem 7 lab value. high plasma osmolality, urine specificgravity, low FeNa, BUN and S. Cr, and BUN:Scr ratio .20:1 hyline casts, low urine PH (acidic), low UOP. and low fluid (give fluids)( high UOP in ATN.)

urine Specific gravity: 1.003-1.030 g/ml (normal). Nonspecific to assess urine concentrating ability. ? means more solute in same volume of water and shows dehydration. Unlike urine osmolality, specific gravity is affected by both the number and size of particles in solution. so osmality is are accurate for urine conc.

serum osmolrity – 275-295 mosm/kg. Calculated serum osmolality = (2 X serum [Na]) + [glucose]/18 + [BUN]/2.8. high in dehydration and prerenal RF.

• FENa (%) = (UNa/SNa) / (UCr/SCr) x 100
*Kidneys ability to handle Na, help in deciding whether impaired kidney function is due to dehydration or actual kidney damage.
low value ;1 show that Na retention due to hypovolemia or prerenal desease.* since kidney is trying conserve Na by reabsorbing and less excreted High value ; 2 shows, Na wasting, due to intrarenal disease. since tubules and not working and not able to reabsorb

Normal BUN:Scr ratio is 10:1 to 15:1 if elevated suggests decreased circulating volume, since this would stimulate increased water reabsorption and therefore urea reabsorption.
;10:1- intrarenal AKI. Renal damage causes reduced reabsorption of BUN, therefore lowering the BUN:Cr ratio. 10-20:1 Normal range. Can also be postrenal disease. BUN reabsorption is within normal limits. ;20:1 – prerenal AKI. BUN reabsorption is increased. BUN is disproportionately elevated relative to creatinine in serum. Dehydration or hypoperfusion is suspected.

ACR

Normal: 4.6-8.01 (urine has slightly *basic PH.* Blood Ph- 7.35-7.45)
? PH (alkaline) pH-caused by presence of urea split bacteria (UTI), severe *vomiting, kidney disease*, and asthma.
? PH (acidic) pH – caused by metabolic or respiratory acidosis, COPD due to* hypoxia* (emphysema- pink puffers . affected at the alveolar level), uncontrolled diabetes, severe* diarrhea, dehydration*, starvation, drinking too much alcohol.

Presence of large amout of RBC (Nephritic syndrome- Hematuria), WBC and casts can indicate several conditions including urinary stasis, UTI’s, tubular damage, obstructions, etc. crystals in the urine including: uric acid, calcium salts and cysteine( AA)

Bacterial count- ? 105 cfu/ml (traditional definition), ? 102 cfu/ml with significant symptoms
? PH (alkaline) pH-caused by presence of urea split bacteria (UTI)
Nitrite reduction test: Nitrite test- signifies the presence of bacteria (gm -)
Leukocyte esterase: signifies presence of WBC’s.
Urine Dipsticks Leukocyte esterase- When used together with nitrite, excellent sensitivity and specificity for the detection of bacteriuria
*Pyuria:*- ; 10 WBC/hpf in centrifuged urine nonspecific for inflammation or infection
Hematuria- nonspecific

Proteinuria- in infection; glomerular disease
Casts- small cylinder-shaped formations of cells and debris from inside the tubules of the kidneys
Squamous Epithelial Cells: represent contaminated urine sample
Color: cloudy, turbid (normally amber-yellow and clear to slightly cloudy)

Electrolyte lab
Normal Na-135-145 mEq/L .
Mild Hyponatremia -125-130mEq/L
Moderate Hyponatremia -115-125 mEq/L
Severe Hyponatremia- ;115 mEq/L Hypernatremia (rarely seen) -; 135 mEq/L. or increase ;12 mEq/L/dayGoal for K replacement – 4 mEq/L
ECF Potassium Normal Range: 3.5-5 mEq/L.
Mild hypokalemia – 3-3.5 mEq/L
Moderate hypokalemia – 2.5-3 mEq/L
Severe hypokalemia – ;2.5 mEq/L Mild hyperkalemia – 5-6 mEq/L asymptomatic Moderate hyperkalemia – 6-6.9 mEq/L Severe hyperkalemia – ;7 mEq/L worry due to cardiac issue (;6.5 in CKD)

Normal Mg Range: 1.5-2.2 mEq/L. low Mg in RF is common. since kidney reabsorb it.
• Hypomagnesemia (;1.5 mEq/L).
severe Mg ; 1mEq/L • Hypermagnesemia (;2.2 mEq/L) .
severe Mg ; 4 mEq/L
Normal PO4 Range: 2.5-4.5 mg/dL
• Mild to moderate hypophosphatemia (1-2.5 mg/dL)
• Severe hypophosphatemia (;1mg/dL) • Hyperphosphatemia (;4.5mg/dL)

Normal Range Ca: total Ca in blood is 2.5 mmol/L or 5 Meq/L or 10mg/dL. calcium test can’t be used to check for a lack of calcium in your diet or for the loss of calcium from the bones. An ionized calcium (1.16-1.32 mmol/L or 4.65-5.28 mg/dL) test checks the amount of calcium that is not attached to protein in the blood. The level of ionized calcium in the blood is not affected by the amount of protein in the blood.
serum value is ca level Bound to plasma proteins and albumin. >99% found in bone. ~0.5% found in plasma.Correction for hypoalbuminemia
SCa (mg/dL) + [0.8 x (4-SAlb (g/dL) )] if pt has normal albumin. Make sure check ionized ca level. • Hypocalcemia <8.5 mg/dL, (<4.4 mg/dL ionized) • Hypercalcemia >10.5 mg/dL, (>5.2 mg/dL ionized)
hypercalcemic crisis ->14mg/dl. may lead to RF

Major extracellular anion. Normal serum range 96 – 106 mEq/L
• Vital signs- temperature, pulse, BP, respiration.
• Body Temperature- range between 97.8 to 99.1 degrees Fahrenheit (31 C). below 95 degrees Fahrenheit is defined as hypothermia.
• Pulse: ranges from 60 to 100 beats per minute
o Bradyarrhythmias: Heart rate < 60 bpm o Tachyarrhythmias: Heart rate > 100 bpm.
• Respiratory rate- at rest is 12 to 20 breaths per minute. A respiration rate under 12 or over 25 breaths per minute while resting is considered abnormal.
• BLOOD PRESSURE- Average: 120/80 mm Hg

Normalize serum TSH levels-Normal 0.5 – 5 mIU/L, if on rx target TSH levels- 0.3-3

Atom, ions, & salt, anions, cations, electron, protone and neutrons, acidosis and alkalosis, PH and PKa and ionisation

atoms and ions-anions and cations

atom is neutral with equal amount of proton (positively charges) and electrons (negatively charged) with no net electrical charge. remember neutrons are neutrally charged. *sodium atom become Na ion or sodium cation* when it looses a electron and gains a Positive charge ie, too much proton. oxygen atom like to exist as O-2 ion or anions with negative charge since it likes to gain electrons. Cations (Na) has too much proton and can donate proton *when it gets in to water* (electrically neutral but highly polar) thus it act as acids. *cations always act as acids*. solution become acidic when too much proton in the water for ex a salt (electrically nutral, not ion) NaCl when Cl attract all the Oxygen leaving too much proton/ H in the water. this happen * in salt based on the strength of acidity or alkalinity of the salt.*

in chem 7, Na and K are *cations (has CAT and thus PAWS so pawsitively chaged* /positively charged with too much protons by *looseing the electron -ve charged)*, Cl and HCO3 are Anions (ONIONS so cry and _ve enery. easily gain electon or has too much elecron). ie, anions has less proton and more electon, waiting to accept proton or act as a base in water. Ions are atoms that has electrical charge. Salt is electrically neutral, until it is near highly polorised neutral ph water.

ions and salt, acidity and alkalinity

acids release proton *(protone doner, +ve represented as HA) *to water. (remember a cation has more protone and thus positively charged. it gained +ve charge by loosing electrone. when it goes to water it like to donate protone thus *cations act as acids* in water and become electrically neutral with oxygen. now water has too much free hydrogen or protone and solution is acidic. when a salt ex NaCl goes in to water it dissociates in to Na + and Cl- based on the strong acid/ bases and then Cl which has too many electones and thus -vely charged binds to H+ ion in water and Na+ binds to O- of water. NaCl is a proton acceptor thus and acid)
base is protone acceptor (represented as B or A- . *anions act as a base* . since it has too much _ve charge it can accept protone). when body has too much acids like lactic acid or ketoacids, *anions accept protone from the acids to get electrically neurtral.* this is the basis of high anion acidosis. too much acids means too protons NaCl is a acid and also acetazolamide. cause hyperchloremic acidosis.

PH and PKa and ionisation
*PH shows the power of Hydrogen or proton.* Ph is -ve log of H+ ion conc (inversely proportional. since Ph is a log scale, small change in Ph make a big change in Hydrogen ion conc.) Ph 7 is neutral. PH less than 7 means too much hydrogen ions and acidic. acid put in water makes too much proton. *when increase hydrogen ion, PH is is low since its -ve log and result in acidic solution.* PH is acidic means there is a substance in water that causes an excess of Hydrogen ion or proton. water is neutral ph. Acid put in acids, due to mass action, proton cannot be removed or keep it in *unionized state ie, easily lipid soluble. *acids in base solution, remove proton from the base and ionised form and water soluble.
PKa is the PH at with drugs are balanced between unionised and ionized form. blood ph is 7.34-7.45. most drugs are weak acids or weak base since only small change in PH is need to shift the drug between lipid soluble to water soluble (not easily pass through lipid layers). Henderson Hasslebach eqn for PKa

• drugs that are weak acids – in acidic gastic PH is unionized and absorbed in to plasma (easily pass through the lipid membrane to get to plasma). When u change ph, less absorption of week acids
• drugs that are weak bases- in acidic gastic PH is ionized and not absorbed into plasma. Antacid change ph and more absorption.
The pKa of a drug is the pH at which 50% of drug molecules in solution are ionized. To measure ratio of ionized to unionized, use Henderson-Hasselbach equation. Ionized form are water soluble does not cross the lipid membrane.
Weak acids; pKa < 7: HA (non ionized) ? A- + H+ Weak bases; pKa > 7: BH+ (ionized)? B + H+
Weak acid in weak base, more ionized forms (water soluble), do not cross lipid membrane between plasma (PH – 7.4) and gastric juice (PH-1.4 )

remember body want to keep acid and base balance. acidemia means PH of the blood low or high Hydorgen ion con. acidosis (metabolic or respiratory) is process. many different process happens. pt can be acidosis (process), but can be alkalemic based on PH (compensation or uncompensated).

Water+ *CO2 (acid or end product of kerbcycle*, body get rid of it by respiration) in equilibrium with carbonic acid in equilibrium with H+ (too much proton in acid, HA) + *bicarbonate* (A- or Base B, buffer from kidney, to make equlibrium in blood).
anything to do with bicarbonate is metabolic process by kidney. anything affect CO2 is a respiratory process (only one way). conc of HCO3 and CO2 affect PH of blood. know normal value of blood PH, pCO2 and HCO3 (CO2 in chem 7, normal 22-26), Po2
PH in +ve term is henderson eqn
PH= PKa + log conc of base/acid or proton.

• Blood lab
• Chem 8 assess Na, K, Cl, HCO3, BUN, S.Cr. Glucose and Ca
• Chem 7 in fish bone assess Na, K, Cl, HCO3, BUN, S.Cr. and Glucose
• goal Hb is 8, blood transfusion in esophageal varices in cirrhosis
• goal Hb is 10, for ESA therapy in CKD (or cancer chemotherapy)
. in sepsis infection, Blood: transfuse if Hgb < 7g/dL
• INR- normal (<1.7 CI if giving throbolytics in stroke) 1.5 if warf giving in stable angina framingham score instead of aspirin
in cirrhosis Child-Pugh Scoring-INR(<1.7 is normal). but if cirrhosis • PT time, INR (coagulopathy ref DIC in sepsis ) high
• platelets *low*
Coagulopathy (also called a clotting disorder) is a condition in which the blood’s ability to coagulate (form clots) is impaired• Platelet (thrombocyte) count- 150,000-450,000 platelets per mm3 or 1.5-4.5 x 1010/L.
;100000, is a CI if giving throbolytics in stroke life span of platelet is 10d. • platelets *low* in cirrhosis (back flow of blood, traped in spleen or no thromobopoetin production and no more stimulus to produce platelets in BM) CKD cause anemia due to lack production of erythropeitin. Platelets Homeostasis – process that halts bleeding following vascular injury. Minimum injury to vascular or endothelium. Endothelin cause vasoconstriction and reduse the blood flow to site. Platelet plug formed by platelet adhesion, activation and aggregation. Then fibrin ( from coagulation cascade) stabilize it by attaching to the glycoprotein receptors of the platelet . When collagen at the base of the vasculatre is released it activates the* intrinsic coagulation* cascade of thrombin and fibrin formation. Injured vessel release *thromoboplastin and activates extrinsic pathway*. Both pathway activates factor 10 in common pathway. Thrombin (factor 2) stimulate platelet aggregation and activates protein C the fibrinolytic system. Protein C, S and antithrombin 3 are inhibitor of coagulation, plasminogen Test to assess platelet (bleeding time), coagulation (PT and INR) and clot degradation ( D dimer). PT for warf- plasma (use Na citrate as anicogulate blood. it binds to ca (chelation) and prevent spontaneous clotting) + tissue thromboplastin (tissue factor and phospholipids of platelet) and Ca. them time to form a fibrin clot is measured. measure coagulation involving *extrinsic and common pathway* (facter 2 7 9 10). Normal PT -*10-13 sec. prolonged ;15 in vitamin K deficiency, *hormones drugs including hormone replacements and oral contraceptives, disseminated intravascular coagulation (a serious clotting problem that requires immediate intervention), liver disease, and the use of the anti-coagulant drug warfarin. Additionally, the PT result can be altered by a diet high in vitamin K, liver, green tea, dark green vegetables and soybeans.

INR- standardized PT ratio. since different reagent (thromboplastin from rabit. Need to know sensitivity of thromboplastin) and different instrumets used. Pts PT/ mean Normal PT= 1-1.7. ;1 INR (low INR) means faster cloting or hypercoagulation than STD PT. INR 5 means pts PT took 5 times long time than a standard PT to clot. Ie high INR, tendency to bleed. Maintain INR *2-3 for pt on coumadin, *DVT, Venous, pherpheral thrombolism, PE, AF, with cardioversion, MI cardio myopathy. 2.5-3.5 in mechanical valves.

*aPTT for heparin*to determine if heparin (blood thinning) therapy is effective, does not show effect of LMWH. to detect the presence of a clotting disorder, liver problems, lupus. plasma (use Na citrate as anicogulate blood) + tissue phospholipid (and ground glass a surface content) and Ca. them time to form a fibrin clot is measured. measure coagulation involving *intrinsic and common pathway *(facter 7 9 11 12 and 2 5 10). Normal *21-45 sec*. therapeutic range of *heparin is aPTT ratio of 1.5 -2.5 times control*. Give wt based dose of heparin draw blood in 6 hrs ie 4 t1/2 after continuous infusion or mid point values after IVB of q8 or q12 hr dosing. But don’t adjust for IVB . Use nomogram gusto to adjust dose in infusion
*ACT for high dose heparin- Whole blood* (has platelet inside. use Na citrate as anicogulate blood) at the bed side. Value relates to dose

Firbrinogen assay to measure lytic state with tpa when PT and aPTT are high. Thrombin time is the most sensitive test for fibirnogen defeciency.

D dimer- activation of thrombin and clot activates fibrinolytic system and FDP firbin degradation product. D dimer a neoantigen is formed when thrombin initiate the transition of fibrinogen to fibrin and activates factor 13 to cross link the fibrin formed.this neoantigen is formed as a result of plasmin digestion of cross linked fibrin. Used to rule out DIC. VTE is DVT+PE. D dimer is a degradation product of firbin clot when plasmin act on it. Elevated in acute thrombosis. Very sensitive not specific. So used to rule out other causes not for diagnosis. ESR and WBC are also elevated.

O2 ref slide 15 &18 in set – COPD
Goal Pao2 (ABG) >60 mmhg (normal PaO2: 80-100 mmHg). PaO2-Subtract 1 mm Hg from the minimal 80 mm Hg level for every year over 60 years of age.Not applicable for age over 90. (other normal values in ABG PaCO2: 35-45 mmHg, pH: 7.4 (7.35-7.45), HCO3-: 22-26 mEq/L- calculated
Goal O2 saturation (pulse oximeter) >90% (normal SaO2: 95% ) higher than that cause respiratory failure (vasoconstrictor high o2)
Rx for O2 show, method of delivery (O2 cylinder or O2 concentrator), flow rate 1-2l/min at sleep in COPD, duration of delivery -15hrs/day in COPD.
In hospital, use nasal canula, high flow o2 mask (better control of o2 level), positive pressure ventilator (NPPV- non invasive), mechanical ventilator (intubation if acidosis)
cyp

• Loavastatin and simvastatin (Metabolized by *CYP3A4*). CI with 3A4I: “azoles”, protease inhibitors, gemfibrozil, cyclosporine, Grape fruit juice. Non DHP and amiodarone also interact with it.

o Cimetidine – inhibits P450 enzymes! (3A4, 2D6, 1A2, 2C9)
o Ranitidine minimally inhibits P450 enzymes
o Famotidine and nizatidine do not inhibit P450 enzymes

Omeprazole inhibits *CYP2C19.* Clopidogrel/ lavix (prodrug) has to be activated by 2C19. *So change to protonix*

CYP450 1A2 involved in metabolism of theophyllin
Barbituates, Phenytoin, Rifampin, Smoking

Increased levothyroxine metabolism- Phenytoin, carbamazepine, rifampin (through induction of hepatic CYP3A4)

Fluvoxamine inhibits CYP1A2, 3A4, 2C9, 2C19 and it carries the highest risk. Fluoxetine and paroxetine inhibit CYP2C9 and 2D6.
Prozac = Paxil>Zoloft (low effect on P450)
Citaprolam & escitaprolam – do not block P450 enzymes
DI- SSRIs may increase antiarrhythmic, anticonvulsant, anticoagulant, lithium, antipsychotic & oral hypoglycemic level
SSRIs & TCAs combo closely monitored due cyp interactions (ref slide 5 of this set)
SSRIs & MAOIs contraindicated due to serotonin syndrome (wait 5 wks (5 t1/2) before MAOI). SSRI block 80% of transporters.
XR means drug absorbed slower but half-life same
SNRI DI- cyp 2D6 (fluoxetine) and cyp3A4 inhibitors like cimetidine

Codeine binds poorly to opioid receptors. Its analgesic effect due to its demethylation to morphine (only occurs in 10% of administered drug). Conversion to morphine requires* CYP2D6* in liver. in people with polymorphism no morphine and durgs not effective.

in people with polymorphism (no enzyme), TCA toxicity due to too much drug in blood.

Enzyme inducer AED cause OCP failue. ex- older agents phenytoin, CBZ, phenobarbital. (others rifamin)
Enzyme inhihitor AED- VPA (others- cimetidine, erythromycycin, fluoxetine, INH
OCP are *CYP3 A4* substrate, Warfarin is 2 C9 substrate

enzyme inducers- barbs funny mom (modafanil for narolepsy. not milk of mag) refuses (rifampin) greasy (*g*risiofulvin) carb shakes (st. johns wart)
enzyme inhibitor- gee queen grace is inhibited.
*G*emfibrozil, quinidine, *g*rapefruit juice, retonovir, azole, cimitidine, erythromycin, isoniazid, sulfonamide.

Cyclophosphamide used in chemotherapy (alkylating agent of the nitrogen mustard type)
cyclosporine group of macrolides isolated from fungi. Like tacrolimus, it is calcineurin inhibitor, used immunosuppressive drugs.

receptors

a receptor is a protein-molecule that receives chemical-signals from outside a cell. e.g. an acetylcholine-receptor recognizes and responds to its endogenous-ligand, acetylcholine. receptors are drug tagets ie, rx bind to a receptor, they cause some form of cellular/tissue-response, e.g. a change in the electrical-activity of a cell.

*Cell surface receptors* (membrane receptors, transmembrane receptors) are specialized integral membrane proteins which communicate signals between the cell and the outside world. Extracellular molecules such as: hormones; neurotransmitters; cytokines (ex is erythropeitin receptors); growth factors; cell recognition molecules; nutrients; or waste products; all react with the archetypical receptor to induce changes in the metabolism and activity of a cell. The process is referred to as signal transduction: in which Ligand Binding affects a cascading chemical change through the plasma membrane. In this way, surface receptors act as triggers of cellular communication and signal transduction.
Transmembrane receptors are composed of two or more peptides which cooperate and may dissociate when ligands bind, or fall off during another stage of their signaling cycles. They are typically classified based on their tertiary structure or kind of protein ex. G-protein coupled receptors, glycoprotein and lipoprotein.Many membrane receptors include transmembrane proteins.
Like any integral membrane protein, a transmembrane receptor may be divided into three domains. The extracellular domain juts externally from the cell or organelle. Transmembrane domain with transmembrane alpha helices. The intracellular (or cytoplasmic) domain of the receptor interacts with the interior of the cell or organelle, relaying the signal. There are two fundamental paths for this interaction:The intracellular domain communicates via protein-protein interactions against effector proteins, which in turn pass a signal to the destination.With enzyme-linked receptors, the intracellular domain has enzymatic activity. Often, this is tyrosine kinase activity. The enzymatic activity can also be due to an enzyme associated with the intracellular domain.
*Membrane receptors* are mainly divided by structure and function into 3 classes: The ligand gated ion channel-linked receptor; The enzyme-linked receptor (thyrosin receptors); and The G protein-coupled receptor.
two types of neurotransmitter receptors: ligand-gated receptors or ionotropic receptors and G protein-coupled receptors or metabotropic receptors. Ligand-gated receptors can be excited by neurotransmitters (ligands) like glutamate and aspartate. These receptors can also be inhibited by neurotransmitters like GABA and glycine. Conversely, G protein-coupled receptors are neither excitatory nor inhibitory. Rather, they modulate the actions of excitatory and inhibitory neurotransmitters. Most neurotransmitters receptors are G-protein coupled.

*Nuclear receptors*- Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D. unique property of nuclear receptors that differentiates them from other classes of receptors is their ability to directly interact with and control the expression of *genomic DNA.* As a consequence, nuclear receptors play key roles in both embryonic development and adult homeostasis. Nuclear receptors are modular in structure and contain the following domains N-terminal regulatory domain, DNA-binding domain , Ligand binding domain, C-terminal domain, The N-terminal.
Based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors. Both receptor types are activated by specific neurotransmitters.
Ionotropic receptors form an ion channel pore. When an ionotropic receptor is activated, it opens a channel that allows ions such as Na+, K+, or Cl? to flow. Ligand-gated ion channels. ionotropic receptors, which open quickly but only remain open for a few milliseconds and have an effect only in the immediate region of the receptor, the effects of metabotropic receptors can be more widespread through the cell.
metabotropic receptors is a type of membrane receptor, that are indirectly linked with ion channels on the plasma membrane of the cell through signal transduction mechanisms, often G proteins or acts through a secondary messenger. Ex.of metabotropic receptors by mechanism are G protein-coupled receptors , tyrosine kinases and guanylyl cyclase receptors. It may be located at the surface of the cell or in vesicles. when a metabotropic receptor is activated, a series of intracellular events are triggered that can also result in ion channels opening but must involve a range of second messenger chemicals.This class of receptors includes the metabotropic glutamate receptors, muscarinic acetylcholine receptors, GABAB receptors, and most serotonin receptors, as well as receptors for norepinephrine, epinephrine, histamine, dopamine, neuropeptides and endocannabinoids.
Structure of The G protein-coupled receptors have seven hydrophobic transmembrane domains. Most of them are monomeric proteins, although GABAB receptors require heterodimerization to function properly. The protein’s N terminus is located on the extracellular side of the membrane and its C terminus is on the intracellular side. The 7 transmembrane spanning domains, with an external amino terminus, are often claimed as being alpha helix shaped, and the polypeptide chain is said to be composed of ~ 450-550 amino acids.
Metabotropic receptors have neurotransmitters as ligands, which, when bound to the receptors, initiate cascades that can lead to channel-opening or other cellular effects. When a ligand (the neurotransmitter) binds to the receptor (the transducer) the latter activates a primary effector via the G-protein, which can go on to activate secondary messengers or have other effects. Since opening channels by metabotropic receptors involves activating a number of molecules in turn, channels associated with these receptors take longer to open than ionotropic receptors do, and they are thus not involved in mechanisms that require quick responses. However, metabotropic receptors also remain open from seconds to minutes. Thus they have a much longer-lasting effect than ionotropic receptors, which open quickly but only remain open for a few milliseconds. the effects of metabotropic receptors can be more widespread through the cell.
Metabotropic receptors can both open and close channels. They can make a membrane more excitable by closing K+ channels, retaining positive charge within the cell and thus reducing the amount of current necessary to cause an action potential. Metabotropic receptors on the presynaptic membrane can inhibit or, more rarely, facilitate neurotransmitter release from the presynaptic neuron. These receptors can be further classified into receptor tyrosine kinases and G protein-coupled receptors, or GPCRs.

nerve action potential and nerve signal transmission
*(signal/impuse transmission in nerve- electrical to chemical then to electrical to chemical…..* neuron use *electrical activity or AP *to transmit impulse across axone then use *chemical or neurotransmitter *to transmit impulse across the synpase. the chemically activated receptor at the post synaptic neuron activates ion channels or G proteins based on the receptor type and need of fast of slow action. this chemical transmission of impulse help to depolarise or repolarise the neuron until it reaches the neuronal body, then impulse is again converted to electrial or AP at the axone of the second neuron based on the *sum of all charges of impulse* that reaches the cell body. remember several dentrites bring the impulse to cell body. some synapse of the 2nd neurons can be excitaory and produce AP/depolarisation and some are* inhibitory producing hyperpolarisation.* if too many hyperpolarised AP, may not *reach threshold* even though there is some excitatory AP. based on that AP may or may not be generated at the axone of the second neuron.
Chemical/neurotransmitters are *limited supply* at the presynaptic neuron. after it *trigger the 2nd neuron* postsynaptically through ions or G protein to produce a long lasting impulse transmission to the cell body, it goes back to the presynaptic neuron and restored. if that is inhibited, more neurotransmitters available at the synapse to produce a good effect, but we may *ran out of the supply* at the presynapse for next action in postsynapse. *Adrenalin is a neurotransmitter and also a hormone. *dopamine is excitatroy is balance by inhibitory serotonin or Ach based on the area. exitatory glutamate is balanced by inhibitory GABA)Factors that play a role in seizure activity: Neurons in the epileptogenic focus show *Abnormal AP generation *(high-frequency bursts of Aps)-Due to Instability of resting potential ? high frequency bursts of APs. Tx is targeted on Voltage-gated Na+ and Ca2+ channels AND (must)
*Defective synaptic function*- Normally, the spread of bursts of surrounding AP inhibition and *synchronization* of adjacent neurons is prevented by intact *GABA-mediated hyperpolarization* process. An enhancement of excitatory synaptic activity (*glutamate generate EPSP*) or reduction of inhibitory synaptic activity (GABA) may be expected to trigger a seizure. Tx is targeted on GABAergic and glutamatergic synapse. *remember 2nd neuron may or maynot generate a AP based on net EPSP/IPSP that reaches the cellbody in a noral brain with out any defecieny in GABA)*

Mechanisms of epileptogenesis
Seizures are initiated by a sudden membrane depolarization within a group of neurons caused by abnormalities in Ca2+ conductance *(paroxysmal depolarization shift, PDS)*
PDS then results in opening of VG Na+ channels = generation of high-frequency bursts of APs
These bursts of APs then spread to surrounding neurons, causing synchronization. Normally, this spread of bursting activity and neuronal recruitment is prevented by intact surround inhibition created by GABA neurons. Decreases in GABA-mediated inhibition, because of exogenous factors, degeneration of GABA neurons, or changes at the receptor level, are major factors that aid the synchronization process
Repetitive firing of neurons leads to:
? extracellular K+ ? ? K+ gradient ? ? K+-mediated hyperpolarization ? spreading of seizure activity
Accumulation of Ca2+ in presynaptic terminals ? leads to ? neurotransmitter release (including glutamate)
Depolarization-induced activation of NMDA receptors ? causes more Ca2+ influx and further neuronal activation

Neuronal signal transmission from presynaptic to post synaptic neurons and propagation of AP – first step in the chemical activity in the synapse is synthesis, transport and storage of neurotransmitters in the presynaptic axone. AP propagation changes the membrane potential in the presynaptic axone, causing* Ca channel to enter through voltage gated Ca channel and trigger release of neurotransmitters*. Now neurotransmitters cross the synapse and attach to post synaptic receptors and cause postsynaptic activity. Some are reuptake back to the presynaptic site by transporter and broken down by MAO.

Due the propagation of AP, a brief reversal of charge across the nerve membrane occur. AP causes a All-or-none response *once the membrane potential reach threshold* and can reverse charge from -70 to +40. Phases neuronal AP (cardiac AP is different)
1. Depolarization -*Opening of VG Na+ channels* ? *Na+ ions enter the cell at the threshold.* At this stage K start leaving the cells as well. Once membrane potential reaches +40, Na channel become *refractory (inactivated state. Na channel cannot be activated)*, and no more Na enter then repolarization starts.
2. Repolarization -*Opening of VG K+ channels* ? *K+ ions leave the cell (move from high to low conc to maintain equlibrium)* causing the membrane potential to reach resting level. Then K channel closes, Na channel resets.
3. *Hyperpolarization (mediated by GABA)* when extra K outside diffuses away to reach resting membrane potential. Now Na channel can be opened.
4.* RMP (resting membrane potential, -ve inside axone and +ve outside axone)* – K inside the cell keeping it -ve inside and Na out side of the cell keeping that +ve out side of the cell. in order to maintain this RMP cells push Na out and K in.

gaba glutamate recptors
2 kind of glutamate (excitatory) receptors
1. Ionotropic glutamate receptors -Ligand-gated ion channels composed of 3-4 subtypes, based on the action of selective agonists:1. *NMDA* (N-methyl-D-aspartate). 2. *AMPA *(?-amino-3-hydroxy-5-methylisoxasole-4-propionic acid). 3. *Kainate* (KA) receptors. Ionotropic glutamate receptors are permeable for Na+ only (AMPA) or Na+ and Ca2+ (NMDA receptor) when glutamate binds to receptor ? receptor activation causes channel opening and membrane depolarisation = generation of *EPSPs or excitatory post synaptic potential* by AMPA (neurone at the EPSP can reach threshold and generate its own AP spike). Neuron A sends excitatory projections to surrounding neurons. But neuron A also activates GABA interneurons (C), which then send *inhibitory projections (IPSP)* to surrounding neurons (D) (through opening of *chloride* channel in *ionotropic GABA A* or taking* K out in metabotropic GABA b receptor* as in baclofen. eventhoug K is + ve charge, it will keep inside of the axone -vely charged throgh protins inside the axone. *K goes out or cl come in to the axone to make it hyperpolarise/repolarise*. GABA A receptor is make of 2 alpha, 1 beta and 1 gama subunit. it has a endogenous GABA ligand site, BDZ1 ligand site ( for BNZ, new hypnotic, alcohole, muscle relaxant, anesthetic like propafol and etomidate, flumanazil .BDZ 2 ligand site for barbiturates). The result is that APs generated by neuron A do not activate the surrounding neurons thus prevents *synchronization* of adjacent neurons
2. Metabotropic glutamate receptors- GPCRs (G protein coupled receptors). these produce slow response through 2nd messengers unlike ionotropic receptorsNMDA receptors* (Youtube)*
When glutamate binds to AMPA and KA Rs ? *immediate* receptor activation and cause short duration membrane depolarization by the influx of Na and it conduct EPSP.
However, when glutamate binds to the NMDA R at resting membrane potentials ? no immediate R activation* (the pore is blocked by Mg2+ which prevent the passage of Ca)*. Even though the channel opening is *not immediate,* once its open (high Na inside the postsynaptic region repulse Mg block), it producing* longer lasting* membrane depolarization through influx of Na and Ca. Ca can binds to calmodulin (activates CAM kinase and add PO4 to AMPA) or calcinurin (when there is very low ca, it ativates phosphatase and takes out PO4 from AMPA and reduce AMPA receptors no and cause *long term depression* of AMPA) takes to produce seconday messenger signal effect. activated calmodulin can phosphorylate the AMPA receptor throgh CAM kinase and increase Na conductance or activated calmodulin can increase the number of AMPA receptors by moving from intracellular stores to memebrane (cause* long term potentciation (LTP)* or strengthening of synapse by increasing AMPA).
Requirements for the NMDA R activation and channel opening are ? binding of *glutamate and binding of glycine*, and membrane depolarization (to overcome voltage-dependant Mg2+ blockade). Membrane depolarization is usually provided by activation of surrounding AMPA and KA Rs

Dementia of Alzheimer type (neurodegerative disease, loss of synapse. low Ach and glutamate. in parkinsonism imbalance with high ACH and low dopa). tx of dementia with Cholinesterase inhibitors such as donepezil (Aricept. aripitrazole- abilify anti psychotic), Rivastigmine (Exelon), Galantamine (Razadyne),
N-methyl-D-aspartate (NMDA) receptor blockers such as memantine (nemenda)

(propofol and barbiturates act on 2 different sites of GABA a receptor. PAD guidelines use propofol for agintaion tx. intubation is done when pt cannot breath them self. curarium a neuromuscular blocking agent is used sometimes. coma is done to protect brain cells, if still seizing its refractory seizure and can cause brain damage, so need to give agents that can cause *medically induced coma* (phenobarbital, pentobarbital,
midazolam, propafol).

The types of feeding tubes include those placed through the nose, including nasogastric *(NG tube)*, nasoduodenal, and nasojejunal tubes, and those placed directly into the abdomen, such as a *gastrostomy*, gastrojejunostomy, or jejunostomy feeding tube.

Percutaneous endoscopic gastrostomy *(PEG)* is an endoscopic medical procedure in which a tube is passed into a patient’s stomach through the abdominal wall. providing gastric or post-surgical drainage. commonly to *provide feeding, *making use of the natural digestion process of the gastrointestinal tract in pts (stroke) who are at risk of aspiration pneumonia due to poor control over the swallowing muscles ; *PEG-J tube* goes up to intestine. does not require a general anesthetic (unlike gastrostomy).

ref slide 13 pain 27
plant based narcotics are opium (Heroin), cocca, cannabis.
Opium and alcohol are CNS depressants while, amphetamine and cocca are stimulant, cannabis (less stimulant and some depressant action.If you have a *opiate receptor on the GABA an inhibitory interneuron, opiate block GABA release and no more inhibitory response thus turn on excitation pathway like dopa and serotonin.*

Opioid receptor : a GPCR member (not nuclear receptors like steroids/hormones or tyrosin kinase receptors). The opioid receptors are ~40% identical to somatostatin receptors. Opioids (peptide inhibitory neurotransmitter) act as a ligand.
Peptides neurotransmitters (based on the str) ex: somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptides.

There are two types of neurotransmitter receptors based on the mode of action: ligand-gated receptors or ionotropic receptors and G protein-coupled receptors or metabotropic receptors. Ligand-gated receptors can be excited or inhibited by neurotransmitters glutamate or GABA. Conversely, G protein-coupled receptors are neither excitatory nor inhibitory. Rather, they modulate the actions of excitatory and inhibitory neurotransmitters.
There are two principal signal transduction pathways involving the G protein-coupled receptors: the cAMP signal pathway and the phosphatidylinositol signal pathway. When a ligand binds to the GPCR it causes a conformational change in the GPCR and activate an associated G-protein by exchanging its bound GDP for a GTP. The G-protein’s ? subunit, together with the bound GTP, can then dissociate from the ? and ? subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the ? subunit type
You can also classify neurotransmitter receptor based on the type of neurotransmitter attached to it.

(opioids ligands with receptors and activates opioid receptor in presynapitc nurons which is a Gi protein coupled receptors , it activates k channel and hyperpolizes it (pain AP is inhibited and analgesia). also it closes Ca channel and thus no neurotransmitter release to post synaptic area . thus decrease glutamate, ach, substance P, and serotonin release if opioid nerve synapse with other exicitatory neurones. but if opiod receptor synapse with inhihitory neurone GABA it uninhibit the inhitory action of GABA. opioids can enhance *excitatoty dopamine (reward) but when this reward system is desensitized it cause dependence*

*(low NT* in the synaptic cleft cause *upregulation of receptors * (more receptor more chance of receiving that very low NT) in the postsynaptic receptor. since SSRI increase NT immediately but take 6-8 weeks to *downregulate* those receptor. this is the reason for opiod tolerene). normally chemcical stimuli is stopped when NT are sucked back up to presynatpic neurone or by degration of NT by enzyme. Overstimulation by coccain causes changes in brain by stutting down of receptors to calm stimulaion eventhough u are still getting same amount of coccain is called *tolerence.* once your body gets used external coccain, it dont produce any more NT by its own and cause withdral symptoms when u dont give coccain.

Sedative-hypnotic drug withdrawal: barbiturates, alcohol (GABA a agonist. but cause imbalance with glutamate and get low due to exhauston of GABA when a chronic user stop drinking. reward pathway is through high dopamine in synapse *through opioid receptor* action. alcohol induce endorphine)

Dopamine is a precursor of NE in the periphery. NE (Levaphed), epinephrine (epipen).

antimetabolite
immunosuppressive drugsref slide 19 set CKD13

Types- Main categories of these drugs include:
1. base analogs (altered nucleobases):
a. purine analogues- Mercaptopurine, azathioprine
b. pyrimidine analogues- 5-Fluorouracil (5FU),
Floxuridine, Cytarabine.
2. nucleoside analogues:
nucleosides with altered nucleobases
nucleosides with altered sugar component (e.g. Cytarabine, …)
3. nucleotide analogues- are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B.
4. antifolates- methotrexate and trimethoprimimmunosuppressive drugs can be classified into five groups:
1. glucocorticoids- also Anti-inflammatory effects
2. cytostatics- Alkylating agent (Cyclophosphamide), Antimetabolites
3. antibodies- Polyclonal and Monoclonal antibodies
4. drugs acting on immunophilins- Ciclosporin, Tacrolimus, Sirolimus
5. other drugs-Interferons, Mycophenolate, Opioids, TNF binding proteins, Small biological agents

Plasmapharesis to remove antibody.

Tumor-Associated SIADH
Normal trigger of ADH and water balance:
when we *drink too much water (? water in blood, ? plasma osmolarity), pituitary ? ADH secretion (dilute urine)* to balance fluid. when ? water in blood (? plasma osmolarity), pituitary ? ADH secretion (dilute blood) to balance fluid.how exactly ADH ? /? water: when *ADH is ?, ? aquaporin channels (dilute blood)* is high in distal convoluted tubule and collecting duct. aquaporin channels help to reabsorb water.

in SIADH pituitary is producing too much* ?ADH*, regardless of blood volume. then *? aquaporin channels, ? water in blood (dilute blood)* (? plasma osmolarity but its a dilution effect), then *aldosterone is ?* is secreted to regulate Na (it think that high BP due too much BV), and excrete *Na excrete in urine*. this further *? plasma osmolarity* (now *hyponatremia, low serum osmolarity, oliguria and high BV and edema*).

Most patients with ectopic vasopressin production develop hyponatremia over several weeks or months. The disorder should be corrected gradually unless mental status is altered or there is risk of seizures. Retention of water with hyponatremia and low serum osmolality and inability to form dilute urine in the fully hydrated condition is characteristic of SIADH. *Antagonists of ADH *are needed to treat this condition

Treatment of the underlying malignancy may reduce ectopic vasopressin production, but this response is slow if it occurs at all.
Fluid restriction to less than urine output, plus insensible losses, is often sufficient to correct hyponatremia partially. However, strict monitoring of the amount and types of liquids consumed or administered intravenously is required for fluid restriction to be effective. Salt tablets and saline are not helpful unless volume depletion is also present.

Demeclocycline (150-300 mg orally three to four times daily) can be used to inhibit vasopressin action on the renal distal tubule, but its onset of action is relatively slow (1-2 weeks).

Conivaptan, a nonpeptide V2-receptor antagonist, can be administered either PO (20-120 mg bid) or IV (10-40 mg) and is particularly effective when used in combination with fluid restriction in euvolemic hyponatremia. Tolvaptan (15 mg PO daily) is another vasopressin antagonist. The dose can be increased to 30-60 mg/d based on response.

saline + furosemide= Severe hyponatremia (Na ;115 meq/L) or mental status changes may require treatment with hypertonic (3%) or normal saline infusion together with furosemide to enhance free water clearance. The rate of sodium correction should be slow (0.5-1 meq/L per hour) to prevent rapid fluid shifts and the possible development of central pontine myelinolysis.

desmopressin is a vasopressin analogue for tx of bed wetting.

TREATMENT Humoral Hypercalcemia of Malignancy and CKD

tx of hypocalcemia.

The management of HHM begins with removal of excess calcium in the diet, medications, or IV solutions.

normal saline + furosemide- Saline rehydration (typically 200-500 mL/h) is used to dilute serum calcium and promote calciuresis; exercise caution in patients with cardiac, hepatic, or renal insufficiency. Forced diuresis with furosemide (20-80 mg IV in escalating doses) or other loop diuretics can enhance calcium excretion but provides relatively little value except in life-threatening hypercalcemia. When used, loop diuretics should be administered only after complete rehydration and with careful monitoring of fluid balance. Diuretic therapy of hypercalcemia requires a reduction in calcium reabsorption in the thick ascending limb, an effect of loop diuretics. However, a loop diuretic alone would reduce blood volume around the remaining calcium so that serum calcium would not decrease appropriately. Therefore, saline infusion should accompany the loop diuretic. but thiazide increase blood ca.

Oral phosphorus (e.g., 250 mg Neutra-Phos 3-4 times daily) should be given until serum phosphorus is ;1 mmol/L (;3 mg/dL).

Bisphosphonates such as pamidronate (60-90 mg IV), zoledronate (4-8 mg IV), and etidronate (7.5 mg/kg per day PO for 3-7 consecutive days) can reduce serum calcium within 1-2 days and suppress calcium release for several weeks. Bisphosphonate infusions can be repeated, or oral bisphosphonates can be used for chronic treatment.

Dialysis should be considered in severe hypercalcemia when saline hydration and bisphosphonate treatments are not possible or are too slow in onset.

Previously used agents such as calcitonin and mithramycin have little utility now that bisphosphonates are available. Calcitonin (2-8 U/kg SC every 6-12 h) should be considered when rapid correction of severe hypercalcemia is needed. it moves ca to bone

Hypercalcemia associated with lymphomas, multiple myeloma, or leukemia may respond to glucocorticoid treatment (e.g., prednisone 40-100 mg PO in four divided doses).

in hyperparathyroidism, increased blood calcium tx with sensispar. cause decrease calcium in blood and decrease PTH.

vitamin D increases calcium in the blood.

renal calculi/ nephrolithiasis or kidney stone -The formation of crystal aggregates in the urinary tract results in kidney stones, the clinical condition referred to as nephrolithiasis. due to mineral and *acid deposition in urine not in blood*. symptoms -flank pain, gross or microscopic hematuria, obstruction of one or both kidneys, and urinary infections. The stones are usually formed by one of substances of minerals and acids: calcium oxalate/phosphate, magnesium ammonium phosphates (or struvite), cystine and uric acid. xanthine and triamterene stones, which are seen in patients taking xanthine oxidase inhibitors and triamterene-containing diuretics, respectively. Other risk factors for calcium stones include chronic low urine output, hyperuricosuria, and low urine citrate, which occurs most often in patients with inflammatory bowel disease, *chronic metabolic acidosis (excretion of bicarbonte), and renal tubular acidosis (RTA)*. crystalisation of minerals happen .* (in gout urica acid in body/ blood not in urine* due to xanthine (purine convert to xantine convert to uric acid), dehydration and crystalisation. pain tx colchicine, NSAID, steroids. chronic tx with in over producers – xanthine oxidase inhibitor (ppt goute attack) allopurinol,febuxostat (Uloric) and under exretors- uricossuric agent (ppt kidney stone), probencid, sulfinpyrazole )

when urine is supersaturated with these minerals due to lack of inhibitors like citrate, Mg, pyrophospahte as in metabolic disturbance* (acidosis*, dehydration, uricoseurea (too much protein), high Na (cause excrection of Ca, and reduce citrate), drugs (*acetazolamide, topiramate, zonisamide,* phosphate binder, Ca suppliment, uricosruine agent, Vit C)

treatment – high fluid intake, dietary *sodium restriction (not Ca restriction* unless hypercalcemic hypercalciuric stone, due to the potential for negative calcium balance and because a low-calcium diet increases the gastrointestinal absorption of oxalate and increased oxaluria and supersaturation ), and *thiazide diuretics (not loop diuretics)* reduce urinary calcium excretion by inducing extracellular volume depletion, which in turn causes increased renal sodium and K and *calcium reabsorption (hypercalcemia),* and by directly increasing distal calcium reabsorption. Correcting the metabolic acidosis in RTA and inflammatory bowel disease increases the urinary citrate excretion, an inhibitor of crystallization, and lessens the urinary calcium excretion.

diuretics

manitol – An osmotic agent is needed to remove water from the cells of the edematous brain and reduce intracranial pressure rapidly. Mannitol causes a small increase in both sodium and potassium excretion and no change in body pH.

acetazolamide- is acid used for tx of metabolic alkalosis. cause hyperchlormic metabolic acidosis in overdose. Carbonic anhydrase inhibitors are useful in the prevention of altitude sickness. potassium sparing diuretic also cause acidosis.
loop and thiazide cause metabolic alkalosis.
Furosemide causes a marked increase in sodium and a moderate increase in potassium excretion. Thiazides cause alkalosis and a greater increase in sodium than potassium excretion.Structue has sulfonamides

MOA- Carbonic anhydrase is an enzyme found in red blood cells that catalyses conversion of carbonic acid to water and co2. Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid and reduce ph to acidic. so help with alkalosis tx. hence lowering blood pH, by means of the following reaction that carbonic acid undergoes: carbonic acid convert to bicarbonate and water. In the eye this results in a reduction in aqueous humour.

MOA of diuresis involves the proximal tubule of the kidney. The enzyme carbonic anhydrase is found here, allowing the reabsorption of bicarbonate, sodium, and chloride. By inhibiting this enzyme, these ions are excreted, along with excess water, lowering blood pressure, intracranial pressure, and intraocular pressure. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation, increasing levels of oxygen and decreasing levels of carbon dioxide in the blood.

Water+ *CO2 (acid or end product of kerbcycle*, body get rid of CO2 by respiration) in equilibrium with carbonic acid in equilibrium with H+ (too much proton in acid, HA) + *bicarbonate* (A- or Base B, buffer from kidney, to make equlibrium in blood, body get rid of bicarbonate through kideny). conc of HCO3 and CO2 affect PH of blood. in the kidney bicarbonate convert to carbonic acid then carbonic unhydrase (CA) enzyme convert carbonic acid to CO2 and water. CO2 absorbed back and excreted by lung (quick). if no CA enzyme in kidney, can in cause acidosis. ( high carbonic acid acid formed is converted back to bicarbonate and which can attached with Na. sod. bicarbonate is excreted in the urine, water goes along with Na (remember Na can be abosorbed in to the blood later in LOH, so not a good diuretic). when too much base is lost in urine, then cause acidosis (blood).

Most loop diuretics (and carbonic unhydrase inhibitors) are sulfonamide derivatives; the exceptions are ethacrynic acid, which is a phenoxyacetic acid derivative, and torsemide, which is a sulfonylurea. Due to the lack of a sulfur atom, ethacrynic acid causes fewer hypersensitivity reactions.
Mechanism of Action-The molecular target of furosemide and other loop or high-ceiling diuretics is the sodium-potassium-2 chloride cotransporter (NKCC2), which transports 1 Na+, 1 K+, and 2 Cl?. The activity of this transporter is blocked by loop diuretics.

pregnany and blood pressure

Methyldopa is often recommended in pregnant patients because it has a good safety record. Calcium channel blockers (nefidipine) and ? blockers (atenolol and propranolol) are not contraindicated.

In contrast, ACE inhibitors and ARBs (choice B) have been shown to be teratogenic.

reflex tachycardia- Other direct vasodilators (choice D) regularly increase heart rate, and minoxidil, a very efficacious vasodilator, causes severe tachycardia that must be controlled with ? blockers. also DHP

orthostatic hypotension or postural hypotension by alpha blockers like prazosin

1st dose hypotension by ACEI

cloidine- low HR since it decrease central sympathetic release an increase vegal tone. centrally acting alpha 2 agonist

Hydralazine (choice B) is sometimes used in heart failure. Beta blockers (choice C) are not associated with hematologic abnormalities, but methyldopa is. The thiazide diuretics (choice E) often cause mild hyperglycemia, hyperuricemia, and hyperlipidemia but not lupus; hydralazine is associated with a lupus-like syndrome. Aliskiren (choice D) and other inhibitors of the renin-angiotensin-aldosterone system may cause hyperkalemia, not hypokalemia. Verapamil (choice A) often causes constipation, probably by blocking L-type calcium channels in the colon.

The thiazides (cause hypercalcemia) are useful in the prevention of calcium stones because these drugs reduce tubular calcium concentration, probably by increasing passive proximal tubular and distal convoluted tubule reabsorption of calcium. In contrast, the loop agents facilitate calcium excretion. Diazoxide is a thiazide-like vasodilator molecule but has no diuretic action; in fact, it may cause sodium retention. It is used in hypertension and insulinoma.

Loop diuretics (cause hypocalcemia) increase urinary calcium excretion and decrease blood pressure (in hypertension) and pulmonary vascular pressure (in congestive heart failure). They have no recognized teratogenic action. They cause metabolic alkalosis (Table 15-1). Loop diuretics also cause ototoxicity.

reasons for fall and mental status changes
reasons for fall, low Bp , heart block, seizure. low bp due to disease or BP rx like alpha blocker ex. prazocin. over diuresis.
vasodilators like hydralazine, nitropusside, CCB cause reflex tachycardia so used along with BB.reasons for mental status changes- encephalopahy (alcohol, liver disease, ketone issues), SIADH ( high ADH, high blood volume and low Na), metabolic acidosis/ alkalosis

(Free Fatty acids oxidised to ketone to get energy. In DM lack of insulin, so no energy from sugar so make ketones from Fat. alcohol cause dehydration and blocks the first step of gluconeogenesis by depleting oxaloacetate. lactic acidosis is due to anerobic metabolism)

Lactatic acid metabolism
Glucose to pyrovate to acetyl coA or lactate/lactic acid (absense of O2 or presense of LDH). If severe lactate not transported back to liver and lactic acidosis. Happens in liver dx.
Lactate/lactic acid to pyruvate in the liver with oxygen.
S lactate is a biproduct of anaerobic metabolism of glucose and is produced in all metabolically active cells and circulates in the blood not stored excreted by kidney. *Tissue hypoxia (CHF, sepsis, severe exersise) *make it elevate in min to hrs and and normalise in days or with administration of oxygen.
High LDH conc occures in liver, sk muscles and heart., RBC and kidney. Not stored and excreted via kidney.* High LDH conc result in inflamation, MI *(initial elevation in 12 hrs, peak 2-3 day and normalise in 1-2 weeks), liver disease , hemolysis

PCOS- polycystic ovarian disease.

PCOS- normal FSH but too much LH is released from pitutory gland, too much immature ovum or follicule produced in overy and *no ovulation* to follopian tube due *no mature ovum. LH and high insulin* makes lots of androgen by the follicular memebrne and is *not converted to estrogen.* so acini, hair growth etc (overies has egges, fetilisation happens in follopen tube, utrus, vagina)

SJS/ TENS toxic epidermal necrotic syndroms – any epilepticaus rx adr. Carbamazepine has a black box warning in certain allele asians. testing needed. skin makes blisters and burns from inside out. stop rx immediateley.
(general rule for any drug- reduce dose 50% 1st week, then 25% next 2 week then stop). If stoping permenanantly go by D/C over 6 months like any antisiezure rx

IV antiseizure tx – keppra (levitiracetam. *Levitra* is vardenafil), vimpat, phenytoin, forsphenytoin, ethosuximide *(Zarontin)*, VPA, phenobarbitol and diazepam, clonazepam, midazolam
antiseizure in stroke/intracranial hemorrage- phenytoin and keppra
*zaroxolyn* is metolazone (thiazide like diuretic),
metaxalone is skelaxin (musle relaxant)
sulfonamide is zonismamide and also a carbonic unhydrase inhibitor
acetazolamide like carbonic unhydrase inhibitor is topamax or dopamax
Cerebyx (fosphenytoin), *celebrex * is celecoxib
primidone is mysolin
depakote is DR divalproex Bid
Depakot ER is divalproex ER QD

Ethosuximide Serum conc: 40-100 mcg/ml
VPA s. conc 50-125 for bipolar and sezure. not for migrain
Phenytoin s. Conc -10-20
carbamazepine – 4-12 for seizure not for trigerminal neuralgia
barbirutate-15-45
lamical Serum conc: 4-20 mcg/ml ( for sizure only. No conc. Required for bipolar)- tab
Keppra (IV) Serum conc: not necessary (10-40 mcg/ml)
Serum conc: not necessary for vimpat IV

rufinamide -Cardiac Arrhythmia, QT interval* shortening*, Contraindicated in familial short QT syndrome, Make sure *ECG on chart (like dofetilide (tykosyn) long QT )*.

*antidepresants are not good drugs due to CNS depression/ suicidal idealation and reduced ability to conc and memeory, TDM, FDA warning, but some can be used for bipolar. but best drug is gabapentin and keppra (IV) due low DI*
bipolar rx- CBZ ,VPA ,lamotrigine
CBZ (trigermianl neuralgia, secondline phentoin),
phenytoin (arrhythmia), prevention of migrain (VPA), barbiturate (sedative hypnotic), primidone (tremor), Topiramate- weight loss, VPA wt. gain, Gabapentin (postherpetic neuralgia, RLS, alcohol withdrawal), lyrica (Diabetic peripheral neuropathy pain, Postherpetic neuralgia, Fibromyalgia),

Topiramate cause oligohydrosis and hyperthermia. along with kidney stone and acidocis. hyperhydroisis is caused by desvenlafaxin (pristique)

(cardiotoxic propylene glycol solvent as in phenytoin a class 1b antiarrhythmic agent like lidocaine and also a antiseizure drug. adjust the rate of IV to prevent toxicity) ethanol or MUDPILE cause acidosis. TCA cause arrhythmia. caution with antiarrthymic class Ia. TCA cause hypotension, sedation due to alpha block and histamine block unlike coccain.
Treatment – Cardiac toxicity in TCA and coccain
IV NaHCO3 to uncouple the TCA from cardiac Na+ channels ? may improve cardiac arrhythmias and hypotension (arrythmia due K toxicity give CaCl, NaHCO3 to tx acidosis).
Lidocaine (class 1b) and phenytoin (not in cacain overdose) can be used for cardiac arrhythmias in TCA. but type IA arrhythmic agents are contraindicated. (quinidine, procainamide and disopyramide)

morphine which blocks sympathetic efferent (NE) from CNS and thus decrease vasoconstriction (also through Histamine release which also cause itching), decrease oxygen demand and symptomatic improvement in MI. action similar to clonidine. reduce BP, but no effect on HR (but methadone prolonged QT). it cause CNS and respiratory depression, sedation and hypotension.
withdrawal symptom of heroin- Insomnia:* trazodone* 100mg Qhs *(No BDZ if addiction problem*. antidepressants are not addictive but cause withdrawal symptoms)
Anxiety GAD withdral heroin symptom: *hydroxyzine* 25-50mg Q6 hr prn

Norepinephrine and iv fluids for hypotension in TCA toxicity (TCA alpha blocker).
For hypertension coccain toxicity (alpha agonist, vasoconstictor) ? *alpha blocker*- phentolamine
chest pain coccain toxicity ? benzodiazepines, nitroglycerin (vasodilator)
For tachycardia (if needed) coccain toxicity ? metoprolol . *PROPRANOLOL should NEVER be given ALONE *because it is non selective and beta 2 block could *increase Bp* so high (when NE, increase alpha agonism and the vasoconstriction and *beta 2 stimulation can cause some vasodilation*)

phenytoin can be used for seizure in TCA toxicity.
For seizures due to coaccin overdose ? BDZ (phenytoin Na blocker are antisezure rx. caccain block Na as well. but seizure is due to CNS stimulation).
Treatment of alcohol Withdrawal Seizures -Do NOT typically require anti-convulsant EXCEPTION: progression to status epilepticus. But *phenytoin is not used* since no cross reactivity with alcohol or GABA. Use BDZ (even if pt has substance abuse issue. admit pt in a hospital setting. Anti-convulsants Topiramate good for tx craving of alcoholism if pt has DT during withdrawal. act by blocking Na and increasing GABA and reducing glutamate).

alcohol is cardiotoxic. Local anesthetic effects of cocaine – through the blockade of voltage gated Na+ channels which results in local nerve block. it can also block Na in heart and cause cardiotoxicity in overdose. cause hypertension due to alpha 1 agonism/ vasoconstriction due to high NE.

agitation/ delirium caused by hallucinogen LSD tx with *Diazepam effective* (not normally used in people with substance abuse issues, not used if cocaine anxiety/ delirium/*psychosis.* In PAD guidelines opioids and BDZ cause delerium); *antipsychotic agents (ex haloperidol. 5 HT2 antagonist AAP) are not.

cardiotxic drugs (prolong QRS and QT intervals and cause conduction block) cocaine, methamphetamine, TCA, BB (reduce HR), CCB and digoxin. TCA cardio toxic by QT prologation.
ethanol (affect myocardial contracton, CHF) is a *cardiotoxic* like doxorubicin, cyclophosphamide, amphetamine (Na blocker in anesthetic, dopamine transporter blocker).

confedence intertervel and p value (probability of ocuurence) 5% chance that we regected the null hypothesis when shouldnt have.

somnolesence- drowsiness

ADRENAL MEDULLA
1. epinephrine;
2. norepinephrine.

ADRENAL CORTEX
1.mineralocorticoid (aldosterone) -regulates water and electrolyte levels inthe blood (regulates blood pressure);
2. glucocorticoid (cortisol) -regulates glucose metabolism;
3. sex hormones ( androgen) that supplement those of the ovary and testis.

Pheochromocytoma, by producing too much adrenaline. Primary hyperaldosteronism, by creating excess levels of aldosterone. Cushing’s syndrome, body levels of cortisol is high.
Addison’s Disease develops when the adrenal glands do not make enough cortisol. the body also fails to make enough of the hormone aldosterone. Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus which can suppress production of ACTH and lead to adrenal deficiency

GAD, PD. OCD, PTSD

SSRI/antidepressants need higher target dose than antidepressant action when used for OCD. try at least 2 or 3 SSRI/ 1stline (never combine) before switching to 2nd line (no combination). if it fails can add alternate therapy.

Ist line rx SSRI
2nd line TCA (not all due to suicidal problem and anticholinergic issue)
3rd line MAOI or AAP
BDZ add in acute phase in GAD and PD only

GAD- after diagnosis, CBT or 1st line rx x 4weeks +/- BDZ x 2-4 weeks. Acute phase – Minimum: *4 weeks, Up to: 12 weeks*. Adequate trial – 12 weeks (weekly titration) on the maxium dose. Start low, go slow. MUST start with higher dose than PD starting doses But end dose lower than PD end dose
1. If no response- switch agent by titration.
2. If partial response after adequate trial, add another agent
3. If full response, move into maintenance phase Minimum: 1 year. then titrate down to d/c (antidepressants every other day to d/c. std method 50% reduction 1st week, 25% reduction in next 2 weeks, seizure rx over 6 months)

PD *(only antidepresnt in tx)*- CBT and / or ? 1st line rx x 6-8 wks+/- BDZ x 2-4 wks. acute phase 6-8 (up to 12wks). MUST start lower dose or with ¼ to ½ of AD usual starting doses due to heightened anxiety. But end/target dose is higher than GAD
1. If no response- switch agent by titration. agents include only antidepresent unlike GAD
2. If partial response after adequate trial, add another agent
3. If full response, move into maintenance phase Minimum: 1-2 year. then titrate down to d/c.

. OCD- after diagnosis, CBT (min 13 session upto 20 session) +/- 1st line rx x 6-8weeks. Acute phase – Minimum: 4-6 weeks Up to: 12 weeks*. titrate weekly (for quick dose titration) x 4 weeks then every other week
1. If no response- switch agent by tapering and titration. try at least 2 or 3 SSRI/ 1stline (never combine) before switching to 2nd line (no combination). if it fails can add alternate therapy.
2. If partial response after adequate trial, add another agent
3. If full response, move into maintenance phase Minimum: 1 year Taper dose by 25% every 1-2 months to d/c other wise *relapse*.
*response*- minimum 25% reduction in Y-BOCS score after adequate trial/dose for adequate period.
*Remission* = Y-BOCS score of 8 or less.

(suboxone- A mu receptor partial-agonist and an antagonist at kappa receptor. High *affinity* for the mu receptor but low *efficacy* and *efficiency*)

PTSD- after diagnosis, CBT (12) *with* 1st line rx x Up to: 12 weeks*. titrate weekly (for quick dose titration) x 4 weeks then every other week
1. If no response- switch agent by tapering and titration. try at least 2 or 3 SSRI/ 1stline (never combine) before switching to 2nd line (no combination). if it fails can add alternate therapy.
2. If partial response (25-50% reduction in symptoms) after adequate trial, add another agent
3. If full response, move into maintenance phase Minimum: 1 year Taper dose by 25% every 1-2 months to d/c other wise relapse.
response- minimum 50% reduction in score after adequate trial/dose for adequate period.
Remission = 70% reduction in symptoms for 3 continuous months

1st line agent
GAD- SSRIs, SNRIs
PD- SSRIs, SNRIs (venlafaxine *XR*)
OCD- SSRIs (sertraline, paroxetine, fluoxetine, Fluvoxamine are FDA approved). but all can be used
PTSD- SSRIs (sertraline, paroxetine, fluoxetine are FDA approved). but all can be used, SNRIs (venlafaxine XR – non FDA approved)

2nd line agents
GAD- TCA (imipramine), BDZ, *Buspirone*, pregabline
PD- TCAs (imipramine, clomipramine), BDZ
OCD- TCA’s – Clomipramine
PTSD- TCAs (Imipramine and amitriptyline), Mirtazapine (Remeron)
Adrenergic inhibitors- Prazosin, Clonidine
Anticonvulsants (as adjunctive) – Carbamazepine, valproic acid, lamotrigine, *topiramate.*
Atypical antipsychotics (add-on therapy) – Olanzapine, quetiapine, risperidone

alternate/ 3rd line agnts
GAD- hydroxazine, *quitapine*
PD- MAOIs (phenalazine)
OCD- Venlafaxine XR (Non FDA-approved SNRI)
Antipsychotics- Haloperidol (Haldol), Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel)
PTSD- MAOI, Phenelzine

QUESTIONS TO FIND ANSWERS
IV antidepresents?
vedeo of STAR D optimisation, cytokinins, estogen hormone premenustral, post partrum , IBS, ECT
K toxicity, TCA toxicity, phenytoin toxicity
ex of enzyme inducers and inhibitors
compaire Priapism, a painful erection that does not go away and erectyl dysfunction.
(Wellbutrin, Zyban. amphetamine metabolite) *(IR*- 225-450 mg/day), *(SR ), (XL*-150-400 mg/day). like depakote?
ketamine and felbamate moa
d1 and d2 receptor
relation between smoothe muscle relaxant, skeletal muscle relaxant and genereal antestetic or medically induced comaefficacy and effectivenss (naloxone, naltrexone, buprenorphin), respone and relapse and remsission. (full, partial and no response)

1-1In regard to lipids, the term unsaturated refers to A) the ring structure of steroids. B) the lack of double bonds between adjacent carbon atoms in a fatty acid. C) glycerol, which acts as an anchor for joined fatty acids. …

A 30-year-old female presents with a five day history of a sore throat. She denies cough or nasal congestion. She also denies vomiting or diarrhea. On physical exam, her temperature is 101˚F, the pharynx is red with tonsillar exudates, and …

Which is considered a normal physiologic change during pregnancy? a. ECG T-wave changes b. Increased cardiac output c. Increased bleeding time d. Decreased renal perfusion increased cardiac output Which of the following exercises should be taught to a pregnant woman …

Pneumo 1 A 28-year-old man is evaluated for a 6-month history of episodic dyspnea, cough, and wheezing. As a child, he had asthma and allergies, but he has been asymptomatic since his early teenage years. His recent symptoms started after …

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