Cardiovascular-Pharmacology: Akeberegn G 1
Cardiovascular-Pharmacology: Akeberegn G 1
Cardiovascular-Pharmacology: Akeberegn G 1
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At the end of this section students should be able to
understand the pharmacology of
Anti-hypertensive Agents
Anti-angina Drugs
Drugs used for the management of heart
failure
Agents used in the management of
Arrhythmia
Diuretic agents
Agents Used in Cardiac Arrhythmias
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Introduction
Blood Pressure
Blood pressure is the force exerted by the blood against any
unit area of the vessel wall and is usually measured as mmHg.
The highest pressure during a heartbeat is systolic pressure (120
mmHg)
The lowest point of the pressure is called diastolic pressure and
it is approximately 80 mmHg
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Introduction…
Systolic pressure (SP) is the peak aortic pressure that occurs during the ejection of
the blood from the left ventricle into the aorta during the contraction of the heart.
Factors:
stroke volume and the
compliance of the arteries and
heart rate.
Diastolic pressure (DP) is the minimum aortic pressure during relaxation of the heart
when there is no blood ejection to the aorta.
Factors:
peripheral resistance (TPR)
stroke volume and
heart rate.
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Introduction…
Arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac
output, CO) and the resistance to passage of blood through pre capillary arterioles (peripheral
vascular resistance, PVR):
BP = CO × PVR
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Introduction…
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Postural Baroreflex
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Hypertension
Hypertension is the most common cardiovascular disease
sustained arterial hypertension damages blood vessels in
kidney, heart, and brain and leads to an increased incidence of
renal failure, coronary disease, heart failure and stroke.
Classifications of Bp
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Terminologies
Gestational hypertension – Gestational hypertension refers to
elevated blood pressure first detected after 20 weeks of gestation in
the absence of proteinuria or other diagnostic features of preeclampsia
Chronic (preexisting) hypertension – Chronic hypertension is
defined as hypertension that antedates pregnancy, is present before
the 20th week of pregnancy, or persists longer than 12 weeks
postpartum
Preeclampsia: refers to the syndrome of new onset of hypertension
and proteinuria or new onset of hypertension and end-organ
dysfunction with or without proteinuria
most often after 20 weeks of gestation in a previously normotensive
woman
Eclampsia is diagnosed when seizures have occurred
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Etiology of Hypertension
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Renal Response to Decreased Blood Pressure
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Stimulation of aldosterone synthesis in the adrenal cortex, which
increases renal sodium absorption and intravascular blood volume.
Vasopressin released from the posterior pituitary gland also plays a role
in maintenance of blood pressure through its ability to regulate water
reabsorption by the kidney
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Basic Pharmacology of Antihypertensive Agents
antihypertensive agents act at one or more of the four anatomic control sites
Classifications
Diuretics
Reduce blood pressure and volume by depleting the body of sodium and reducing
blood volume and perhaps by other mechanism.
Sympathoplegic agent
lower blood pressure by reducing peripheral vascular resistance and inhibiting
cardiac function.
Direct vasodilators
Reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels
and—to varying degrees—increasing capacitance as well.
Agents that block production or action of angiotensin and thereby reduce
peripheral vascular resistanc
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Fig: Sites of action of the major classes of antihypertensive drugs.
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Diuretics
Mechanism of action
lower blood pressure primarily by depleting body sodium stores.
Sodium is believed to contribute to vascular resistance by increasing vessel
stiffness and neural reactivity.
Initially they BP by reducing blood volume and CO how ever, peripheral
vascular resistance may increase.
After 6–8 weeks, cardiac output returns toward normal while peripheral vascular
resistance declines
lowering BP by 10–15 mm Hg (used for mild-moderate HTN alone and in
combination with other agents for severe HTN ).
Types of diuretics and their role in HTN
Thiazide diuretics –For mild or moderate hypertension and normal renal and
cardiac function They result in potassium depletion .
Potassium-sparing diuretics are useful both to avoid excessive potassium depletion
and to enhance the natriuretic effects of other diuretics.
Aldosterone receptor antagonists: have a favorable effect on cardiac function in
people with heart failure.
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Diuretics
When the dose of
Loop diuretics is increased BP response continues to increase at doses many times greater
than the usual therapeutic dose but not for thiazide diuretics.
Drugs That alter Sympathetic Nervous System Function
Mechanism of action
Reduce sympathetic outflow from vasomotor centers in the brain stem.
Drugs:- Clonidine, Methyldopa, Guanabenz and guanfacine.
Clonidine:-
Clonidine Controls Bp by the following effect
Reduce CO due to decreased heart rate
relaxation of capacitance vessels,
reduction in peripheral vascular resistance.
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Pharmacokinetics & Dosage
Clonidine is lipid-soluble and rapidly enters the brain from the circulation.
Because of its relatively short half-life oral clonidine must be given twice a day.
When applied as transdermal patch, clonidine reduces blood pressure for 7 days
after a single dose.
This preparation appears to produce less sedation than clonidine tablets but may
be associated with local skin reactions.
Side effects
Dry mouth and
Sedation
Contra-Indications
Patients who are at risk for mental depression
Patients with tricyclic antidepressants
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Methyldopa (L-α-methyl-3,4-dihydroxy phenylalanine )
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Pharmacokinetics & Dosage
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Adrenergic Neuron-blocking Agents
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Reserpine
MOA:
Reserpine blocks the ability of aminergic transmitter vesicles to take up and store
biogenic amines, by interfering with the vesicular membrane-associated transporter
(VMA).
Dosage and PK of reserpine
Half life=24–48hrs
Bio-availablity= 50 %
Dose= 0.25 mg/d
Toxicity
At low doses-------little postural hypotension, EPS
At high dose-----------sedation, lassitude, nightmares, and severe mental depression
(stop medication if it occurs), mild diarrhea and gastrointestinal cramps and
increases gastric acid secretion
C/I
PUD
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Adrenoceptor Antagonists
Of the large number of β blockers tested, most have been shown to be effective in
lowering blood pressure.
All β-adrenoceptor-blocking agents are useful for lowering blood pressure in mild to
moderate hypertension.
In severe hypertension, β blockers are especially useful in preventing the reflex
tachycardia that often results from treatment with direct vasodilators.
Beta blockers have been shown to reduce mortality after in myocardial infarction
and in patients with heart failure.
Drugs in this class: propranolol, metoprolol & atenolol, nadolol, carteolol, betaxolol,
& bisoprolol, labetalol, carvedilol, & nebivolol, esmolol.
Propranolol
Propranolol was the first β blocker shown to be effective in hypertension and
ischemic heart disease.
MOA:
Decrease cardiac output
Inhibits the stimulation of renin production by catecholamines (mediated by β1 receptors).
Reduce peripheral presynaptic β adrenoceptors to reduce sympathetic vasoconstrictor nerve
activity.
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Propranolol…
Toxicity
Bradycardia (Due to B1- blocking agent )
Asthma (β2-blocking action)
Metoprolol & Atenolol
Metoprolol = propranolol (in β1 adrenergic blockage) and 50- to 100-fold less potent
than propranolol in blocking β2 receptors (make it good for people with asthma and
diabetes)
Metoprolol is extensively metabolized by CYP2D6 with high first-pass metabolism (t
½=4-6 h).
Atenolol
Not metabolized (t ½ = 6h and once daily dose 50-100 mg/d)
Atenolol is reported to be less effective than metoprolol in preventing the
complications of hypertension
Patients with reduced renal function should receive lower doses.
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Nadolol, Carteolol, Betaxolol, & Bisoprolol
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Pindolol, AcebutoloL, & Penbutolol
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Labetalol, Carvedilol, & Nebivolol
These drugs have both β-blocking and vasodilating effects.
Labetalol Blood pressure is lowered by reduction of systemic vascular resistance
(via α blockade) without significant alteration in heart rate or cardiac output.
Because of its combined α- and β-blocking activity, labetalol is useful in treating
the hypertension of pheochromocytoma and hypertensive emergencies.
Dose =
Oral = 200 to 2400 mg/d
IV bolus = 20–80 mg for hypertensive emergencies
Carvedilol for ordinary hypertension is
Initial dose =6.25 mg twice daily.
reduces mortality in patients with heart failure
Nebivolol
is a β1-selective blocker with vasodilating properties that are not mediated by α
blockade.
Nebivolol is extensively metabolized and has active metabolites (t1/2 = 10-12
hrs)
Starting dose = 5 mg/d – 40 mg/d.
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Esmolol
Esmolol is a β1-selective blocker
metabolized via hydrolysis by red blood cell esterases (t1/2=9–10
minutes)
is administered by intravenous infusion.
is used for management of intraoperative and postoperative
hypertension
Alpha1 Blockers (Prazosin, terazosin, and doxazosin)
These agents produce less reflex tachycardia when lowering blood
pressure than do nonselective α antagonists such as phentolamine.
The drugs are more effective when used in combination with other
agents, such as a β blocker and a diuretic, than when used alone
Useful with Prostatic hyperplasia and bladder obstruction symptoms
with HTN.
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Alpha1 Blockers (Prazosin, terazosin, and doxazosin)
Dose =Terazosin can often be given once daily, with doses of 5–20
mg/d.
Doxazosin is usually given once daily starting at 1 mg/d and progressing
to 4 mg/d
MOA =
Blocking α1 receptors in arterioles and venules
Alpha blockers reduce arterial pressure by dilating both resistance
and capacitance vessels
Toxicity
Retention of salt and water occurs when these drugs are administered
without a diuretics.
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Vasodilators
Drugs in this class includes:
Oral vasodilators: minoxidil, hydralazine
Parenteral vasodilators, nitroprusside and fenoldopam, which are used to treat
hypertensive emergencies;
Calcium channel blockers
Hydralazine
MOA
Potassium opener (Increased potassium permeability stabilizes the membrane at its
resting potential and makes contraction less likely)
Dialtes only arterioles
minoxidil should replace hydralazine when maximal doses of the latter are not
effective or in patients with renal failure and severe hypertension, who do not
respond well to hydralazine.
TOXICITY
Tachycardia, palpitations, angina, and edema if co-administered with β blockers
and diuretics are inadequate.
Headache, sweating and hypertrichosis.
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Nitroprusside
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Pharmacokinetics & Dosage
Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety.
Metabolized by uptake into red blood cells with release of nitric oxide and
cyanide.
Cyanide in turn is metabolized by the mitochondrial enzyme rhodanese, in the
presence of a sulfur donor, to the less toxic thiocyanate.
Thiocyanate is distributed in extracellular fluid and slowly eliminated by the
kidney.
Effects of Nitroprusside disappear within 1–10 minutes after discontinuation.
Toxicity
The most serious toxicity is related to accumulation of cyanide; metabolic
acidosis, arrhythmias, excessive hypotension, and death have resulted.
Sodium thiosulfate and Hydroxocobalamin are used for the
management of cyanide toxicity
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Diazoxide
Diazoxide is an effective and relatively long-acting potassium channel opener that
causes hyperpolarization.
Has same chemical structure with diuretics but do not have any diuresis activity
Used to treat hypertensive emergencies.
Non-cardiovascular action
Inhibits insulin release from the pancreas (used orally in the USA for the treatment
of hypoglycemia in hyperinsulinism )
Pharmacokinetics & Dosage
t1/2 = 24 hours,
Onset = 5 minutes
Duration =4–12 hours.
The hypotensive effects will greater when patients are pretreated with β blockers to
prevent the reflex tachycardia and associated increase in cardiac output.
Toxicity
Hypotension (may result angina and MI)
Hyperglycemia
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Fenoldopam
It is a peripheral arteriolar dilator used for
hypertensive emergencies and
postoperative hypertension.
MOA
It acts primarily as an agonist of dopamine D1 receptors, resulting in dilation of
peripheral arteries
Pharmacokinetics
Fenoldopam is rapidly metabolized, primarily by conjugation.
Its half-life is 10 minutes.
Fenoldopam is initiated at a low dosage (0.1 mcg/kg/min).
Toxicity
The major toxicities are
reflex tachycardia,
headache,
flushing.
glaucoma.
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Calcium Channel Blockers
Calcium channel blockers reduce peripheral resistance and blood pressure.
The mechanism of action in hypertension (and, in part, in angina) is inhibition of
calcium influx into arterial smooth muscle cells
Classified in to two
Dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine,
nisoldipine, and nitrendipine
Non- dihydropyridine (Verapamil, diltiazem )
Difference between them
dihydropyridine are more selective as vasodilators and have less cardiac depressant
effect than verapamil and diltiazem
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Inhibitors of Angiotensin…
Renin release from the kidney cortex is stimulated by
Reduced renal arterial pressure,
Sympathetic neural stimulation, and
Reduced sodium delivery or increased sodium concentration
at the distal renal tubule.
Angiotensin II has vasoconstrictor and sodium-retaining
activity.
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Inhibitors of Angiotensin
MOA
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Angiotensin-converting Enzyme (ACE) inhibitors
MOA
Inhibit the converting enzyme that hydrolyzes angiotensin I to angiotensin II and
inactivates bradykinin, ( a potent vasodilator )
blood pressure principally by decreasing peripheral vascular resistance. Cardiac
output and heart rate are not significantly change
Drugs in this classes are:-
captopril, Enalapril (pro-drug) , Lisinopril, Benazepril, fosinopril, moexipril,
perindopril, quinapril, ramipril, and trandolapril
S/E:
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Pharmacokinetics & Dosage
Toxicities
Hypotension
Enalaprilat, acute renal failure
Peak time = 3-4hrs hyperkalemia,
T1/2 = 11hrs dry cough
Dose = 10–20 mg once or twice daily C/I
Lisinopril Second and third trimester Pregnancy
T1/2 = 12hrs because of feta anuria and hypotension
Dose = 10–80 mg once daily
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Angiotensin Receptor-blocking
MoA
complete inhibition of angiotensin action (greater than ACE- inhibitors)
Agents losartan, valsartan. azilsartan, candesartan, eprosartan, irbesartan,
olmesartan and telmisartan
Toxicities
• Similar to ACE- Inhibitors with low dry cough effect
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