F. F. Alpha and beta blockers:Alpha and beta blockers:

* * 1 antagonists (Prazosin, terazosin, doxazosin)1 antagonists (Prazosin, terazosin, doxazosin)dilate aa & veins but cause minimal change in dilate aa & veins but cause minimal change in CO, RBF & GFR; reflex tachycardia & CO, RBF & GFR; reflex tachycardia & first dose syncope are universal adverse effectsfirst dose syncope are universal adverse effects

* * Clonidine:Clonidine: an an 22 agonist that reduces central agonist that reduces central sympathetic outflowsympathetic outflowMethyldopaMethyldopa ↓↓ adrenergic outflow from CNS; in adrenergic outflow from CNS; in renal insufficiency; sedation & drowsiness arerenal insufficiency; sedation & drowsiness arecommon side effectscommon side effects

* * labetalollabetalol (mixed (mixed 11, , 11 & & 22 antagonist) dilates antagonist) dilates bld vv. w/o bld vv. w/o HRHR

** blockersblockers prevent sympa stim of heart & prevent sympa stim of heart & renin release; also particularly useful forrenin release; also particularly useful forHPN with angina or migraineHPN with angina or migraine

atenololatenolol 11 antagonistantagonistmetoprololmetoprolol ““acebutololacebutolol 11 anta plus some sympanta plus some symp

activityactivitypropranololpropranolol (prototype) (prototype) 11 and and 22 antagonistantagonisttimololtimolol ““

ββ blockers:blockers:1. activate 1. activate ββ11 receptors receptors ↓↓ COCO2. 2. ↓↓ renin renin ↓↓ angio II angio II →→

1) 1) ↓↓ peripheral resistance peripheral resistance →↓→↓ TPRTPR2) 2) ↓↓ aldosterone aldosterone →→ ↓↓ bld vol bld vol →→ ↓↓COCO

ββ blockersblockers= are useful in HPN w/ coexisting= are useful in HPN w/ coexisting

supraventricular tachyarrhythmia, previous supraventricular tachyarrhythmia, previous MI, angina, glaucoma (applied topically) & MI, angina, glaucoma (applied topically) & migraine headachemigraine headache

= more effective in whites than blacks, in = more effective in whites than blacks, in young than elderlyyoung than elderly

= = propranololpropranolol undergoes metabolismundergoes metabolism= takes several wks to develop full effects= takes several wks to develop full effects= adverse effects: fatigue, lethargy,= adverse effects: fatigue, lethargy,

insomnia, hallucinations, hypotension, insomnia, hallucinations, hypotension, ↓↓ libido, impotence, libido, impotence, ↓↓ HDL, HDL, ↑↑ triglyceroltriglycerol

= = abrupt withdrawal abrupt withdrawal →→ rebound HPNrebound HPN due to due to upup--regulation of receptorsregulation of receptors

IV. Antiarrhythmic DrugsIV. Antiarrhythmic Drugs

A.A. Class I Drugs (Sodium Channel Blockers)Class I Drugs (Sodium Channel Blockers)1.1. Class 1 A drugs ( Procainamide, Quinidine)Class 1 A drugs ( Procainamide, Quinidine)

= slows phase 0 depolarization= slows phase 0 depolarization= atrial and ventricular arrhythmias.= atrial and ventricular arrhythmias.

2.2. Class 1B drugs (Class 1B drugs (Lidocaine is the drug of choiceLidocaine is the drug of choice))= shortens phase 3 repolarization= shortens phase 3 repolarization= ventricular arrhythmias ( tachy, fibril, ectopy)= ventricular arrhythmias ( tachy, fibril, ectopy)

3.3. Class 1C drugs (incainide, flecainide, etc.)Class 1C drugs (incainide, flecainide, etc.)= markedly slow phase 0 depolarization= markedly slow phase 0 depolarization= ventricular arrhythmias.= ventricular arrhythmias.

B.B. Class II Drugs (Class II Drugs (--Blockers)Blockers)= supresses phase 4 depolarization= supresses phase 4 depolarization* * PropranololPropranolol suppress tachyarrhythmias of suppress tachyarrhythmias of

sympathetic stimulationsympathetic stimulation

C. C. CLASS III Drugs (K+ Channel Blockers)CLASS III Drugs (K+ Channel Blockers)

* Prolong phase 3 repolarization* Prolong phase 3 repolarization* Bretylium, amiodarone, dofetilide, * Bretylium, amiodarone, dofetilide,

sotalolsotalol* for intractable ventricular arrhythmias* for intractable ventricular arrhythmias

D. Class IV Drugs (Ca++ Channel Blockers)D. Class IV Drugs (Ca++ Channel Blockers)

* slow conduction thru AV node and inc* slow conduction thru AV node and incthe effective refractory period in the AVthe effective refractory period in the AVnodenode

* more effective agts atrial than * more effective agts atrial than ventricular a.ventricular a.

E.E. Other Antiarrhythmic DrugsOther Antiarrhythmic Drugs

** Adenosine = the drug of choice Adenosine = the drug of choice for Rx for Rx of of paroxysmal supraventricular paroxysmal supraventricular tachycardiatachycardia

* * DigoxinDigoxin = control ventricular rate in = control ventricular rate in atrial fibrillation or flutteratrial fibrillation or flutter

F.F. Drugs that Increase HRDrugs that Increase HR

* Drugs that can be used to * Drugs that can be used to ↑↑HR include HR include Atropine, Isoproterenol, andAtropine, Isoproterenol, andEpinephrineEpinephrine

LIPID LOWERING DRUGSLIPID LOWERING DRUGS

HDL, LDL, VLDLHDL, LDL, VLDL = lipoprotein = lipoprotein cholesterolscholesterols

Drugs lower lipids byDrugs lower lipids by1. 1. ↓↓ production of lipoprotein production of lipoprotein

cholesterol = statinscholesterol = statins2. 2. ↑↑ degradation of a lipoprotein = degradation of a lipoprotein =

fibratesfibrates3. 3. ↑↑ removal of cholesterol from the removal of cholesterol from the

body = bile acidbody = bile acid--binding resinsbinding resins

Mechanisms of action:Mechanisms of action:

1. Inhibit the HMG1. Inhibit the HMG--CoA reductaseCoA reductase* lovastatin, simvastatin, other statins* lovastatin, simvastatin, other statins* liver failure, myopathy as ADR* liver failure, myopathy as ADR

2. Bile acid 2. Bile acid –– binding resins (Cholestyramine, binding resins (Cholestyramine, colestipol) colestipol) →→ bile acids excreted bile acids excreted →→ body converts body converts cholesterol to bile acidscholesterol to bile acids

3. Niacin (lowers plasma cholesterol & TG levels3. Niacin (lowers plasma cholesterol & TG levelsdue to due to hepatic secretion of VLDL due to hepatic secretion of VLDL due to TG TG synthesissynthesis

4. 4. lipoprotein lipase activity (Bezafibrate, clofibrate,lipoprotein lipase activity (Bezafibrate, clofibrate,fenofibrate, gemfibrozil)fenofibrate, gemfibrozil)

5. S5. Selectively inhibits small int’l absorption of dietary &electively inhibits small int’l absorption of dietary &biliary cholesterol biliary cholesterol →→ ↓↓ delivery to liver delivery to liver →→ ↓↓ hepatichepaticchol stores chol stores →→ ↑↑ clearance from bloodclearance from blood

DRUGS THAT AFFECT BLOOD

1. Antiplatelet drugs = (NSAIDs, anagrelide, dipyridamole, ticlopidine & clopidogrel, platelet glycoprotein IIb/IIIa receptor antagonists (abciximab, eptifibatide, tirofiban), ridogrel

2. Anticoagulants = HEPARIN & LMWH ( ardeparin, dalteparin, danaparoid, enoxaparin, tinzaparin); Oral (WARFARIN, dicumarol); Thrombin Inhibitors ( hirudin, argatroban, desidrudin, lepirudin); Others ( fondaparinus, drotrecogin alfa)

3. Thrombolytic drugs = First Gen (STREPTOKINASE, urokinase); 2nd Gen (tissue plasminogena activator or t-PA (recombinant forms are alteplase, anistreplase, reteplase, lanoteplase tenecteplase)

4. Drugs for anemia = erythropoeitin, iron, vit B12 (cyanocobalamin), epoitin alpha, darbepoeitin alpha, folic acid

5. Drug for Sickle cell anemia = hydroxyurea

Hemostasis

= control & prevention of blood loss

Vascular phase → platelet phase →coagulation phase (activation of the intrinsic & extrinsic pathways)

3 steps in coagulation:1. formation of prothrombin activators which 2. convert prothrombin to thrombin which 3. converts fibrinogen to fibrin

Platelet Aggregation Inhibitors

1. ASA* platelet membrane phospholipase liberates arachidonic acidMOA: inhibits the enzyme COX-1 thus no synthesis of thromboxane A2 by irreversible acetylation of a serine → shifts the balance of chemical mediators to favor anti-aggregatory effects pf prostacyclin (PGI2)

2. Ticlopidine & Clopidogrel= closey related thienopyridinesMOA: interfere w/ the binding of ADP to receptors in platelets inhibiting the activity of GPIIb/IIIa receptors required for platelets to bind to fibrinogen & to each otherTI: preventing cerebrovascular, cardiovascular & peripheral vascular diseases; routinely used in stent insertion during MI

Pharmacokinetics:food interferes w/ absorption of

ticlopidine, not clopidogrel → extensively bd to PP → active metabolites → urine & feces= maximum effect in 3-5 days; can cause prolonged bleeding w/ no antidoteDI: interfere w/ met of drugs as phenytoin, tolbutamide, warfarin, fluvastatin, tamoxifen; phenytoin toxicity w/ ticlopidine

ANTICOAGULANTS

Heparin1. binds to antithrombin II producing a complex that inhibits

thrombin2. inactivates factors IIa, IXa, Xa, XIa, XIIa, XIIIa,

& neutralizes tissue thromboplastin (factor III)

= low-molecular weight heparins (ardeparin,dalteparin, danaparoid, enoxaparin) have greater bioavailability after SC & have longer half lives

= protamine is antagonist

Warfarin= vitamin K antagonist= delay activation of factors II, VI, IX, X, & XIII= many drug interactions

Fibrinolysis is initiated by activation of plasminogen to plasmin which lyzes the fibrin that holds the clot.

Thrombolytic drugs are plasmingen activators

1. Older or first generation = streptokinase, urokinase

2. Newer or 2nd generation = selectively inactivates plasminogen bound to fibrin

Phosphodiesterase inhibitors(pentoxifylline & cilostazol) are used to treat intermittent claudication since they inhibit

DRUGS TO TREAT BLEEDING

A. Aminocaproic acid & tranexamic acid= synthetic, inhibit plasminogen

activation, orally active, excreted inurine

= potential AE is intravascularthrombosis

B. Protamine Sulfate= from fish sperm or testes; high in

arginine w/c is basic= AEs: hypersensitivity, dyspnea,

flushing, bradycardia, hypotensionwhen rapidly injected

C. Vitamin K= slow response, 24 hours fresh frozen

plasma given if immediate need)= vitamin K supplementation for

patients taking cefamandole, cefoperazone, & moxalactam

D. Aprotinin= serine protease inhibitor that blocks

plasmin;inhibits streptokinase

= reduce periop bld loss & need for blood transfusion in cardiopulmonary bypass surgery

= attenuates inflammatory response;= minimal adverse effect

Anemia = ↓ Hb, Hct, RBC

Erythropoeitin = synthesized in kidneys to ↑RBC production

Iron deficiency = microcytic, hypochromic anemia

B12 & Folic acid deficiency = megaloblastic anemia since there is defective DNA synthesis

B12 needs intrinsic factor produced by gastric cells for absorption in ileum

Pernicious anemia = achlorydia

Folic acid = tetrahydrofolate is active ingredient