Cardiovascular Pharmacotherapy 2014-05-21¢  1 Cardiovascular Pharmacotherapy Review Edward JN Ishac,

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    Cardiovascular Pharmacotherapy Review

    Edward JN Ishac, Ph.D.

    Department of Pharmacology and Toxicology Medical College of Virginia Campus of Virginia Commonwealth University Richmond, Virginia, USA

    Smith Building, Room 742 eishac@vcu.edu 828-2127

    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

    aaa a

    aaNitrates

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

    aaa a

    Na+-Channel blockers

    Flushing, dizziness, headache, nausea, reflex tachycardia 

    aaaaaVasodilators

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

    aaaCardiac glycosides Digoxin

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

    aaa a

    aaa a

    Diuretics (Thiazides)

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

    aaa a

    aaa a

    ACEI / ARBs / Aliskiren

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

    aaa a

    aaa a

    Noaaa a

    Ca++-Channel blockers (CCBs)

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

    aaa a

    aaaaaaaaa a

    Beta-Blockers (BBs)

    Contraindications/Cautions/Notes AnginaArrhyth mia

    HFHyper- tension

    Drug Class

    Cardiovascular Pharmacotherapy $4/$10-Plans

    WarfarinISDN, ISMNGlycosideMethyl-dopa

    AspirinNitroglycerinTimololClonidine

    PentoxifylineHydralazineDigoxinGuanfacine

    Others/PVDVasodilatorsCarvedilolAlpha2-agonists

    SpironolactoneStatinsPindololPrazosin

    TriamtereneLovastatinBisprololTerazosin HCTZ + 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 2002 Year

    % o

    f T re

    at ed

    P at

    ie nt

    s on

    M ed

    ic Calcium Channel Blockers Beta Blockers Diuretics ACE Inhibitors ARBs Alpha Blockers

    CCBsCCBs

    ßß--BlockersBlockers

    ACEIsACEIs

    DiureticsDiuretics

    ARBsARBs

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

    αα--BlockersBlockers

    Hypertension Treatment by Drug Class

    MSAXXXXXMetoprolol short acting; operative arrhythmiaXEsmolol

    XXXXBisoprolol MSAXXXBetaxolol

    XXXXAtenolol ISAXAcebutolol

    β1-selective primarily used for glaucomaXXXXTimolol also K-channel blockerXSotalol MSA; prototypical beta-blockerXXXXPropranolol ISA; MSAXXPindolol ISAXXPenbutolol long actingXXXXNadolol ISA; α-blocking activityXXLabetalol α-blocking activityXXCarvedilol ISA; long acting; also for glaucomaXCarteolol

    Non-selective β1/β2

    CommentsHFMIArrhAnginaHTClass/Drug

    Clinical use – Beta-blockers

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    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 activity BlockadeBlockade

    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 effects ie. 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 Vasodilators Ca++ Antagonists Verapamil Diltiazem Nifedipine

    Nitric oxide (NO) β-natriuretic peptide Nitroprusside Nitrates

    Open K+ Channels Minoxidil Diazoxide

    Direct Vasodilation Hydralazine

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    Nitrates - MOA

    a. Formation of NO in endothelial cells involving sulfhydral (SH) groups b. Interaction between NO and thiols in smooth mus. to form nitrosothiols c. 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

    Nitroglycerin Nitroprusside Nitrates

    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 agents Bidil: (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 pa