Cardiovascular Pharmacotherapy Review M2 CV...  1 Cardiovascular Pharmacotherapy Review Edward JN

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    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: 1)

    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 1-)

    aaaa

    aaaaaaaaaa

    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

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    10

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    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

    --BlockersBlockers

    ACEIsACEIs

    DiureticsDiuretics

    ARBsARBs

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

    --BlockersBlockers

    Hypertension Treatment by Drug Class

    MSAXXXXXMetoprololshort acting; operative arrhythmiaXEsmolol

    XXXXBisoprololMSAXXXBetaxolol

    XXXXAtenololISAXAcebutolol

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

    Non-selective 1/2

    CommentsHFMIArrhAnginaHTClass/Drug

    Clinical use Beta-blockers

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    -Blockers: Adverse Effects, Cautions

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

    Cardiac: reserve, fatigue, dizziness

    Asthma: Blockade of pulmonary 2-receptors leads to increase in airway resistance. 1-selective better

    Diabetes: Compensatory hyperglycemic effect of EPI in insulin-induced hypoglycemia is removed by block of 2-ARs in liver. 1-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)-natriuretic peptideNitroprussideNitrates

    Open K+ ChannelsMinoxidilDiazoxide

    Direct VasodilationHydralazine

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    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 acidgout, 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, -blockers, K-sparing Increased mortality

    Phosphodiesterase III inhibitors (chronic) Neutral on survival

    Digoxin, Loop diur

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