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What are the different categories of HTN?

1. Normal (SBP/DBP, below 120/below 80)
2. Prehypertension (SBP/DBP, 120-139/80-89)
3. Stage 1 HTN (SBP/DBP, 140-159/90-99) [often controlled with a single drug]
4. Stage 2 HTN (SBP/DBP, over 160/over 100) [often requires multiple drugs]


What are the compensatory reflexes to HTN treatment?

HTN → treatment → decreased BP →

(1) increased sympathetic outflow → tachycardia → increased blood pressure

(2)increased renin release → salt and retention → increased blood pressure


ACE inhibitors?

Lisinopril, Captopril, Enalapril

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II. Therefore the vasoconstriction from angiotensin II cannot be performed (esp effect of effect renal artery causing decreased peritubular hydrostatic pressure and increased sodium and water reabsorption) as well as release of aldosterone.

ACE inhibitors are used for pts wtih HTN (esp diabetic/non-diabetics who need renal function preserved), chronic HF, and post MI.

Bradykinin (vasodilator) is usually broken down by ACE and when it is inhibited there is an increase in bradykinin levels leading to even more vasodilation (causing angioedema) as well as a dry cough.

Other side effects include: hypotension, hyperkalemia, acute renal failure in pts with bilateral renal artery stenosis

**do not use in patients who are pregnant as it may cause fetal hypotension, anuria or renal failure or patients with bilateral renal artery stenosis


ARB blockers?

Losartan ("-artan")

ARBs block the type 1 receptors of angiotensin-2 causing a decreased sodium and water retention but increased arteriolar and venous dilation. These drugs are alternatives to patients who cannot handle the bradykinin induced cough with ACE inhibitors. [These pts have increased angiotensin II levels as their receptors are being blocked.]

Decreased risk of angioedema due to break down of bradykinin and there is a lack of a dry cough.

other side effects include hypotension, hyperkalemia, acute renal failure

**do not use in pts who are pregnant or have bilateral renal artery stenosis



Aliskiren is an renin inhibitor used to treat HTN preventing the conversion of angiotensinogen to angiotensin I. The end result is a decreased in aldosterone production therefore decreased absorption of sodium and water.

Side effects include: hyperkalemia, hypotension, low risk of angioedema, acute renal failure, and altered taste (same as ACEIs and ARBs)


What Ca2+ chanbel blockers can be used to treat HTN?

Block L-type calcium channels allowing for relaxation of myofibril and vascular SM. Used to control HTN in black or elderly opts, or pts with diabetes or asthma.

1. Verapamil [non-dihydropyridine] - side effects include constipation and negative inotropic effects so don't take if pt is on B-blocker, has 2nd or 3rd deg block or LV failure
2. Diltiazem [non-dihydropyrdine]
3. Nifedipine [dihydropyrdine] (1st generation)
4. Amlodipine [dihydropyrdine] (2nd generation)

Non-dihydropyridine - not selective, binds vSM as well as cardiac muscle therefore can treat HTN as well as arrhythmias

Dihydropyridine - selective for vSM -- high doses can increase risk of MI because it causes massive reflex cardiac stimulation post hypotension - can cause gingival hyperplasia


What B-blockers can be used to treat HTN?

1. Propranolol → non-selective B1 and B2 receptor antagonist
2. Metoprolol and Atenolol [most common] → selective B1 receptor antagonists
3. Pindolol → non-selective B1 and B2 partial agonist with intrinsic sympathomimetic activity [preferred B-blocker in pregnancy]

B-blockers decrease renin release as well as CO, HR and contractility - there may be sympathetic reflex with exercise

Adverse effects include:
1. bradycardia
2. CNS effects – fatigue, lethargy, insomnia, hallucinations
3. Hypotension
4. Decreased libido and impotence
5. Disturbed lipid metabolism → increased TAGs and decreased HDL
6. Hypoglycemia (B2 blockers)
7. Drug withdrawal → therefore there is a need to taper off dose in pts
8. Propranolol is contraindicated in asthmatics and COPD pts


a1 blocker tx of HTN?

Prazosin and Doxazosin are competitive a1-adrenoceptor blockers. They decrease peripheral vascular resistance and arterial BP by relaxing BOTH arterial and venous smooth muscle. Unlike thiazides and furosemides, there is sodium and water retention to decrease bp and decreased perfusion to kidneys so with chronic use Na+ and water retention needs to be managed. These drugs have more side effects than other antihypertensives, therefore are no recommended as first line treatments.
Because of a1 selective effect, the NE in the synapse is able to create a negative feedback mechanism on the a2 receptors thereby decreasing amt of NE released - this can help decrease the risk of reflex tachycardia.


Adverse effects
1. orthostatic hypotension upon first dose or large increases in dose
2. concomitant use of B-blockers may be necessary to blunt reflex tachycardia
3. dizziness, drowsiness, headache, lack of energy, nausea, palpitations
4. Doxazosin is shown to increase rate of congestive HF on its own
5. Na+ and water retention - with chronic administration therefore you should administer with diuretic to minimize potential for edema


What is Labetalol? (HTN)

This is a mixed a- and B-blocker that can be administered orally and parenterally. It is used in the management of HTN (even with pregnant women). It is generally given IV for a RAPID REDUCTION in BP during HYPERTENSIVE EMERGENCIES. An advantage of Labetalol is that there is a decrease in BP associated with a1-blockade WITHOUT the reflex tachycardia.

-orthostatic Hypotension may be seen upon 1st use


Clonidine and methyldopa (HTN)

central a2-agonist used in emergencies. They decrease sympathetic output and BP but not renal blood flow or CO. Clonidine may cause reflex tachycardia upon withdrawal.

Methyldopa associated with positive Coombs test and depression.


Which drugs are direct vasodilators?

Hydralazine and Minoxidil – these are NOT used as first-line anti-hypertensives. They act directly on vascular SM as relaxants. The vascular relaxation produces reflex tachycardia and increases plasma renin causing sodium and water retention. Major side effects can be prevented if combined with diuretic and B-blockers.

Hydralazine AE:
1. fluid retention
2. reflex tachycardia
3. reversible lupus-like syndrome
4. headache, nausea, sweating, flushing
5. usually administered with B-blocker and thiazide

Minoxidil AE:
1. reflex tachycardia
2. fluid retention
3. Hypertrichosis → causes excessive hair growth


What are the treatments for pulmonary HTN?

1. prostaglandins [epoprostenol] - Synthetic PGI2 that lower peripheral pulmonary and coronary resistance via a vasodilatory effect. It is given via continuous infusion. Adverse effects include flushing, headache, jaw pain, diarrhea and arthralgias.

2. inhibitors of endothelin synthesis and action [bosentan] - Nonselective endothelin receptor blocker that blocks both the initial transient depressor (ETA) and the prolonged pressor (ETB) responses to endothelin. This medication falls into pregnancy category X [aka DO NOT USE!].

3. vasodilators [Sildenafil] - Inhibitor of phosphodiesterase 5 (PDE5). It increase the amt of cGMP leading to smooth muscle relaxation. Adverse effects include headache, flushing, dyspepsia and cyanopsia (BLUE VISION). Contraindications include individuals on nitrates b/c they also give an increase in cGMP leading to a possible hypotensive crisis.


Discuss what occurs at the proximal tubule, thick ascending limb, distal convoluted tubule and collecting duct.

Proximal tubule → reabsorbs 65% filtered Na, 85% NAHCO3, 65% K+, 60% water, all glucose and AA. The most important ions in regards to diuretic actions are NaHCO3 (sodium bicarb) and NaCl (sodium choride). The Na+-H+ antiporter movement from lumen then into blood via Na+-K+ transporter is the main driving force for water reabsorption. HCO3- wants to be reabsorbed as well but has poor permeability so via the carbonic anhydrase enzyme it is converted to H2CO3 → OH- + CO2. CO2 quickly diffuses into cell and OH- turns to water with the addition of a proton. CO2 in the cell quickly turns back to H2CO3 then intracellular carbonic anhydrase dissociates it to H+ (for the antiporter) and HCO3-.

Thick ascending
The thick ascending loop of henle receives hypertonic filtrate and allows for reabsorption of NaCl without water. Na+ is reabsorbed via Na+/K+/2Cl- cotransporter (NKCC2). Cl- exits basolateral side of cell, Na+ exits via Na+/K+ ATPase on basolateral side and K+ is recycled back to the lumen for the NKCC2 function. There is also additional reabsorption of Na+, Ca2+ and Mg2+ from lumen to the interstitium driven by K+ recycling.

Distal convoluted
Distal convoluted tubule activity reabsorbs4-8% of filtered NaCl. Na+ enters via Na+/Cl- cotransporter (NCCT) and Na+ exits on basolateral side via Na+/K+ ATPase. Ca2+ is reabsorbed via Na+/Ca2+ exhcnagers.

Collecting duct
The collecting duct is the final site of NaCl reabsorption and this determines the final Na+ concentration in the urine. Luminal Na+ enters cell via ENaC and exits basolateral side via Na+/K+ ATPase. K+ is secreted into the lumen. ENaC and K+ movement is under the control of aldosterone. Collecting duct also expresses vasopressin (ADH) channels that controls the permeability of the collecting tubule to water. (without ADH the urine is dilute)


Loop diuretics

Furosemide - blocks NKCC transport preventing K+ recycling leading to hypocalcemia (increasing kidney stones), hypomagnesemia, hypokalemia (due to increased na+ reabsorption in CD), hyperuricemia, increased COX-2 production. May result in gout and ototoxicity.
All together by decreasing sodium and water reabsorption there is a decrease in renal vascular resistance and an increase in renal blood flow.


Thiazide diuretics

hydrochlorothiazide, chlorothalidone, metalazone - block NCCT transporter, increases Ca2+ reabsorption decreases calcium stone risk.
AE: hyponatremia and hyperGLUC, hypokalemia (increased absorption in CD)


K+ sparing diuretics

Spirnolactone, eplernone - blocks aldosterone receptors [aldosterone dependent]

Spirnolactone AE - galactorrhea (progesterone and androgen receptors activated), hyperkalemia, peptic ulcers, hyperchoremic metabolic acidosis

Amiloride, Triamterene - ENaC blockers, not dependent on aldosterone
AE - hyperkalemia, hyponatremia, Triamterene (photosensitivity, interstitial nephritis, renal stones, reduced glucose tolerance)


carbonic anhydrase inhibitors?

Carbonic anhydrase inhibitors [ACETAZOLAMIDE] inhibit intracellular and extracellular forms of carbonic anhydrase resulting in a reduction of bicarb reabsorption in the proximal convoluted tubules and decrease production of H+ inside the cell therefore decreasing Na+/H+ antiporter activity. This decreases Na+ reabsorption. This drug only has a mild diuretic action b/t bicarb depletion enhances NaCl reabsorption by remainder of nephron.

Used to treat...
1. Glaucoma → decreases formation of aqueous humor and thereby decrease intraocular pressure, pre-op management of angle-closure glaucoma and tx for open-angle glaucoma
2. Mountain sickness → excrete bicarb, acidify blood, increase ventilation, increase amt of O2 in blood
3. Metabolic alkalosis → increased H+ in blood
4. Epilepsy
*medication is given orally and is excreted unchanged in proximal renal tubule – therefore, dose must be reduced if there is renal insufficiency

1. metabolic acidosis → reduction in bicarb stores
2. hyponatremia
3. hypokalemia
4. renal stones (Crystalluria) → phosphaturia and hypercalciuria during bicarbonaturic response
5. malaise, fatigue, depression, drowsiness, paresthesias (with large doses)
6. hypersensitivity allergic reactions



Osmotic diuretics - increase osmotic pressure of the plasma thus draws water out of the body tissue and produces osmotic diuresis. Osmotic diuresis expands the extracellular fluid volume, decreases blood viscosity and inhibits renin release. There is an increased urine excretion of nearly all ions/electrolytes: Na+, K+, Ca2+, Mg2+, Cl-, bicarb, phosphate. There is no effect on sodium excretion directly only that it increases urine volume. Administered via IV b/c low oral bioavailability

Used for..
1. reduction of increased intracranial pressure associated with cerebral edema
2. reduction of increased intraocular pressure
3. promotion of urinary excretion of toxic substances
4. genitourinary irrigant in transurethral prostatic resection
5. other transurethral surgical procedures

1. extracellular volume expansion and hyponatremia
2. tissue dehydration

Contraindicated for
Active cranial bleeding, CHF, pulmonary edema



ADH antagonist - activates and inhibits CYPT3A4, administered via IV in people with hypervolemia hyponatremia, SIADH, and heart failure

1. nephrogenic diabetes insipidus
2. infusion site reactions
3. atrial fibrillation, GI and electrolyte disturbances

Contraindicated for patients
1. kidney failure
2. hypovolemia hyponatremia


What drugs are used in hypertensive crisis?

1. sodium nitroprusside - may cause cyanide toxicity that is fixed with sodium thiosulfate -- best drug b/c it releases NO from its structure
2. Labetalol - a,b antagonists therefore doesn't cause reflex tachy - do not use with pts with asthma or cardiac conditions (2nd or 3rd deg block)
3. Fenoldopam - D1 agonist that causes arteriolar dilation but maintains kidney perfusion, promotes naturesis, contraindicated for pts with renal insufficiency and glaucoma

4. Nicardipine (Ca2+ blocker)
5. nitroglycerin (venodilator)
6. Diazoside (stablizes membrane by allowing K+ channel to remain open, also decreases insulin release so can be used to treat hypoglycemia)
7. Phentolamine - catecholamine emergency
8. Esmolol - aortic dissection or post op Hypertension
9. Hydralazine - arterial dilator


What are the different classifications of heart failure described by the AHA? What treatments should be used at each stage?

Stage A → high risk for developing heart failure (HTN, diabetes, CAD, hx of cardiomyopathy)
Stage B → asymptomatic heart failure (previous MI, LV dysfunction, valvular disease)
Stage C → symptomatic heart failure (structural heart disease, dyspnea, fatigue, impaired exercise tolerance)
Stage D → refractory end-stage heart failure (marked symptoms at rest despite maximal medical therapy)

Stage A → ACEI, ARB
Stage B → ACEI, ARB, B-blockers
Stage C → diuretics, ACEI, B-blocker [routine drugs], aldosterone antag, ARB, digoxin or hydralazine/isosorbide dintrate [if symptoms do not improve]
Stage D → specialized therapies, continuous support, continuous IV positive inotropic therapy, cardiac transplantation or hospice care


What are the neurohumoral compensatory responses to HF?

1. Sympathetic nervous system activation – low bp is detected by the baroreceptors leading to B1-activation increasing both HR and contractility. A1 receptors are also activated causing increased peripheral resistance.
2. RAA activation – decreased CO, decreased blood flow to kidneys stimulating renin release therefore increasing peripheral bp
3. Increased release of ADH and ANP


What is the basis behind long term treatment of HF?

1. RAA inhibition
2. SNS activation
*These decrease amt of cardiac remodeling. Remodeling is irreversible so surgical intervention is the only tx when drugs stop working.
**reduce preload, reduce afterload, enhance inotropic state


ARBs used for HF?



Hydralazine and Isosorbide Dinitrate in HF?

Used in combination - hydralazine dilates arterials whereas isosorbide dinitrate (same category as nitroglycerin) dilates veins -- all causing improvement of LVEF, increased CO and SV, also reduces cardiac remodeling


What is the clinical application, MOA and adverse effects for Carvedilol and Metoprolol?

Clinical application → B blockers use to treat HTN, angina, MI, arrhythmias, HF. B-blockers slow disease progression, reduce mortality in pts with HF, reduce LVEF, pts should receive B-blockers even if symptoms are mild or well-controlled with ACE inhibitors and diuretic therapy, also recommended for pt with asymptomatic reduced LVEF (stage B), slows the HR and reduces myocardial oxygen

Mechanism of action → antiarrhythmic effects, slowing or reversing ventricular remodeling, improving LV systolic dysfunction, decreasing HR and ventricular wall stress, inhibiting plasma renin release, negative inotropic effect therefore need to be started at low dose

Adverse effects → drug withdrawal, CV effect (bradycardia, reduced exercise capacity, HF, hypotension, AV block), disturbed lipid metabolism, hypoglycemia, bronchoconstriction, CNS effects

Contraindicated → reactive airway disease (asthma, COPD), pts with sinus bradycardia and partial AV block



Cardiac glycoside, inotropic agent
Decreases symptoms of HF, BUT NOT DOES increase survival.
Benefits of digoxin in tx with HF has been due to its positive inotropic effect on failing myocardium and efficacy in controlling the ventricular rate response to atrial fibrillation. Digoxin is both positively inotropic (increases contractility of heart) and negatively chronotropic (decreases heart rate).
Digoxin is a selective and potent inhibitor of cellular Na+/K+ ATPase allowing for an increase in myocardial intracellular calcium. Inhibition of the Na+/K+ ATPase in vascular smooth muscle causes depolarization which causes smooth muscle contraction and vasoconstriction. Digoxin binds to phosphorylated form of a-subunit of Na+/K+ ATPase. Extracellular K+ promotes dephosphorylation of the enzyme decreasing affinity of enzyme for digoxin.

Decreases HR due to increased activation of vagal nerve
**note that at high digoxin concentrations there is an increase in SNS activity increasing the automaticity of the cardiac tissue contributing to development of atrial and ventricular arrhythmias

Digoxin causes baroreceptor sensitization thereby off setting them in the case of HF leading to sustained elevation of plasma NE, renin, etc

Digoxin has a narrow therapeutic window and is excreted by the kidneys. Therefore if the pt has kidney damage, there could be an increase in Digoxin concentration leading to toxicity. Toxicity can cause: cardiac effects (atrial tachycardias and AV block), GI effects (anorexia, nausea, vomiting), and CNS effects (headache, fatigue, YELLOW VISION), and HYPERKALEMIA (because Na+/K+ ATPase normally causes sodium to leave cells and potassium to enter cells resulting in higher serum potassium).

Note that also since potassium decreases the affinity of digoxin for the Na+/K+ ATPase then hypokalemia causes increased activity which can lead to toxicity. Hyperkalemia has the opposite effect decreasing digoxin activity and toxicity.

Digoxin-induced arrhythmias - due to hypercalcemia enhancing digoxin-induced increase in intracellular Ca2+overloading Ca2+ stores

Hypomagnesemia - sensitizes the heart to digoxin-induced arrhythmias

Hypothyroidism - increases digoxin concentration
Hyperthyroidism - decreases absorption of digoxin making it less active

-don't use in diastolic fx or right side HF, uncontrolled HTN, bradyarrhythmias, hypokalemics

Drugs that bind same receptors....
1. quinidine (class I antiarrhythmic)
2. amiodarone (class III antiarrhythmic)
3. Verapamil

*diuretics cause hypokalemia which can increase digoxin activity

Tx digoxin overdose with...
Lidocaine and or Mg+
severe toxicity - tx with digitalis antibodies that bind and inactivate the drug


What phosphodiesterase III inhibitors can be used to treat acute cardiac failure?

Inamrinone, Milrinone

These are inotropic agents that inhibit PDE III used to treat short-term HF pts. DO NOT USED AS LONG-TERM THERAPY. Inhibition of the enzyme leads to increased cAMP producing positive inotopy causing ARTERIAL AND VENOUS VASODILATION. IV administration.

AE - Arrhythmias, hypotension, thrombocytopenia


Dopamine with HF?

Dopamine is used in the treatment of shock post fluid volume replacement. Dopamine is dose-dependent (D1 then B1 then a1). Dopamine can induce natriuresis increasing urine output, stimulate heart and increase blood flow to kidneys.

AE - cardiac arrhythmias esp at high doses due to increased myocardial oxygen demand


Dobutamine with HR?

B1 agonist used to increase CO in acute HF (cardiogenic shock, MI). Dobutamine is a racemic mixture where (-) is a1 agonist and weakly B1 agonist but (+) is a potent B1 agonist and mild B2 agonist. Vascular effect causes vasodilation and cardiac effect is potent inotropic agent. Dobutamine increases CO without elevating O2 demands which is major advantage over other symp drugs.

AE - less arrhythmogenic compared to dopamine



cardiac stimulant in MANAGEMENT OF SEVERE B-BLOCKER OVERDOSE - glucagon stimulates adenylyl cyclase to produce increase in cAMP levels leading to positive inotropy and chronotropy.
This means that glucagon is able to produce the same effects as a B-agonist without the need for activating B-receptors thereby preventing B-blocker overdose.


Class Ia antiarrhythmics

Quinidine, Procainamide. Disopyramide

Na+ blocker, K+ blocker, anti-cholinergic activity

increased AP, increased ERP, increased QT

used for both atrial and ventricular arrhythmias

Quinidine - causes thrombocytopenia, cinchonism, inhibits CYP3A4, P-glycoprotein and CYP3A4 - but it is also converted to an active metabolite by CYP3A4

Procainamide - causes lupus, metabolized by CYP2D6 and partially acetylated by NAPA

Disopyramide - strong anticholinergic effects causing peripheral constriction, pronounced negative inotropic effect

*state dependent


Class Ib antiarrhythmics

Mexilitine, Lidocaine

Na+ blocker, no anti-cholinergic activity

decreased AP

used for ventricular arrhythmias, GIVE THIS POST MI

Lidocaine - low oral bioavailability, give IV
Mexilitine - oral form of Lidocaine

Both - CNS depression, GI disturbance


Class Ic antiarrhythmics

Propafenone, Flecainide

Na+ blocker, anti-cholinergic activity, Propafenone (has B-blocker activity as well)

No prolonged AP, but slow phase 0

used for mainly atrial arrhythmias or as a last resort for ventricular arrhythmias, NEVER USE POST MI

Propafenone - bronchospasm, CNS, GI


Class II antiarrhythmics

Propanolol and Metoprolol - prolongs PR interval, mainly affects the nodal APs

Esmolol - short acting, used during emergencies to subside arrhythmias


Class III antiarrhythmics

K+ blockers
Sotalol, Dofetilide, Amiodarone

increased AP, increased ERP, increased QT interval

Sotalol - VENTRICULAR ARHYTHMIAS, also has B-blocker activity

Dofetilide and Amiodarone - used for atria and ventricles

Amiodarone - has activity from I,II, III and IV

Amiodarone toxicity - pulmonary fibrosis, hypo/hyperthyroidism, blue coloration, hepatotoxicity


Class IV antiarrhythmics

Ca2+ blockers - dihydropyridines [verapamil and diltiazem]

decreases conduction velocity of nodal AP, increases ERP, increases PR interval


Atropine, magnesium, Digoxin, adenosine as antiarrhythmic

Atropine - bradyarrhythmia

Magnesium - competes with Ca2+ stopping torsades de pointes and digoxin induced arrhythmia

Digoxin - vagal activation that depressed AV signaling

Adenosine - SVT, may cause bronchoconstriction, increases K+ efflux hyperpolarizing AP


What pts should NOT take Amiodarone?

Pts taking: digoxin, theophylline, warfarin, quinidine.
Pts with: bradycardia, SA or AV block, severe hypotension, severe respiratory failure.


What drugs control a-fib/flutter rhythm? Rates?

Class IC anti-arrhythmics → Flecainide, propafenone
Class III anti-arrhythmics → amiodarone, dofetilide

Rate (what is being sent to the ventricles)
1. Ca2+ channel blockers
2. B-blockers
3. Digoxin (in pts with reduced EF or CHF)
4. Amiodarone (when other agents can’t be used)


What classes of antiarrhythmics control ventricular signals sent from a-fib or flutter?

Class II or IV


Which anti-arrhythmics act on the SA and AV node?

B-Blockers (II), calcium-channel blockers (IV), digoxin


Which anti-arrhythmics act on the accessory pathway in the heart?

Class IA and K+ channel blocker (III)


What are the 6 categories of Fredrickson Classifications of Lipid disorders?

Type I → familial hyperchylomicroenmia [elevated chylomicrons due to LPL or apoCII def]
Type IIA → familial hypercholesterolemia [elevated LDL due to decreased LDL function] – DO NOT BENEFIT FROM STATIN TX due to defective LDL receptors
Type IIB → familial combined hyperlipidemia [elevated LDL and VLDL due to overproduction of VLDL by liver]
Type III → familial dysbetalipoproteinemia [elevated IDL due to abnormal apoE]
Type IV → familial hypertriglyceridemia [elevated VLDL due to impaired catabolism of VLDL]
Type V → familial mixed hypertriglyceridemia [elevated chylomicrons and VLDL due to increased production/decreased clearance of VLDL and chylomicrons]
**These are all primary hyperlipidemias most commonly seen in children, not adults (secondary hyperlipidemias are associated with adults)


What are the common secondary causes of hypertriglyceridemia? Hypercholesterolemia?

1. diabetes mellitus
2. chronic renal failure
3. hypothyroidism
4. alcohol excess
5. contraceptives
6. B-blockers
7. Glucocorticoids

1. hypothyroidism
2. nephrotic syndrome
3. obstructive liver disease
4. glucocorticoids



1. Atorvastatin – second most potent behind Rosuvastatin (2) [also lowers TAGs]
2. Fluvastatin – least potent (5)
3. Lovastatin – (4), prodrug
4. Pravastatin – (4)
5. Rosuvastatin – most potent in lowering LDL (1) [also lowers TAGs]
6. Simvastatin – 3rd most potent (3), prodrug?
**potency depends on ability to lower LDL

Statins are analogs of HMG that act as competitive inhibitors of HMG-CoA reductase – the 1st committed step of cholesterol biosynthesis. By inhibiting de novo cholesterol synthesis they decrease intracellular supply of cholesterol leading to an upregulation of HMG-CoA reductase and LDL receptors thereby clearing LDL from the blood.

DO NOT use on people who are pregnant, lactating, or hoping to become pregnant.

Along with decrease LDL statins also...
1. improve endothelial function
2. decrease platelet aggregation
3. stabilize atherosclerotic plaque
4. reduce inflammation

1. Elevated aminotransferase – usually not associated with other liver toxicity
2. Myopathy and rhabdomyolysis – rhabdomyolysis may cause myoglobinuria leading to renal injury


Niacin in tx of hyperlipidemias?

Niacin inhibits adenylyl cyclase in adipocytes through Gi activation leading to inhibition of adipocyte hormone-sensitive lipase. By inhibiting this enzyme there is a reduced transport of fatty acids to the liver and decreases hepatic TG synthesis (inhibited synthesis and esterification of FAs). Therefore, Niacin leads to a decreased hepatic VLDL production and release, reduction of LDL, reduction of Lp(a), increase of HDL [decreased HDL catabolism].

1. decrease in fibrinogen levels and increase in tissue plasminogen activator leading to decreased endothelial cell dysfunction
2. effective in combination with statins

1. intense cutaneous flush after each dose that can be decreased by aspirin administration 30 minutes prior to niacin ingestion
2. pruritis, rashes, dry skin, acanthosis nigricans
3. nausea, abdominal discomfort
5. Use cautiously in pts with diabetes mellitus due to induced insulin resistance leading to severe hyperglycemia
6. Niacin elevates uric acid levels precipitating gout [HYPERURICEMIA]
7. May cause atrial arrhythmias
8. Toxic amblyopia and toxic maculopathy


Fibrates in the tx of hyperlipidemias?

Gemfibrozil, fenofibrate

Fibrates are the drug of choice for severe hypertriglyceridemia as they lower serum TGs and increase HDL levels by activating nuclear receptors (peroxisome proliferator-activated receptor-a – PPAR-a). This receptor is expressed in the liver and brown adipose tissue (and to less of an extent in the kidney, heart and skeletal muscle). By activating the receptor there is an increase in LPL expression, decreased hepatic apoC-III expression and increased hepatic oxidation of fatty acids → decreasing plasma TG levels. Fibrates can increase LDLs, esp if TAGs are greater than 400 mg/dL

1. mild GI disturbance
2. myositis in pts with renal insufficiency
3. avoid fibrates in pts with hepatic or renal dysfunction
4. lithiasis due to fibrates increasing biliary cholesterol excretion leading to gallstone production


Why should Gemfibrozil (fibrate) not be used with statins?

Gemfibrozil inhibit hepatic uptake of states by OATP1B1 thereby increase statin plasma concentration. Gemfibrozil also competes for glucoronosyl transferase which metabolizes statins. Co-administration of these drugs leads to increased risk of rhabdomyolysis.
*Fenofibrate DOES NOT inhibit statin metabolism


bile acid binding resin drugs

1. Cholestyramine – impair liposoluble vitamin absorption (DAKE)
2. Colestipol -- impair liposoluble vitamin absorption (DAKE)

Bile acid-binding resins are only useful in pts with ONLY elevated LDL. This drug may worsen the pts condition if other lipid profiles are elevated. Bile acid-binding resins cannot be absorbed nor metabolically altered in the intestines due to their water insolubility and large MW, therefore are completely excreted in the feces.
When ingested, these resins bind to anionic bile acids in the intestinal lumen preventing their reabsorption thereby preventing fat absorption and reabsorption of bile acids. Because there is a decrease in bile acids the lvier converts cholesterol in to bile acids therefore decreasing hepatic cholesterol. Because hepatic cholesterol is decreased there is an upregulation of LDL receptors on the liver decreasing LDL levels. There is also an upregulation of HMG-CoA reductase increasing cholesterol synthesis which partially offsets the drugs action. There is also a rise in HDL seen.

1. bloating, nausea, cramping, constipation
2. Colesevelam has the fewest GI adverse effects
3. Contraindicated in pts with TAGs as there is an elevation in TAGs with these drugs


cholesterol absorption inhibitor

Ezetimibe – inhibits intestinal absorption of cholesterol and phytosterols to lower LDL. Do not give with bile-acid sequestrants as they inhibit absorption of ezetimibe.

Ezetimibe is a selective inhibitor of transport protein (NPC1L1) in jejunal enterocytes which takes up cholesterol from the lumen (from the diet OR bile acids). By inhibiting the receptor there is a decreased cholesterol absorption leading to a compensatory increase in cholesterol synthesis and upregulation of LDL receptors. When used as a monotherapy, Ezetimibe will lower LDL by 15-20%. Rather if they are used in combination with statins they prevent the enhanced cholesterol synthesis.

1. reversible impaired hepatic function (esp when given with statins)
2. myositis


Fish oils

1. Lovaza – contains ethyl esters EPA and DHA
2. Vascepa – contains ethyl esters of EPA only
*these are used in adjnct to the diet to reduce TAG levels in adult pts with TAG levels over 500 mg/dL

w-3 fatty acids = EPA and DHA [fish oils]
Fish oils reduce TAG biosynthesis and increase FA oxidation in the liver. Exact mechanism is unknown. Just as with nitrates, there may be an increased amt of LDL-C with this treatment if TAGs are greater than 400 mg/dL. EPA alone, may lower TG levels without increasing LDL cholesterol levels.


What are the different antihyperlipidemic drugs used in pregnancy?

1. Colesevelam [Category B]
2. Cholestyramine and Colestipol [Category C] – may interfere with absorption of important nutrients
3. Gemfibrozil and fenofibrate [Category C] – potential risk to the fetus so make sure benefit outweighs risk
4. Ezetimibe [Category C] – has caused skeletal defects in some animal studies
5. Niacin [Category C] – safety is unknown
6. Statins [Category X] – DO NOT USE


What are the different classes of chronic stable angina?

Class 0 → asymptomatic
Class 1 → angina with strenuous exercise
Class 2 → angina with moderate exercise
Class 3 → angina with mild exertion (walking a block, climbing 1 flight of stairs)
Class 4 → angina at any level of physical exertion


Tx of angina.

1. Isosorbide Dinitrate – long term management, oral admin → 100% bioavailability
2. Isorbide Mononitrate – used orally for prophylaxis of angina (long term management), oral admin → 100% bioavailability
3. Nitroglycerin – 1st line therapy for tx of acute angina symptoms, rapid onset
4. Sodium Nitroprusside – used in ICU and emergency settings (ex. hypertensive emergencies), rapid onset, IV prep, short half life
**Also acts as anti-inflammatory and anti-thrombotic (same as statins)
**notes that tolerance can build up with nitrates

B-blockers - Propranolol, Metoprolol, Atenolol

Ca2+ channel blocker
1. Dihydropyridine (Amlodipine, Nifedipine (short acting), Felodipine) → more selective for vascular SM therefore can relieve variant angina. Short acting (Nifedipine) should be used with B blocker to reverse a strong reflex tachycardia, but long acting has a reduced reflex response.
2. Verapamil → greater negative inotropic action than other CCBs, but has a weak vasodilatory effect. By reducing HR and contractility symptoms can be relieved.
3. Diltiazem → intermediate effect on vascular calcium channels b/t Dihydropyridine and Verapamils. Diltiazem can relieve coronary vasospasms by dilating coronary arteries and relieving symptoms of variant angina.

Ranolazine - late Na+ influx channel blocker which normally would drive calcium in to the myocyte but now prevents the influx of calcium therefore causing relaxation


When are anti-anginal drugs not indicated?

B-blockers - do not use with variant prinzemetal, pt has asthma

Ca2+ blockers - do not use if pt has bradycardia, HF, or conduction defects

Nitrates - DO NOT take if you are taking sildenafil

Ranolazine - metabolized by CYP3A4, can cause QT prolongation


What drugs do you use for acute attacks of angina? long term management of stable angina? Unstable angina? Variant prinzemetal?

Acute - nitroglycerin

Stable maintenance - nitrates with B-blockers (then add other things if it is not working, Ranolazine should be added last)

chronic Unstable - nitroglycerin with B-blockers

Prinzmetal - nitroglycerin and calcium channel blockers


Aspirin (acetylsalicylate)?

Aspirin is an irreversible cyclooxygenase inhibitor used to antagonize thromboxane A2 synthesis. Aspirin acetylates COX enzymes and due to the lack of platelet nuclei there is an inability to synthesize more COX in the individual platelet. Therefore, once the platelet COX enzyme is acetylated it will be unable to produce COX again and therefore will be inactive during its 10 day lifetime. Thromboxane A2 normally causes platelet aggregation and degranulation. TXA2 usually activates the Gq receptor signal leading to PLA2 activation and fibrinogen binding to GPIIb/IIIa. [fibrinogen forms bridges between adjacent platelets] By inhibiting TXA2 there is no platelet aggregation therefore a prolonged bleeding time.

1. prophylactic tx for transient cerebral ischemia
2. reduce incidence of recurrent MI
3. decrease mortality in post MI pts

*some people cannot tolerate Aspirin and therefore take clopidogrel (ADP R inhibitor)


ADP receptor blockers.

1. Clopidogrel (Plavix) – preferred over Ticlopidine due to fewer adverse effects
2. Ticlopidine

Clopidogrel and Ticlopidine are irreversible inhibitors of P2Y12 (located on surface of platelet). They are used to reduce the rate of stroke, MI and death in pts with recent MI, stroke and acute coronary syndrome. This can be given as an alternative to pts who are unable to tolerate Aspirin.

Clopidogrel is PRODRUG activated by CYP2C19. Omeprazole inhibits CYP2C19, so do not take with Clopidogrel.


Phosphodiesterase inhibitors for clotting.

Phosphodiesterase normally breaks down cAMP and cGMP. An increased amt of cGMP allows for vasodilation. When Dipyrodamole is given, it inhibits phosphodiesterase preventing a decrease in cAMP/cGMP levels allowing for coronary vasodilation. Dipyrodamole is used prophylactically to treat angina pectoris. This drug has little beneficial effect when used alone but does have therapeutic effect when used in combination with warfarin or aspirin.


blockers of platelet GP IIb/IIIa receptors?

1. Abciximab – monoclonal Ab against the GP IIb/IIIA receptor
2. Eptifibatide – cyclic peptide reversible antagonist of the GP IIb/IIIa receptor
3. Tirofiban – non-peptide reversible antagonist of the GP IIb/IIIa receptor

Fibrinogen binds to GP IIb/IIIa on platelets. Activation of the receptor is the final common pathway for platelet aggregation. These blockers are used to reduce thrombotic CV events in pts with non-STEMIs. It is also used as an adjunct to PCI for the prevention of cardiac ischemic complications.



Heparin is a mixture of straight chain, sulfated mucopolysaccharides give as an injectable, RAPIDLY ACTING ANTICOAGULANT, used acutely to interfere with formation of thrombi. UFH has a molecular weight range of 5,000-30,000 [wide range!]. LMWH is produced by depolymerized UFH that ranges from 1,000-5,000. LMWH have equal efficacy to UFH, higher bioavailability, longer half-life and less frequent dosing requirements therefore are replacing UFHs in many clinical situations.

LMWH - Tinzaparin, Enoxaparin, Dalteparin

UFH - inhibits Xa and II
LMWH - inhibits only Xa

*measure heparin activity with aPTT

use for...
1. DVT
2. Pulmonary embolism
3. MI
4. DOC during pregnancy
**give heparin during pregnancy as Warfarin is Class X and therefore contraindicated as it can cross the placenta

1. Bleeding
2. Hypersensitivity reactions
3. Heparin-induced thrombocytopenia (HIT) – antibodies recognize complexes that consist of heparin and platelet protein (platelet factor 4). The binding of these complexes to antibodies leads to platelet aggregation and release of platelet contents (degranulation) including more PF4 that leads to more immune complexes. This all can result in thrombocytopenia and thrombosis that can be life-threatening, therefore the heparin needs to be discontinued and administration of a DTI or fondaparinux needs to be given.

Reversal - protamine sulfate



Fondaparinux is a synthetic pentasacharide that consists of 5 carbohydrates that bind to antithrombin III and specifically inhibit Xa. This treatment is approved for prevention and treatment of DVTs.


direct thrombin inhibitors (DTIs)

DTIs exert anticoagulant effect by directly binding to the active site of thrombin. DTIs can be administered parenterally or orally.

Parenteral - Lepirudin (HIT), Argatroban (HIT and PCI), Bivalirudin (PCI)

Oral - dabigatran (PE and DVT)


direct factor Xa inhibitors?

1. Apixaban
2. Rivaroxaban
*Direct factor Xa inhibitors are oral administered drugs that do not require monitoring. They are used for prevention and treatment of DVT and PE.


adverse effects of Warfarin

1. hemorrhage
2. cutaneous necrosis [increased clotting] due to reduced activity of protein C
3. Because there is inactivation of protein C (anticoagulant) before inactivation of the other factors there may be an initial pro-coagulant effect prior to the anti-coagulant effect.
4. Warfarin crosses the placenta and can cause a hemorrhagic disorder in the fetus and serious birth defects [Warfarin is category X and should NEVER be administered during pregnancy]


Ateplase, Reteplase, and Tenecteplase? urokinase?

urokinase - PE prevention

1. Ateplase → recombinant t-Pa, indicated for acute MI and acute ischemic stroke management
2. Reteplase → modified recombinant t-Pa, indicated for acute MI management
3. Tenecteplase → mutant form of t-Pa, indicated for acute MI management
**tissue plasminogen activators


What is the action of Mesna?

Mesna → reacts in the bladder with acroleine (metabolite of anticancer drug cyclophosphamide) preventing hemorrhagic cystitis


What is the effect of vinca alkaloids on tubulin?

The vinca alkaloids bind to tubulin preventing its polymerization into microtubules. This results in the cells arresting in metaphase preventing the cells to divide. This is a function of anti-cancer drugs.


What is the equation of the drug concentration v effect curve? drug-receptor binding curve?

E= (Emax*C)/(C+EC50)

B = (Bmax*C)/(C+Kd)


What are the different types of non-receptor antagonism?

1. Functional - includes indirect (ex. binding 2nd messenger) and physiological ( ex. epinephrine increases blood pressure and bronchodilation whereas histamine decreases blood pressure and bronchoconstriction)

2. Chemical - binds with agonist before it get to the receptor (ex. protamine sulfate with heparin)


How does pH affect absorption and excretion (ion trapping)?

Weak acid: AH←→ A- + H+
Weak base: BH+ ←→ B + H+
**only unionized (AH or B) is absorbed and can effectively move through membranes

pH = pKa + log ([unprotonated]/[protonated])

Weak acids are excreted faster in alkaline urine (give sodium bicarb) and weak bases are excreted faster in acidic urine (give ammonium chloride).


What is the role of the P-glycoprotein?

P-glycoprotein (multidrug resistance protein 1 [MDR1]). This is a multidrug transmembrane transporter protein located in the liver, kidney, intestines and brain capillaries. This transporter is responsible for transporting drugs across the cell membrane. This transporter reduces drug absorption and is associated with multidrug resistance.
Liver → into bile for elimination
Kidney → into urine for excretion
Intestines → into intestinal lumen
Brain capillaries → back in to the blood decreases drug access to the brain


What is the pharmaceutical equivalence and bioequivalence?

Pharmaceutical equivalence → contain same active ingredients in identical concentrations, dosage form, route of administration
Pharmaceutical bioequivalence → concentration-time plots are superimposable and one can be safely replaced by the other


plasma protein for acidic and basic drugs?

Acidic drugs → plasma albumin
Basic drugs → a1-acid glycoprotein
*only unbound drugs are pharmacologically active


what is the affect on sulfonamide on kernicterus and warfarin?

sulfonamides take up albumin and release warfarin and unconjugated bilirubin increasing levels either leading to increased bleeding (in case of warfarin) or kernicterus (case of UCB)


What are the reactions of drug metabolism?

Phase I → oxidations, reductions, decarboxylations, deaminations, and hydrolytic reactions to make the drug more polar by adding a functional group that may then be used in phase II reactions – reaction usually makes an inactive metabolite but in the case of a prodrug consumption, it may make it an active metabolite [occurs in ER]

Phase II → conjugation reactions to form covalent bonds b/t functional group and glucuronate, acetate, glutathione, AA, or sulfate [occurs in cytosol]

*Isoniazid undergoes phase II (acetylation) before phase I (hydroxylation)

*morphine-6-glucoronide is a phase II product that is more active than its precursor


antidote for acetaminophen poisoning?

N-acetylcysteine which is a precursor for glutathione therefore increases its production and it also directly interacts/detoxifies NAPQI


Equation for Vd, CL, half-life.

Vd = dose/Co [high Vd drug is in tissues, low Vd drug is in plasma] -- to calculate Co use elimination phase (not distribution)

CL = dose/AUC = rate of elimination/concentration of drug in plasma

Half-life = (.693*Vd)/CL
50, 75, 87.5, 93.75


Rate of elimination with 1st order kinetics and 0 order (aka saturation)

Dosing rate @ ss = Rate of elimination = (CL*Css)/F

Rate of elimination for saturation = (Vmax*C)/Km+C)


Loading dose and maintenance dose for constant infusion.

loading dose = (Vd*TC)/F

Maintenance dose = (dosing rate/F) *dosing interval


accumulation factor? loading dose for intermittent dosing?

accumulation factor = 1/fraction lost in one dosing interval

loading dose (intermittent dosing) = MD*AF


peak concentration @ ss for intermittent dosing?



What are the different categories of adverse reactions

1. Type A = explainable - increased concetration, drug interactions, side effects
2. Type B = unexplainable - HSN, not dose dependent, unpredictable
3. Type C = chronic effects - benzo dependence, or tardive dyskinesia with Metoclopramide
4. Type D = delayed effects - carcinogen or teratogenic


What are the different mechanisms of drug toxicity?

1. “on target” adverse effects - increased amt of drug near receptor, upregulated B receptors with B blockers then you stop medication (ex. insulin leading to hypoglycemic coma]
2. “off target” adverse effects - activation of other receptors, ex thalidomide [R] is good but [S] is not
3. production of toxic metabolites - ex NAPQI
4. production of harmful immune response - ex. hemolytic anemia
5. idiosyncratic response


What are the different FDA classifications of drugs for use in pregnancy?

A - g/g - ex. folic acid
B - g/? or b/g
C - b/? or ?/?
D - known effects but benefits outweigh risk
X - DO NOT USE (ex. warfarin or statins)


How do M3 receptors mediation relaxation of vascular smooth muscle?

M3 receptors are present on endothelial cells of the vasculature. These cells also contain NO synthase (eNOS). eNOS catalyzes the formation of NO from arginine. Activation of M3 receptors causes increase in intracellular calcium mediated by Gq. The calcium activates eNOS leading to formation of NO from arginine. The NO then diffuses from the endothelial cells into the adjacent smooth muscle cells. NO in the smooth muscle cells binds and activates guanylyl cyclase producing cGMP from GTP. cGMP activates cGMP-dependent protein kinase which phosphorylates proteins leading to relaxation fo the SM wall resulting in vasodilation.


B1? B2? B3?

B1 -- Gs (increase cAMP and Ca2+), acting on the heart to increase heart rate, force and AV conduction velocity and on the juxtaglomerular cells to increase renin release

B2 -- Gs (increase cAMP)
1. smooth muscle relaxation
2. skeletal muscle → increase glycogenolysis, increase K+ uptake
3. Pancreatic B cells → increase insulin secretion
4. Pancreatic a cells → increase glucagon secretion
5. Liver → increase glycogenolysis and gluconeogenesis

B3 -- Gs (increase cAMP) → increase lipolysis in adipocytes


Which parts of the eye are controlled by the ANS, through what receptor and for what function?

1. pupillary dilator muscle in iris (radial), a1 receptor, contracts causing mydriasis (pupil dilation)
2. pupillary constrictor muscle in iris (sphincter), M3 receptor, contraction causes miosis
3. ciliary muscle, M3 receptors, contraction adapts to short range focus and relaxation adapts to long range focus (accommodation)
4. ciliary epithelium, B2 receptors, produces aqueous humor


pilocarpine and tropicamide?!

pilocarpine -- Muscarinic agonist that causes ciliary muscle contractions facilitating outflow of aqueous humor into canal of schlem reducing intraocular pressure – used to treat glaucoma

Tropicamide -- Muscarinic antagonist that causes relaxation of pupillary constrictor muscle (sphincter) causing mydriasis (dilation) and cycloplegia (paralysis of ciliary muscles resulting int he loss of accommodation)


What are the AchE inhibitors?

Edrophonium - myasthenia dx, NMJ block reversal
Pyridostigmine, Neostigmine - myasthenia tx, NMJ block reversal
Physostigmine - crosses BBB, reverse atropine block and glaucoma
Donepezil, rivastigmine, galantamine - Alzheimer tx

Tabun, Sarin, soman - nerve block

Malathion, parathion - organophosphate poisoning reversed with PRALIDOXIME

Echothiophate - organophosphate used to tx glaucoma (causes SLUDGE symptoms)


Direct muscarinic agonists

ACh - only used locally to cause miosis

Bethanechol - not broken down my AChE
Carbachol - not broken down by AChE


Muscarine, Arecoline (nicotinic and muscarinic activator), pilocarpine (only therapeutically used natural alkaloid)


What is the effect of nicotine at high and low doses?

Low dose nicotine causes ganglionic stimulation and depolarization.
1. CV system → sympathomimetic effects increasing HR and BP
2. GI and urinary tract → mainly parasympathomimetic causing nausea, vomiting, diarrhea, and voiding of urine (SLUDGE?)
3. Secretions → stimulates salivary and bronchial secretions (parasympathetic?)

High dose nicotine causes a ganglionic blockade and neuromuscular blockade leading to SLUDGE and paralysis.


belladonna alkaloids?

Scopolamine - tx motion sickness and block short term memory
**natural muscarinic antagonists


What is the effect of dose amt on the cardiovascular system?

Low dose → blockade of PRESYNAPTIC M2 (inhibitory) receptors thereby increasing ACh releases which would normally be decreased by binding of ACh to M2 PRESYNAPTIC receptors (inhibiting an inhibitor)
Moderate to High dose → blockade of ATRIAL M2 receptors leading to tachycardia
*High dose of anti-muscarinic agents may cause cutaneous vasodilation = “atropine flush” [unknown mechanism]


Ipratropium and Tiotropium?

Ipratropium and Tiotropium?


Homatropine, Cyclopentolate, and Tropicamide?

These are tertiary amine muscarinic antagonists. These drugs are used in ophthalmology to produce mydriasis WITH cycloplegia. These drugs are preferred to atropine b/c of shorter duration of action.


Benztropine and Trihexyphenidyl?

These are tertiary amine muscarinic antagonists. They are used to treat Parkinson’s disease and extrapyramidal effects of antipsychotic drugs.



Glycopyrrolate is a muscarinic antagonist that does not cross the blood brain barrier. It is consumed orally to inhibit GI motility or parenterally to prevent bradycardia during surgical procedures.



A muscarinic antagonist used to treat an overactive bladder.


contraindications of antimuscarinic agents?

1. pts with angle-closure glaucoma – treat glaucoma with miosis (pupil constriction) so with these pts you don’t want to give pupil dilators b/c then the fluid will not be able to escape through the canal increasing the pressure even more
2. pts with prostatic hypertrophy
3. elderly


Ganglion blockers (Nn)?

Ganglion blockers (ex. Hexamethonium, mecamylamine, trimethaphan) were originally used for HTN, but due to their adverse side effects they have been replaced by superior antihypertensive agents. Ganglion blockers can block both sympathetic or parasympathetic Nn. Whatever the dominant innervation (ex. cardiac with parasympathetic) is, the opposite will occur when ganglion blockers are used.


In what body structures are the sympathetics the predominant tone? Parasympathetic tone?

Sympathetic - sweat glands (Ach), arterioles and veins

Parasympathetic - GI, Urinary, cardiac, iris, ciliary muscle, salivary glands


NMJ blockers?

Tubocurarine - NMJ antagonist (non-depolarizing) relaxes skeletal muscles during surgery

Succinylcholine - NMJ depolarizing agent that stimualtes then desensitizes, used for ECT and intubation -- may cause malignant hyperthermia which is reversed with Dantroline


What drugs affect Ach presynaptically/creation?

Botulinum toxin


Epinephrine - what receptors and uses?

B then a

1. Anaphylactic shock
2. Asthmatic attacks – acute treatments
3. Cardiac arrest – to restore cardiac rhythm in pts with cardiac arrest
4. In local anesthetics – epinephrine increases duration of local anesthetics by producing local vasoconstriction at the site of injection thereby keeping the anesthetic


Norepinephrine - what receptors and uses?

a1 then a2 then B1

Treat shock b/c it increases vascular resistance and therefore blood pressure. On a side note, dopamine is better to treat shock b/c it doesn’t decrease blood flow to the kidneys as NE does.


Dopamine- what receptors and uses?

D1=D2 then B1 then a1

Dose dependent
Low dose → dopamine activates D1 receptors in renal and other vascular beds causing vasodilation, increased GFR, increased renal blood flow, increased sodium excretion
Intermediate dose → dopamine activates B1 receptors in the heart causing an increased CO AND dopamine causes release of NE from nerve terminals contributing to cardiac effects (increased systolic blood pressure, unaffected diastolic blood pressure)
High dose → dopamine activates vascular a1 receptors leading to vasoconstriction and a rise in blood pressure, increase in TPR

1. treat severe CHF
2. treat cardiogenic and septic shock [intermediate to high rates]



B1=B2 agonist
bronchodilation, increased CO, HR, contractility
-used in emergencies



(-) → a1 agonist and weak B1 agonist
(+) → a1 antagonist and potent B1 agonist

Dobutamine has greater iontropic than chronotropic effects. It increased CO, contractility and HR. PVR and BP are not significantly affected. This drug has a significant effect over other sympathomimetic drugs due to no significantly elevating oxygen demand of the myocardium.
Uses → management of acute heart failure and cardiogenic shock


B2 agonists used to tx asthma?

short term - albuterol, terbutaline

long term - salmeterol, formoterol



a1 agonist

use: nasal decongestant, mydriatic (dilates pupils), hypotension (shock)

(may cause reflex tachycardia)


a2 agonist

Brimonidine - tx glaucoma with decreased aqueous humor production AND increased outflow


a2 antagonist



non-selective a-antagonists



Propranolol, Nadolol, Timolol

Propranolol - helps with tremors, HTN, CHF, hyperthyroidism
Nadolol - angina and HTN
Timolol - glaucoma, HTN, migraine prophylaxis


Atenolol, metoprolol, esmolol

Atenolol and metoprolol - angina, CHF

Esmolol - short acting, reduce arrhythmia (SVT) and protect against aortic dissection


Labetalol and Carvedilol

a1 and B blockers


a-methyltyrosine, reserpine, tetrabenazine

a-methyltyrosine - blocks tyrosine hydroxylase

Reserpine - irreversible VMAT blocker

Tetrabenazine - reversible VMAT blocker used to treat huntingtons


B2 agonist tx asthma

SABA - albuterol, terbutaline, pirbuterol
LABA - salmeterol, formoterol

*B2 agonists increase intracellular cAMP resulting in relaxation of the bronchial smooth muscle and subsequent bronchodilation. When administering these drugs they are inhaled minimizing their systemic effects b/c B2 agonists are poorly absorbed into the circulation via the lungs. [available via MDI (metered-dose inhalers), spaces of VHC (valved holding chambers)]


Methylxanthines used to tx asthma.


* inhibit phosphodiesterase (enzyme responsible for metabolism of cAMP → AMP) allowing for increased levels of cAMP resulting in bronchodilation.

*drugs also block adenosine receptors

(increase in caffeine or tea may have similar effects to theophylline with increased CNS and cardiac effects)



Muscarinic antagonists used to tx asthma.

Tiotropium (COPD mainly), Ipratropium

1. Dry mouth
2. Use with caution in pts with Glaucoma, BPH, bladder neck obstruction


corticosteroids used in asthma.

1. Beclomethasone (chronic rhinitis)
2. Budesonide
3. Dexamethasone (IV) -- give before birth to prevent ARDS
4. Flunisolide (chronic rhinitis)
5. Fluticasone
6. Prednisolone (IV)

*Corticosteroids inhibit synthesis of arachidonic acid by phospholipase A2 thereby decreasing leukotrienes, cytokines, and prostaglandins. Steroids bind to intracellular receptors and activate glucocorticoid response elements (GREs) in the nucleus resulting in the synthesis of substances that inhibit expression of inflammation and allergy. They also increase B2 responsiveness in respiratory tract thereby reducing need for B2 agonists as well as prevent remodeling with severe, progressive inflammation of chronic asthma.



this is an anti-IgE antibody that is administered parenterally. It binds to IgE on sensitized mast cells and prevents their activation and thus release of LTs and other mediators. It is used in the prophylactic management in asthmatic patients of inadequate control above the age of 12. There is a slim risk of the development of anaphylaxis.


leukotriene inhibitors used to treat asthma

1. Zileuton – inhibits 5-lipoxygenase which catalyzes the formation of leukotrienes from arachidonic acid
2. Zafirlukast – LTD4 receptor antagonist
3. Montelukast – LTD4 receptor antagonist

*These medications are given orally and useful in exercise, antigen and aspirin induced asthma. They prevent bronchoconstriction and airway inflammation. These drugs are used in chronic maintenance, NOT acute bronchospasm.

Zileuton – elevated liver enzymes
Zafirlukast and Montelukast – development of vasculitis and systemic eosinophilia similar to Churg-Strauss syndrome (p-anca)


Mast cell stabilizers

Cromolyn and Nedocromil -- may cause laryngeal edema, cough and wheezing


mnemonic used to remember medications for asthma exacerbations? COPD exacerbations

A – albuterol/pirbuterol/terbutaline
S – steroids
T – theophylline
H – humidifier O2
M – magnesium (severe exacerbations only when B2 agonists and anti-cholinergics are unsuccessful)
A – anticholinergics [more of a preferred tx for COPD]

C – corticosteroids
O – oxygen
P – prevention
D – dilators (anticholinergics, B2 agonists)
*B2 agonists – Albuterol, Salmeterol
**DO NOT use B-blockers or cholinergic
***Mucolytics (NAC) – liquefies mucus in COPD pts by disrupting disulfide bonds


opioids used as cough mediations (antitussives)?

1. Codeine
2. Dextrometorphan

*MOA →acts on GPCR leading to closure of presynaptic nerve voltage operated Ca2+ channels or open K+ channels inhibiting postsynaptic neurons. These are used to relieve acute debilitating cough or reduce cough reflexes.


1st and 2nd generation H1 antagonists.

1st generation → Diphenhydramine, chlorpheniramine
2nd generation → Loratadine (Claritin), Fexofenadine (Allegra) , Cetirizine (zyrtec)

Diphenhydramine, chlorpheniramine
MOA → competitive pharmacologic block of peripheral and CNS H1 receptors plus a- and M- receptor block. It also has an anti-motion sickness effect
Uses → hay fever, angioedema, motion sickness, OTC for sleep aid, parenterally for dystonias
AE → sedation and anticholinergic effects

Loratadine, Fexofenadine, Cetirizine
MOA → competitive pharmacologic block of peripheral H1 receptors [no CNS involvement so no autonomic or anti-motion sickness effects]
Uses → hay fever, angioedema


Iron def tx.

Oral - ferrous salts

Parenteral - iron dextran, iron sucrose, sodium ferric gluconate complex

**AE are due to GI disturbance (for oral)


acute and chronic iron overload tx.

acute - deferoxamine

chronic - deferoxamine and deferasirox


Myeloid stem cell stimulating factor?

Filgrastim and Sargramostim
-increases neutrophil production


EPO stimulating drug?

Darbepoetin - JAK/STAT pathway - may lead to HTN and thrombotic episodes


drugs can lead to folic acid deficiency?

1. Methotrexate
2. Trimethoprim
3. Pyrimethamine
*all of these drugs inhibit dihydrofolate reductase leads to megaloblastic anemia


Megakaryocyte growth factor?

Interleukin-11 - increases platelet production in someone undergoing chemo, reduces needfor platelet transfusion


Sickle cell tx?

hydroxyuria -- may lead to bonemarrow suppressionand cutaneous vasulitis


Butyrylcholinesterase (pseudoesterase) [BChE] polymorphism?

cleaves succinylcholine and other depolarizing NMJ blockers releasing the skeletal muscle paralysis. BChE activity can differ so low dibucaine number decreases activity and prolongs skeletal paralysis


N-acetyltransferase 2 (NAT2) polymorphism?

NAT2 acetylates drugs to inactivate them. Can be slow or fast acetylators. slow increases amt in blood, fast decreases amt in blood

Isoniazid - neuropathy and hepatotoxicity
Procainamide - SLE
Hydralazine - SLE
Sulfonamides - HSN reactions, hemolytic anemia. SLE


CYP2D6 polymorphisms?

1. Ultrarapid metabolizers → multiple (up to 13 copies) of the CYP2D6 gene
2. Extensive metabolizers → heterozygous or homozygous for the WT allele
3. Poor metabolizers → pt are homozygous for recessive alleles coding for enzymes with low activity

Ex. codeine needs to be metabolized to be active


Thiopurine S-methyltransferase (TPMT) polymorphism?

TPMT catalyzes the S-methylation of the anticancer thiopurines 6-mercaptopurine and azathioprine. Methylation of these drugs inactive them. Thiopurines also have a narrow therapeutic index leading to pts suffering from life-threatening myelosuppression if the incorrect dose is given.

6-mercaptopurine AND Azathioprine



EGFR binder inhibiting tyrosine kinas activity -- EGFR overexpressed in NSCLC


Why is warfarin a dangerous drug?

1. S-warfarin is 3-5x more potent than R-warfarin
2. S-warfarin is metabolized by ONLY CYP2C9
3. R-warfarin is metabolized by CYP1A1, CYP1A2, CYP3A4 and others
4. CYP2C9 alone is a highly polymorphic gene causing some variants to have lower activity than the WT allele – these pts who have the lower CYP2C9 activity required a decreased dose of warfarin
5. The target for Warfarin – vitamin K epoxide reductase [encoded by the gene vitamin K epoxide reductase complex 1 – VKORC1]
6. VKORC1 has polymorphisms that may also affect warfarin dosing requirement


What drugs cause oxidative stress on RBCs? (thereby require fx G6PD?)

1. Sulfonamides
2. Antimalarials (PRIMAQUINE)
3. Chloramphenicol
*Individuals with G6PD deficiency who are exposed to these drugs may develop hemolytic anemia