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Cardiovascular Medications
February 2002
Introduction
• Pharmacology versus Therapeutics
• Diseases
–HTN
–CAD
–AMI
–CHF
–Arrhythmias
–Thromboembolic
Goals and Objectives
• To provide general information about
cardiovascular medications
• Learn pharmacologic properties including
mechanism of action, adverse effects, and
clinical use of the following medications:
–Diuretics
–ACE inhibitors
–ARBs
–Beta blockers
–CCBs
–Vasodilators
–Nitrates
–Digoxin
Hypertension
• BP=CO X SVR
• CO
– Myocardial contractility, heart rate, venous return
• Venous return
– Total blood volume
• Kidney
– Percentage of blood volume circulating centrally
• Venous tone
• SVR
– Arteriolar smooth muscle tone
Hypertension
• Kidney
– Production of renin
– Regulation of blood volume
• Sympathetic nervous system
– Regulation of cardiac output and peripheral
resistance
• Renin-angiotensin-aldosterone
– Vasoconstriction (angiotensin II)
– Increased cardiac output secondary to sodium
retention (aldosterone)
Hypertension Medications
• Diuretics
– Reduce blood volume
• Inhibitors of angiotensin
– Reduce SVR and blood volume
• Sympatholytic agents
– Reduce SVR and CO
• Direct vasodilators
– Reduce SVR
Diuretics
• General mechanism of action
– Decrease blood volume
– Long-term effects from decreased PVR
• Specific mechanisms
– Effect transport proteins of tubular cells
– Prevent water reabsorption
– Inhibit enzymes
– Interfere with hormone receptors
Diuretics
Carbonic Anhydrase Inhibitors
• Acetazolamide, methazolamide
• CA leads to reabsorption of bicarbonate
• Inhibition leads to a sodium bicarbonate
diuresis and reduction in bicarbonate
stores
• Not used for hypertension
– Glaucoma, urinary alkalination (uric
acid elimination, ASA), acute altitude
sickness
Osmotic
• Mannitol, glycerin
• Large, non absorbed molecule passing
through highly water permeable
proximal tubule and descending limb of
Loop decreases reabsorption of water
• Not used for hypertension
– Reduce intraocular, intracranial pressure
Loop
• Furosemide, bumetanide, ethacrynic
acid, torsemide
• Inhibition of Na/K/Cl transport in the
ascending limb of the Loop of Henle,
increases excretion of Na and water.
• CV uses primarily in CHF, also edema,
renal failure
Thiazide
• Hydrochlorothiazide, chlorthalidone,
indapamide, metolazone
• Inhibits NaCl cotransporter in epithelial
cells of distal convoluted tubule
Potassium Sparing
• Spironolactone – competitive antagonist
binds to aldosterone receptors,
increases Na excretion
• Amiloride, triamterene – acts on the
collecting tubule to inhibit sodium
transport through ion channels
Diuretics
Clinical Uses
• Hypertension
– Thiazide, thiazide with potassium sparing
• CHF
– Loop
– Spironolactone
• Edema
– Loop
Adverse Effects
• Thiazide
–
–
–
–
–
Hypokalemic metabolic alkalosis
Hyperuricemia
Impaired carbohydrate tolerance
Hyperlipidemia
Hyponatremia
• Loop
–
–
–
–
Hypokalemic metabolic alkalosis
Ototoxicity
Hyperuricemia
Hypomagnesemia
Adverse Effects
• Potassium Sparing
– Hyperkalemia
– Hyperchloremic metabolic acidosis
– Gynecomastia
– Acute renal failure
– Kidney stones
Diuretic Mechanisms
• Effect transport proteins of tubular cells
– Loop, thiazide, amiloride, triamterene
• Prevent water reabsorption
– Osmotic
• Inhibit enzymes
– Acetazolamide
• Interfere with hormone receptors
– Spironolactone
ACE
Inhibitors
Generic
Benazepril
Captopril
Enalapril
Fosinopril
Lisinopril
Moexipril
Perindopril
Quinapril
Ramipril
Trandolapril
Brand
Lotensin
Capoten
Vasotec
Monopril
Prinivil
Univasc
Aceon
Accupril
Altace
Mavik
Angiotensin Receptor Blockers
Generic
Candesartan
Irbesartan
Losartan
Telmisartin
Valsartan
Brand
Atacand
Avapro
Cozaar
Micardis
Diovan
Angiotensinogen
Renin
Kininogen
Kalikrein
Angiotensin I
Bradykinin
1
1
Converting Enzyme
Angiotensin II
Increased
prostaglandin
synthesis
Inactive
2
2
Vasoconstriction
Increased peripheral
vascular resistance
Aldosterone
secretion
Increased sodium
and water retention
Increased
blood pressure
Vasodilation
Decreased peripheral
vascular resistance
Decreased
blood pressure
Clinical Uses
•
•
•
•
HTN
CHF
Diabetic Nephropathy
Post-MI
Adverse Effects
•
•
•
•
•
•
Hypotension
Acute renal failure
Hyperkalemia
Dry cough
Angioedema
CI in 2nd and 3rd trimester
Beta Blockers
• Competitively antagonize the effects of
catecholamines at B-adrenergic receptors.
• Decrease heart rate, stroke volume and
cardiac output
• Initial increase in peripheral resistance from
blockade of B-receptors in vessels that
promote vasodilation, leaving unopposed
alpha vasoconstriction
Beta Blockers
•
•
•
•
•
•
•
Cardioselective
ISA
MSA
Mixed
First pass
Renal
Half life
Beta Blockers
• Clinical Uses
• Adverse Effects
Calcium Channel Blockers
• Inhibition of calcium influx into arterial
smooth muscle cells
• Nifedipine and other dihydropiridine
agents are more selective as
vasodilators, with less cardiac
depressant effects than diltiazem and
verapamil
CCB
• Smooth muscle – long lasting relaxation
• Cardiac muscle – reduction in
contractility throught the heart and
decrease in sinus node pacemaker rate
and AV node conduction velocity
CCB
• Dihydropyridine
–
–
–
–
–
–
–
Amlodipine
Felodipine
Isradipine
Nicardipine
Nimodipine
Nisoldipine
Nitrendipine
• Miscellaneous
– Bepridil
– Diltiazem
– Verapamil
CCB
• Clinical Uses
• Adverse Effects
Central Alpha2-Receptor Agonists
• Clonidine, guanabenz, guanfacine, and
methyldopa
• Decrease sympathetic outflow from the
vasomotor center in the brain and
increase in vagal tone.
• Peripheral activity plays a lesser role
– Stimulation of presynaptic a2-receptors
decreases sympathetic tone
Central Alpha2-Receptor Agonists
• Effects
– Decreased heart rate
– Decreased peripheral resistance
– Decreased renin activity
– Blunted baroreceptor reflexes
Central Alpha2-Receptor Agonists
• Sedation and dry mouth
• Depression
• Rebound hypertension
Methyldopa
• Catecholamine type molecule
• Stimulates central inhibitory alphaadrenergic receptors
• Decreases peripheral vascular
resistance, decreases systolic and
diastolic BP, decreases heart rate
Methyldopa
• Sodium and fluid accumulation lead to
tolerance of hypotensive effect,
therefore diuretic use is needed
• Rare hepatitis and hemolytic anemia
– Coombs' positive (20%)
– Coombs' positive HA (1%)
Clonidine
• Reduces sympathetic outflow from the
brain secondary to direct stimulation of
alpha-receptors in the medulla
• Increased vagal tone leads to decreases
in peripheral vascular resistance and
heart rate
• Baroreceptors are blunted, leading to
orthostatic hypotension and tachycardia
Clonidine
• Weekly patch for improved compliance
and fewer side effects
• Disadvantages – cost, skin irritation, 2-3
day delay of effect
Clonidine
• Uses
– Hypertensive urgency
– Adjunctive pain therapy
– Withdrawal – alcohol, BZD, nicotine, opiate
– Adjunct to prolong anesthesia
– Migraine prophylaxis
– Menopausal symptoms
– Anxiety-related disorders
Alpha1 Blockers
• Prazosin, terazosin, doxazosin
• Selective alpha-1 blockade decreases
total peripheral resistance and venous
return.
• Inhibition of alpha-1 receptors in the
periphery prevents vasoconstriction
from adrenergic stimulation, allowing
vasodilation without affecting heart rate
or cardiac index.
Alpha1 Blockers
• Benign Prostatic Hypertrophy
– Prevent stimulation of alpha-1 receptors
and subsequent smooth muscle contraction
in the bladder neck and prostatic urethra
– Significantly increase urinary flow rates and
decrease outflow obstruction and irritation
symptoms
Alpha1 Blockers
• CNS side effects – lassitude, vivid
dreams, depression
• First dose phenomenon – dizziness,
faintness, palpitations, syncope
• ALLHAT
Vasodilators
• Hydralazine, minoxidil
• Relax arteriolar smooth muscle by
increasing the intracellular concentration
of cyclic GMP
• Decrease peripheral vascular resistance
• Activate baroreceptor reflexes,
increasing sympathetic outflow
• Activate RAA system
Vasodilator
• Hypotensive effect diminishes over time
without concomitant use of a diuretic
and sympathetic inhibitor.
• Angina can be exacerbated if
vasodilators are used without
sympathetic inhibitor (B blocker)
Vasodilator
• Hydralazine – lupus-like syndrome,
dermatitis, drug fever, peripheral
neuropathy, hepatitis, vascular headache
• Minoxidil – greater compensatory effects
(HR, CO, renin, sodium retention),
hypertrichosis
Vasodilators
• Nitroprusside
• IV used for hypertensive emergency
• Decreases PVR without increasing CO,
unless there is left ventricular failure
• Continuous IV infusion, effect is
immediate and lasts 2-5 minutes
• Thiocyanate levels should be measured
if infusion lasts longer than 72 hours
Vasodilators
• Diazoxide
• Direct acting arteriolar vasodilator
decreases PVR, increases cardiac output,
and maintains or increases renal plasma
flow
• IV use for HTN emergency
• SE – nausea, vomiting, tachycardia,
hyperglycemia
• Use with diuretic
Cardiac Glycosides - Digoxin
• Positive inotropic effect
• Inhibits active transmembrane transport
of sodium and potassium
• Binds to membrane-bound sodiumpotassium ATPase enzyme, disabling
the pump
• Increase of intracellular sodium
activates sodium-calcium pump,
increasing intracellular calcium
Digoxin
• Increased calcium improves myocardial
contractility
• Indirect effect of vagal stimulation on
SA and AB nodes, decreases sinus rate
Digoxin
•
•
•
•
Loading dose 10 mcg/kg IV or PO
75% oral bioavailability
Oral maintenance dose 0.125 to 0.5 mg
Renal function, baseline cardiac
function, size, age affect dosing
• Monitor drug levels
Digoxin
• Used in heart failure with
supraventricular tachyarrhythmias
– Early in therapy to control ventricular
response
• Used in HF with NSR
– No survival benefit
– Reduces symptoms and improves quality of
life
Digoxin
• Adverse effects
– GI- N/V, abdominal pain, anorexia
– CNS- headache, hallucination, delirium,
– Vision changes
– Gynecomastia
– Arrhythmias
• Hypokalemia
• Hypercalcemia
• Hypomagnesemia
Nitrates
• Used in ischemic heart disease
• Reduces myocardial oxygen demand
secondary to venodilation and arterial
dilation, causing a reduction in wall
stress from reduced ventricular volume
and pressure
• Direct dilation of coronary arteries
Nitrates
• Mechanism
– Smooth muscle relaxation
• Nitric oxide stimulates guanylyl cyclase which
increases cGMP leading to relaxation
– Preload and afterload are reduced
– Cardiac output and blood pressure are
reduced
– Oxygen requirement is reduced
Nitrates
• Pharmacokinetics
– Large first-pass effect
– Short half lives (except isosorbide mononitrate)
– Large interindividual variations in blood
concentrations
Nitrates
•
•
•
•
•
Short, intermediate, long
Acute attack v. prophylaxis
IV, sublingual, PO, transdermal
Half life 1-5 minutes
Isosorbide dinitrate is well absorbed
and has half-life of 5 hours
Nitrates
• Tolerance
• Adverse effects – postural hypotension,
headaches, flushing, nausea