1

Cardiovascular Pharmacotherapy Review

Edward JN Ishac, Ph.D.

Department of Pharmacology and ToxicologyMedical College of VirginiaCampus of Virginia Commonwealth University Richmond, Virginia, USA

Smith Building, Room 742eishac@vcu.edu828-2127

Nomenclature – Suffixes, Infixes

Sildenafil, vardenafil, tadalafil-afilPDE 5 inhibitors (cGMP)

Enoxaparin, dalteparin, fondaparinux-parin-LMW Heparins

Aliskiren, remikiren-kirenRenin inhibitors

ExamplesSuffixDrug Class

Fenofibrate, gemfibrozil, clofibrate-fibr-Fibrates

Losartan, valsartan, irbesartan-sartanARBs

Alteplase, retaplase, [streptokinase]-plaseThrombolytic agents

Hirudin, bivalirudin, lepirudin-rudinsDirect Thrombin inhibitors

Nifedipine, amlodipine, nimodipine-dipineDihydropyridines (CCBs)

Captopril, lisinopril, enalapril-prilACE inhibitors

Prazosin, doxazosin, tamsulosin-osinAlpha1-blockers

Propranolol, metoprolol, [sotalol]-ololBeta-blockers (A-M: β1)

Atorvastatin, simvastatin, lovastatin-vastatinHMG-CoA inhibitors

Agents used in HT, CHF, Dysrhythmia and Angina

NO/cGMP, tolerance (off periods), flushing, dizziness, headache, reflex tachycardia, many forms

aaaa

aaNitrates

Effects enhanced in depolarized, damaged tissue, Phase 0, ↓ CV

aaaa

Na+-Channel blockers

Flushing, dizziness, headache, nausea, reflex tachycardia

aaaaaVasodilators

Many Rx interactions, [K+], ↓use HFimportant, low K+→↑toxicity,

aaaCardiac glycosidesDigoxin

GFR >30, hypokalemia (CG); ↑Ca++, diabetes (↓glucose tolerance)

aaaa

aaaa

Diuretics (Thiazides)

Angioedema, hyperkalemia, cough (acei), tetrogenic, glossitis, taste

aaaa

aaaa

ACEI / ARBs / Aliskiren

HF, cardiac depression, constipation, gingival hyperplasia, edema, reflex tachycardia

aaaa

aaaa

Noaaaa

Ca++-Channel blockers (CCBs)

HF (CI: unstable HF, broncho-spasm, significant bradycardia, depression); Raynaud D. Caution in diabetes, asthma (use β1-)

aaaa

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Beta-Blockers (BBs)

Contraindications/Cautions/Notes AnginaArrhythmia

HFHyper-tension

Drug Class

Cardiovascular Pharmacotherapy $4/$10-Plans

WarfarinISDN, ISMNGlycosideMethyl-dopa

AspirinNitroglycerinTimololClonidine

PentoxifylineHydralazineDigoxinGuanfacine

Others/PVDVasodilatorsCarvedilolAlpha2-agonists

SpironolactoneStatinsPindololPrazosin

TriamtereneLovastatinBisprololTerazosinHCTZ + LisinoprilPravastatinSotalol Doxazosin

FrusemideEnalaprilNadololAlpha-blockers

BumetanideBenazeprilAtenololNicardipine

ChlorothalidoneLisinoprilMetoprololDiltiazem

HCTZCaptoprilPropranololVerapamil

DiureticsACE inhibitorsBeta-blockersCa-blockers

0

10

20

30

40

50

60

1978 1981 1984 1987 1990 1993 1996 1999 2002Year

% o

f Tre

ated

Pat

ient

s on

Med

icCalcium Channel BlockersBeta BlockersDiureticsACE InhibitorsARBsAlpha Blockers

CCBsCCBs

ßß--BlockersBlockers

ACEIsACEIs

DiureticsDiuretics

ARBsARBs

IMS Health NDTI, 1978IMS Health NDTI, 1978--20042004

αα--BlockersBlockers

Hypertension Treatment by Drug Class

MSAXXXXXMetoprololshort acting; operative arrhythmiaXEsmolol

XXXXBisoprololMSAXXXBetaxolol

XXXXAtenololISAXAcebutolol

β1-selectiveprimarily used for glaucomaXXXXTimololalso K-channel blockerXSotalolMSA; prototypical beta-blockerXXXXPropranololISA; MSAXXPindololISAXXPenbutolollong actingXXXXNadololISA; α-blocking activityXXLabetalolα-blocking activityXXCarvedilolISA; long acting; also for glaucomaXCarteolol

Non-selective β1/β2

CommentsHFMIArrhAnginaHTClass/Drug

Clinical use – Beta-blockers

2

β-Blockers: Adverse Effects, Cautions

• Supersensitivity: Abrupt withdrawal → Rebound HT, less with β-blockers with partial agonist (ie. pindolol).

• Cardiac: ↓reserve, fatigue, dizziness

• Asthma: Blockade of pulmonary β2-receptors leads to increase in airway resistance. β1-selective better

• Diabetes: Compensatory hyperglycemic effect of EPI in insulin-induced hypoglycemia is removed by block of β2-ARs in liver. β1-selective agents preferred

• Raynaud D: Decreased peripheral circulation

• CNS: nightmares, mental depression, insomnia

• Elderly: ↓Effectiveness, ↑adverse effects (ie. depression)

AngiotensinogenAngiotensinogen

ReninRenin

Angiotensin IAngiotensin I

ACE inhibitorsACE inhibitors((LisinoprilLisinopril))

ACEACE

Angiotensin IIAngiotensin II

AA--II T IIII T II--RR•• VasodilationVasodilation•• Anti proliferationAnti proliferation•• ↑↑ KininsKinins•• ↑↑ NONO

AA--II T III T I--RR•• VasoconstrictionVasoconstriction•• Cell growthCell growth•• Na+/HNa+/H22O retentionO retention•• SNS activationSNS activation•• ↑↑ AldosteroneAldosterone•• ↑↑ AntidiureticAntidiuretic hormonehormone

BradykininBradykinin

Inactive Inactive PeptidesPeptides

BKBK--RR

•• VasodilationVasodilation•• ↓↓ IschemiaIschemia•• ↓↓ Platelet aggPlatelet agg•• ⊕⊕ inotropeinotrope

↑↑ NONO

Enzymatic activityEnzymatic activityBlockadeBlockade

ReninRenin--AngiotensinAngiotensin--AldosteroneAldosterone System (RAAS)System (RAAS)

ARBsARBs((LosartanLosartan))

ReninRenin inhibitorinhibitor((AliskirenAliskiren))

Adverse effects: ACE Inhibitors

- severe hypotension in hypovolemic patients- angioedema, hyperkalemia- dry cough (20-30%, due to ↑bradykinin)- glossitis, oral ulceration, rash- altered sense of taste (loss of zinc, 10-20%)- contraindicated: pregnancy (tetrogenic)- contraindicated bilateral renal artery stenosis- drug interaction with K-sparing diuretics (↑K+)- NSAIDs (↓ effect)

ARBs & Aliskiren: Similar, less adverse effectsie. angioedema, glossitis; NO DRY COUGH

Calcium Channel Blockers

Non-dihydropyridines (non-DHPs):Verapamil, Diltiazem, Bepridil

Dihydropyridines (DHPs): [-dipine]Nifedipine, Amlodipine, Nicardipine, Felodipine

Nifedipine:- mainly arteriole vasodilation, little cardiac effect- reflex tachycardia, flushing, peripheral edema

Verapamil:- significant cardiac depression, ↓HR, constipation- caution in digitalized patients (↑ digoxin levels)

Diltiazem:- similar to Verapamil / Nifedipine (less)- actions on cardiac and vascular beds

Calcium-Blockers: Adverse effects

- constipation (more likely with non-DHPs, ie. verapamil)

- non-DHPs: cardiac depression, bradycardia, AV block

- non-DHPs are contraindicated with beta-blockers

- mostly DHPs: hypotension, reflex tachycardia, flushing, headache, edema

- hypotension (more likely with DHPs ie. nifedipine)

- gingival hyperplasia (nifedipine, 10%)

- CHF non-DHPs contraindicated, DHPs not recommended

- CYP3A4 inhibitors: grapefruit, verapamil, diltiazem

- CYP3A4 substrates: amlodipine, verapamil

Actions of VasodilatorsCa++ AntagonistsVerapamilDiltiazemNifedipine

Nitric oxide (NO)β-natriuretic peptideNitroprussideNitrates

Open K+ ChannelsMinoxidilDiazoxide

Direct VasodilationHydralazine

3

Nitrates - MOA

a. Formation of NO in endothelial cells involving sulfhydral (SH) groupsb. Interaction between NO and thiols in smooth mus. to form nitrosothiolsc. Nitrosothiol activates guanylate cyclase and increased formation of cGMP

Tolerance: oxidation of SH groups and formation of disulfide bonds- develops fast and recovers fast ie. “Monday syndrome or Head”

- Direct smooth m. relaxation- High specificity vascular sm- Vasodilation: veins > arteries- ↓Preload > ↓Afterload

NitroglycerinNitroprussideNitrates

Diuretics - MOA

• Loop diuretics (Furosemide)- Inhibit Na-K-2Cl ion cotransporter, ↓Na+, H2O reabsorption: ascending loop of Henle- hypokalemia, hypomagnesemia, hypocalcemia, ototoxicity, - most potent diuretics

• Thiazides (Hydrochlorothiazide)- Inhibit Na-Cl symporter, ↓Na+, H2O reabsorption in distal convoluted tube- hypokalemia, hypercalcemia, ↑uric acid→gout, DM-2

• K+-sparing (Collecting duct)- Spironolactone, eplerenone: Aldosterone antagonists- Amiloride, triamterene: block Na channel- hyperkalemia, least potent, adjunct, ↓Na+/K+ exchange- decrease HF mortality

Diuretics: Overview

Digoxin Action

Polarized

Inhibition of (Na+, K+-ATPase)→ ↓ exchange Na+ - K+ (3:2) → ↑ [Na+]IC→ ↑ Na+ - Ca++ exchange (3:1) (depolarized)→ ↑ [Ca++]IC → ↑ SR uptake Ca++ (↑stores)→ ↑ contractile force

Toxicity: narrow TI, ventricular tachycardia, visual disturbances, fatigue, hypokalemia enhance effect

Recommended Digoxin* not be used in females for routine CHF. Recommended Pharmacotherapy of CHF requires 4 or more agentsBidil: (isosorbide dinitrate (ISDN) and hydralazine) African Americans very effective

Digoxin*, Furosemide (IV), Thiazide, ACE Inhibitor/AT1 -Receptor blocker, K+-sparing/Inotropic therapy/Beta-type Natruretic peptide

Bi-Ventricle pacing

Bidil

Class IV(complete rest,

confined to bed or chair)

Digoxin*, Furosemide, Thiazide, ACE Inhibitor/AT1 - RB, Beta-blocker/K+-sparing

Bi-Ventricle pacing

Bidil

Class III(marked limitation of

activity, only comfortable at rest)

Digoxin*, Furosemide, ACE Inhibitor/AT1 - RB,Beta-blocker

Class II(slight, mild limitation of activity,

comfortable at rest)

ACE Inhibitor/AT1 - RBClass I (no limitations on activity)

PharmacotherapyNYHA

Pharmacotherapy of Congestive Heart Failure: 2004

Summary: Pharmacotherapy of Heart Failure• Improved survival

– ACE inhibitors/ARBs, ß-blockers, K-sparing• Increased mortality

– Phosphodiesterase III inhibitors (chronic)• Neutral on survival

– Digoxin, Loop diuretics, Thiazides• Increase Quality of life

– Digoxin, Loop diuretics, Thiazides, ß-blockers• Reduction of edema

– Loop diuretics, Thiazides• Tissue Remodeling

– ACE inhibitors/ARBs, K-sparing• Prevention of ischemia

– ß-blockers, Anticoagulant therapy • Hemodynamic improvement: All agents

– ACEI, ARBs, Digoxin, Diuretics, ß-blockers, K-sparing

4

Pregnancy Drug Classification

Risk to the fetus has been proved to outweigh any possible benefit.Cat. X

Evidence shows a risk to the human fetus, but benefits of the drug may outweigh risks in certain situations. For example, the mother may have a life-threatening or serious disorder that cannot be treated with safer drugs.

Cat. D

No adequate studies in animals or humans have been done. ORIn animal studies, use of the drug resulted in harm to the fetus, but no information about how the drug affects the human fetus.

Cat. C

Studies in animals show no risk to the fetus, and no well-designed studies in people have been done. ORStudies in animals show a risk to the fetus, but well-designed studies in humans do not.

Cat. B

These drugs are the safest. Well-designed studies in people show no risks to the fetus.

Cat. A

PregnancyProven safety in pregnancy (A, B):

a. Alpha-methyl dopa (B) b. Clopidogrel (B)

Weigh Risk vs Benefit for use in pregnancy: (C)a. Nifedipine (C) b. Spirolactone (C)c. Beta-blockers (C) d. Labetalol (C)e. Prazosin (C) f. Hydralazine (C)g. Heparin (C) h. Ezetimibe (C)i. Nitroglycerin (C) j. Verapamil (C)k. Cholestyramine (C) l. Quinidine (C) m. Hydrochlorothiazide (B) n. Sildenafil (B)

Not advised/Contraindicated (D or X):a. ACE inhibitors (D) b. Atenolol (D)c. ARBs (D) d. Statins (X)e. Aliskiren (D) f. Warfarin (X)g. Amiodarone (D) h. Phenytoin (D)i. Aspirin (D) j. Bosentan (X)

1. Resins2. Statins3. Niacin4. Fibrates5. Ezetimibe6. Omega-3

Sites of

Action4

3

215

6

Lipid-Lowering Agents - Summary

Clinical value? No major adverse E? Headache, diarrhea, cancer?0%

↑3%

↓↓15%

↓Cholesterol absorptionEzetimibe

↑Bleeding, fishy aftertaste, diabetes, thrombocytopenia, GI disorders

↓↓25%

↑10%

↓5%

Omega-3 Fatty acidsInhibit VLDL-TG synthesis

Nausea, skin rash, ↑statin myopathy(CI: Gemfibrozil; Fenofibrate OK), headache, gallstones. ↑LDL synthesis

↓↓↓

40%

↑↑

15%

↓

10%

Fibrates Activate pparα,Lipoprotein lipase stimulationFenofibrate, Gemfibrozil

Flushed face (↓aspirin), GI, glucose intolerance, gout, liver toxicity, peptic ulcer, diabetes CI: liver D, peptic ulcer

↓↓

30%

↑↑↑

30%

↓↓

15%

Niacin(Nicotinic A. or Vit. B3)↓ VLDL release, ↓ lipolysis

Liver toxicity, myopathy, ↑↑LDL-Rec,↓mylination, m. wasting, P450 3A4CI: pregnancy, children<12,

↓

20%

↑

10%

↓↓↓

40%

StatinsHMG-CoA reductase inhibitAtorvastatin, lovastatin

Hate it, gritty, GI discomfort, ↑VLDL,↑LDL-Rec, constipation, ↓absp. fat sol. Vits. A C D E, warfarin, THZ, ASA

↑

5%

↑

10%

↓↓

15%

Resins↓ Bile A. reabsorptionCholestyramine

NotesTGsHDLLDL

Adult Treatment Guidelines

> 200120-199< 120-150Triglycerides

10 Year CHD Risk>20% High risk (need aggressive therapy)10-19% Moderate<10% Low risk

> 60> 40> 50

HDL Cholesterol: MenWomen

Optimal <100mg/dl> 160130-159< 130LDL Cholesterol

High if >160mg/dl with coronary disease or more than 2 risk factors

> 240200-239< 200Total Cholesterol

NotesHighBorderline to high

Desirable mg/dl

Risk Factors: age > 45 (male) and 55 (females), family history of early vascular disease or hyperlipidemia, current cigarette smoker, elevated BP, obesity, diabetes, high LDL and low HDL. ↑Risk number → ↑TherapyTotal-C = LDL-C + HDL-C + VLDL-C; VLDL-C = TGs/5

Vaughan-Williams Classification

Adenosine, Digoxin, Anticoagulants, ANS agentsOthers

VerapamilDiltiazem

Ca channel blockers. Slow conduction and ↑effective refractory period in normal tissue (A-V node) and Ca-dependent slow responses of depolarized tissue (atria, ventricle, Purkinje)

Class IV

AmiodaroneIbutilide

Prolong repolarization/refractory period other means than exclusively iNa block (mainly K+

channel blockade).

Class III

Propranololothers

Beta blockers; decrease adrenergic input. No major effect on APD, suppress Ph.4 depolarization

Class II

FlecainideEncainide

Marked Na block Ph.0; slow conduction; no change APD or repolarization. Increased suppression of Na channels

IC.

LidocainePhenytoin

Minimal Na block Ph.0; slow conduction (less); shorten Ph.3 repolarization

IB.

QuinidineProcainamide

Moderate Na block Ph.0; slow conduction; ↑ APDIA.

PrototypeMechanismSubclass

5

Action Potential – Ion Flow

0.115010In2.54140OutCa++K+Na+mM

K+ - close4

Ca++ - closeK+o - open

3

Ca++i - openK+o - leak

2

Na+ - closeK+o - open/close

1

Na+i - open0

Na+/Ca++ - exchange (3:1)Na+/K+ - ATPase (3:2)

A. Cardiaci. Sinus bradycardia, increase QT interval → ↑risk TdPii. Negative inotropic action due to block of Ca channels and beta

receptors; but can improve heart failure via vasodilation.iii. A-V block, paradoxical VTs.

B. Non-cardiac:i. Deposits into almost every organii. Reduces clearance of drugs like procainamide, flecainide, digitalis,

quinidine and diltiazem.iii. Thyroid dysfunction (hypo or hyperthyroidism)iv. Pulmonary fibrosis is most serious (usually reversible)v. Paresthesias (tingling, pricking, or numbness) vi. Photosensitivityvii. Corneal microdeposits and blurred visionviii. Ataxia, dizziness, tremorix. Anorexia, nausea

Adverse effects: Amiodarone

Prolonged QT interval

Cardiac Membrane Effects of Antiarrhythmic Drugs

↓↓0↓↓+0IBPhenytoin

↓↓+++0 000IVDiltazem

0↑

↑↑

↑↑

0

↓

↓

↑

0

0

↓

↑

↑

↑

N

RP

00

+00

00

+

+

0

0++

+N

Na-Block CaBlock

vagal stimulation↓ ↑↓ ↑↓↑Digitalis

β-block↓↓0↑↑↑0II/IIISotalol

↑↑↓↓Adenosine

↓↓+++↑+IVVerapamil000IIIIbutilide

α-, β-block↓↓+↑↑+++IIIAmiodarone

β-block↓↓0+IIEsmololβ-block↓↓0↑↑+IIMetoprololβ-block↓↓0↑↑+IIPropranolol

↓↓+↑↑++ICPropafenone

00↑+++ICFlecainide

↓↓0↑↑+++IBMexiletine

↓↓0↑↑+++IBLidocaineM-block, α-block↓+↑↑+++IADisopyramideM-block, α-block↓0↑↑↑+++IAProcainamideM-block, α-block↓↓0↑↑++IAQuinidine

ANS effectsPacemakeractivityDepDepDrug

Cardiac Effects of Antiarrhythmic Drugs

vagal stimulation↓ ↑↓ ↑↓↑OtherDigitalis

β-block↑↑↓↓II/IIISotalol

↑↑↓↓OtherAdenosine

↑↑↓↓IVVerapamil

Sympatholytic↑↑↑↑0↓ ↑IIIBretylium

α-, β-block↑↑↑↑↓↓IIIAmiodarone

β-block↓↓↓↓IIEsmolol

β-block↓↓↓↓IIMetoprolol

β-block↓↓↓↓IIPropranolol

0↑↓↓ICPropafenone

0↑↓↓ICFlecainide

↓↓0↓IBMexiletine

↓↓0↓IBTocainide

↓↓0↓IBLidocaine

M-block, α-block↑↑↓↓IADisopyramide

M-block, α-block↑↑↓↓IAProcainamide

M-block, α-block↑↑↓↓IAQuinidine

ANS effectsAPDRPCVAutoClassDrug

More important agents

Dysrhythmias

TreatmentAcute vs Chronic

SiteVentricular vs SVT

Ventricular

Supraventricular

AmiodaroneSotalolFlecainide

AmiodaroneProcainamideSotalol, BretyliumLidocaine

Beta-blockerCCBs

AdenosineDigoxin, CCBs

ChronicAcute

Antihypertensive Agents (JNC VII, 2003)

1. Diuretics (1st) eg. hydrochlorothiazide2. Renin / AgII (ACEI, ARBs) eg. lisinopril, losartan3. Calcium-antagonists eg. nifedipine, verapamil4. Beta-antagonists eg. propranolol5. Alpha-antagonists eg. prazosin6. Potassium sparing eg. spironolactone7. Vasodilators eg. hydralazine, nitroprusside8. Central acting alpha2-agonists: eg. clonidine, α-methyl dopa9. Renin inhibitor eg. aliskiren (newest agent)10. Dopamine agonist eg. fenoldopam (acute HT)11. Inhibit/reduce NE release eg. guanethidine, reserpine12. Ganglionic blockers eg. mecamylamine

Over 240 different drugs or combinations of drugs

6

Hypertension: General considerations Age: Beta-blocker and ACEI/ARB efficacy may decrease

with age (>70 yrs)

Race: Beta-blockers and ACEI/ARBs less effective in blacks than whites

Renin: Patients with ↑renin may respond better with beta-blockers, ACEI/ARBs/Aliskiren

Smokers: Beta-blockers less effective

Diabetes: ACEI/ARBs/Aliskiren improve renal function

Chronic NSAIDs: ↓response - diuretics, ACEI, beta-blockers

Compliance: treat patient not just BP, quality of life

Lifestyle: smoking, overweight, exercise, alcohol intake

Algorithm for Treatment of Hypertension

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

Lifestyle Modifications

Stage 2 Hypertension(SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg)

Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB,

or combination.

Without Compelling Indications

Not at Goal Blood Pressure

Optimize dosages/add additional drugs

MI = myocardial infarction; CAD=coronary artery disease; Aldo Ant = aldosterone antagonist.*Based on benefits from outcome studies or existing guidelines, the compelling indication is managed in parallel with the BP. JNC 7. JAMA. 2003;289:2560-2672.

xxStroke prevention

xxKidney disease

xxxxDiabetes

xxxxHigh CAD risk

xxxPost-MI

xxxxxHeart failure

Aldo AntCCBARBACE Inhibitor

Beta-Blocker

DiureticRecommended DrugsHigh-Risk Condition

With Compelling Indication*

JNC 7: HT - Compelling Indications for Individual Drug Classes

Hypertension Treatment Chart

Angina Pectoris

Chronic disease, intermittentattacks of chest pain, radiatethrough chest, shoulder & arm3 million in USA (~ 1% pop.)

A. Typical (Stable, Effort) angina:- ↑ O2 demand - fixed supply

B. Variant (Prinzmetal's) angina:- ↓ O2 supply - unchanged demand- ie. at rest, coronary spasm (PGs?)

C. Unstable angina (ACS):- ↓ O2 supply, plaque, platelets, clot

D. Microvascular angina (Syndrome X):- atherosclerosis in small coronary a.

Angina - Pathophysiology

Unstable angina

7

Improving supply/demand ratio

a. Relaxation of resistance vessels (small arteries and arterioles) ↓TPR → ↓BP → ↓Afterload, ↓O2 demand (Nitrates, calcium channel blockers and beta-blockers)

b. Relaxation of capacitance vessels (veins and venules)↓Venous return, ↓heart size, ↓Preload, ↓O2 demand (Nitrates)

c. Blockade or attenuation of sympathetic influence on the heart ↓Contactility, ↓HR, ↓O2 demand(Beta-blockers)

d. Coronary vessel dilation- Important mechanism for relieving vasospastic angina- ↑O2 supply(Nitrates)

Drug Choices in Angina

A. Effort: nitrates, calcium-blockers, beta-blockers, aspirinB. Variant: nitrates, calcium-blockersC.Unstable: nitrates, calcium-blockers, beta-blockers,

aspirin, anticoagulants, thrombolytics

Aims in the use of antianginal drugs:a. Treatment of acute attack - nitroglycerin very effective

(i.v., sublingual, oral spray)b. Short term prophylaxis - taking nitroglycerin prior to

physical or emotional stress to prevent attackc. Long term prophylaxis - objective is to reduce

frequency of angina attacks. Many options are now available ie. long-acting nitrates, Ca++-blockers, β-blockers, aspirin, anticoagulants, thrombolytics

Angina Drug Treatment

Actions of Heparin and related anticoagulantsAT = antithrombin,

Xa = activated factor X.

1 : 1

4 : 1

Rudins:direct thrombin inhibitor Bivalirudin, Lepirudin, Desirudin; Argatroban

Thrombin

Activators of antithrombin (also called antithrombin III)1. Unfractionated Heparin (12,000-30,000MW)

• variable response, need to monitor aPTT, thrombocytopenia (HIT)2. LMW Heparins: Enoxaparin, Dalteparin, Ardeparin, Tinzaparin3. Fondaparinux: pentasaccharide, inhibits only Xa

Vitamin K dependant factorsVitamin K dependant factors

XIIaXIIa

IIa

Intrinsic system Intrinsic system (surface contact)(surface contact)

XIIXII

XIXI XIa

Tissue factorTissue factor

IXIX IXa VIIa VIIVII

VIIIVIII VIIIaVIIIa

Extrinsic system Extrinsic system (tissue damage)(tissue damage)

XX

VV VaVa

IIII

FibrinogenFibrinogen FibrinFibrin

(Thrombin)(Thrombin)IIa

Xa

Coagulation cascade –Vitamin K

HeparinHeparin

((ProthrombinProthrombin))

Warfarin - Vitamin K analog, ↓liver synthesis of functional clotting factors: prothrombin (II), VII, IX, X

Warfarin vs Heparins

ImmediateImmediateDelayed, 12 hrOnset

16 hrs4 hrs2-5 dDuration

Protamine sulfateProtamine sulfate Vit. K or plasmaToxicity Rx

No monitoring, bleeding all drugs

Thrombocytopenia(HIT) Monitor aPTT

Many drugs, resins,(s-) 2C9, (r-) 3A4,

Concerns

OKOKNo (teratogenic)Pregnancy

DVT, PE, AF, MI, angina

DVT, PE, AF, MI, angina

DVT, PE, AF, MI,stroke, (TIA), PCI

Uses

Activate ATIII →Inhibit Xa > IIa

Activate ATIII →Inhibit Xa, IIa

Inh. Vit K action↓ II, VII, IX, X

MOA

5 hrs1.5 hrs2.5 dHalf-life

s.c.i.v., s.c.oral or i.v.Routes

6,000-15,00012,000-30,000308Size (mw)

LMW HeparinHeparin (unfract.)Warfarin

8

Factors involved in Platelet Activation

Abciximab

Block fibrinogen,von Willebrand factors

P2Y

Direct thrombin inhibition (DTI)s:Rudins: Hirudin, Bivalirudin, Lepirudin, Argatroban

Thrombolytics - “Clot busters”Clot selectivity for clot-bound plasminogenCritical factor: elapsed time between thrombotic event and use (<2-3 hr)

PVD, Antiplatelets, Anticoagulants, Fibrinolytics

Calcium blockersRaynaud’s D.

Sildenafil, Vardenafil, TadalafilErectile dysfunction

Heparin, aspirin, clopidogrel, abciximab, (ticlopidine)PCI

Aspirin, (warfarin)TIA

LMWH, (heparin) DVT: Surgical

Warfarin, heparin, LMWH, (alteplase) Pulmonary E.

Aspirin, LWMH, heparin, abciximabUnstable angina

Aspirin, clopidogrel, warfarin, (ticlopidine)Stroke

Aspirin, warfarin, (dipyridamole)Heart valve

Alteplase, heparin, aspirin, abciximabMI: Treatment

Aspirin, clopidogrel, prasugrel, (ticlopidine)MI: Prevention

Warfarin, heparin, LMWHDVT: Treatment

Warfarin, heparin, LMWH, (aspirin)Atrial fibrillation

Pentoxifylline, cilostazolPAD

Total Age (years)Cholesterol(mg/dL) 20-39 40-49 50-59 60-69 70-79<160 0 0 0 0 0160-199 4 3 2 1 0200-239 7 5 3 2 0240-279 9 6 4 2 1≥280 11 8 5 3 1

Cigarette SmokingNonsmoker 0 0 0 0 0Smoker 8 5 3 1 1

?Man With Hypercholesterolemia:?Man With Hypercholesterolemia:Framingham Risk Assessment 1991Framingham Risk Assessment 1991

Expert Panel on Detection, Evaluation, & Treatment of High Blood Cholesterol in Adults. JAMA. 2001; 285:2486.

AgeYears Points20-34 -935-39 -440-44 045-49 350-54 655-59 860-64 1065-69 1170-74 1275-79 13

CHD RiskPoints 10-y

Risk (%)

<0 <10 11 13 14 15 26 27 38 49 5

10 611 812 1013 1214 1615 2016 25

≥17 ≥30

Systolic Blood PressureUntreated Treated

<120 0 0120-129 0 1130-139 1 2140-159 1 2≥160 2 3

HDL-C (mg/dL)Points

>60 -150-59 040-49 1<40 2

Score = 13Risk = 12%

LDL-C goal:<130 mg/dL

Calculated 10-year risk is: ≥20% - ‘High Risk’

11-19% - ‘Moderate Risk’≤10% - ‘Low Risk’Man, 54-yr, 4 risk factors: HTN SBP 150, low HDL-C

HDL-C <40, Total-C= 220, 10-yr CHD risk 12%

Moderate Risk

Prominent grey hair, plays sax, loves McDonald’s

Rationale for Co-administration of Ezetimibe with Statins

One-step co-administration of ezetimibe similar to three-step statin titration

Adapted from Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.

0 60

Three-step titration

One-step co-administrationStatin 10 mg

Statin 10 mg

+ Ezetimibe10 mg

5040302010

20mg

40mg

80mg

% reduction in LDL-C

ZocorSimvastatin

VytorinEzetimibe +Simvastatin

Heparin action

aPTT: activated partial thromboplastin time test

Response is variable,Need monitoring

Thrombocytopenia Thrombosis

Unfractionated Heparin – ThrombocytopeniaTreatment: Lepirudin