Download Antihypertensive drugs

Antihypertensive drugs
• Classification
I. Centrally acting drugs
- α2 agonists
Clonidine, methyl dopa
- Drugs that deplete the central
neurotransmitter amines
Reserpine
II. Adrenegic neuron blockers
Gaunethidine
III. α1 receptor blockers
Prazocin, terazocin, doxazocin
IV. ß blockers
Propranolol, metoprolol, atenolol
V. Vasodilators
a) Arteriolar vasodilators
- hydrallazine
- minoxidil
- diazoxide
- calcium channel blockers
b) Arteriovenus dilators
- Na nitroprusside
VI. Potassium channel activators
- hydrallazine
- minoxidil
- diazoxide
VII. Drugs that block renin-angiotensin-aldosterone
axis
a) Angiotensin converting enzyme inhibitors
- enalapril, captopril
b) Angiotensin II receptor blockers
- sarlasin, losartan, telmisartan
VIII. Oral diuretics
- Thiazides
• Renin-angiotensin-aldosterone axis
Angiotensinogen
renin
↓ renal arterial pressure
sympathetic stimulation
Angiotensin I
converting enzyme kininase II
Angiotensin II
vasoconstriction
aldosterone secretion
↑↑ peripheral vascular
resistance
↑↑ Na & H2O retention
Increased blood pressure
• Captopril was the 1st ACE inhibitor to be
developed
• Lisinopril
• Enalapril
all are prodrugs
• Benazepril
& hydrolyzed to
• Ramipril
active drug
• Perindopril
in the liver
• Trandolapril
Captopril
• It is a powerful inhibitor of the effects of
angiotensin I
• It affects capacitance (veins) & resistance
(arterioles) vessels
• ACEI do not affect cardiac contractility
cardiac output (CO) normally ↑↑
• They act preferentially on angiotensive vascular
beds - those of kidney, heart & brain
• This selectivity is important in sustaining
adequate perfusion of these vital organs in the
presence of ↓↓ perfusion pressure
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Kinetics
Captopril is administered in doses of 25 mgm 2-3
times a day 1-2 hours before meals
It is rapidly absorbed
Bioavailability ↓↓ if the drug is taken with food
Less than ½ of oral dose excreted unchanged
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Enalapril
It is a prodrug
More potent than captopril
Its action is slower but lasts longer
Food does not interfere with absorption
Dose –
Initial dose - 2.5 mgm/day - ↑ 60 years of age
- 5 mgm/day - younger age
Given once daily
Maintenance – 10-20 mgm/day
Adverse effects
• Severe hypotension after initial dose in elderly,
patients on diuretics, GI fluid loss
• Acute renal failure – in patients of bilateral renal
artery stenosis
• Hyperkalemia ↑↑ in patients with renal failure
• Dry cough & angioedema (bradykinin
accumulation)
Clinical uses of ACE inhibitors
• Hypertension
• Diabetic nephropathy
- it stabilizes renal function without lowering blood
pressure
- ↓ glomerular arteriolar resistance
- improved intra-renal hemodynamics
- delays diabetic nephropathy
• Congestive heart failure
• Myocardial infarction
Causes better preservation of LV function in post MI
cases
It ↓↓ post infarction remodelling
Angiotensin receptor blockers
• Losartan
• Valsartan
• Eprosartan
• Irbesartan
• Telmisartan
• They are more selective blockers of angiotensin
effects than ACE inhibitors
• They have no effect on bradykinin metabolism
• Angiotensin blocking effect is more complete than
ACE inhibitors as other enzymes can also generate
angiotensin II
• Losartan orally effective
• ½ life – 2 hours
• Active metabolite – 6-9 hours
• Dose – 25- 100 mgm/day
50 mgm /day
ß blockers
• They act by blocking ß1 receptors
• Peripheral resistance lowered during chronic
administration
• ↓↓ in cardiac output & plasma renin - variable
• They ↓↓ elevated blood pressure in
hypertensive patients
• Both systolic & diastolic blood pressure ↓↓
• They are cardio-protective – particularly in
patients with concurrent IHD
Propranolol
• It is a nonselective ß blocker
• It is very useful in mild – moderate HTN
• Acts on both ß1 & ß2 receptors
• It reduces blood pressure primarily by ↓ cardiac output
• It also inhibits stimulation of renin production –
↓↓ renin-angiotensin-aldosterone system
Dose – 80-480 mgm /day – divided doses
ADRs
• Due to ß blocking effect – bronchoconstriction
• Should never be stopped abruptly
Myocardial infarction (MI)
Cardioselective ß1 blockers
Metoprolol
• Inhibits stimulation of ß1 receptors in the heart
• Broncho-constriction less than propranolol as
cardioselectivity is not complete
• Asthmatic symptoms exacerbated in asthma
patients
Dose
• 100-450 mgm/day
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Atenolol
Given in a dose of 50-100 mgm/day
More cardio-selective
Dose should be reduced in renal failure
Labetalol
Has both α & ß blocking actions
Used in hypertensive emergencies & treatment of
pheochromocytoma
Daily dose
200-250 mgm/day
Hypertensive emergencies- Intravenous bolus 20-80
mgm
Carvedilol
• Non selective ß blocker with equal α blocking
effect
• HTN dose – 6.25 mgm twice daily
α1 receptor blockers
Prazocin, terazocin, doxazocin
• Antihypertensive effect produced by blocking α1
receptors in the arterioles & venules
dilatation of resistance & capacitance
vessels
• Blood pressure reduced more in upright than
supine position
• These drugs more effective when given along
with other agents - ß blockers, diuretics
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Kinetics & dosage
Prazocin
Well absorbed orally
½ life 3-4 hours but anti-hypertensive effect longer
Dose – 1 mgm thrice daily
Treatment should be initiated with a low dose (1stdose
at bedtime) to prevent postural hypotension & syncope
Uses
In moderate & severe hypertension as an adjunct to
other drugs
Terazocin – 5-20 mgm once daily
Doxazocin – 1-4 mgm once daily
Calcium channel blockers
• Dihydropyridines –
- amlodipine - isradipine
- nifedipine - lacidipine
- felodipine - cilnidipine
- nicardipine - benidipine
- nimodipine
• Non-dihydropyridines
- verapamil
- diltiazem
Mechanism of action
• Inhibition of Ca2+ influx into arterial smooth muscle cells
• All Ca2+ channel blockers effectively ↓↓ blood pressure –
hemodynamic differences influence the choice of a particular agent
• Vasodilatation
- ↑↑ with dihydropyridines
(nifedipine)
- Reflex sympathetic activation
tachycardia
↑CO
• Cardiac depression
- ↑ diltiazem
- ↑↑↑ verapamil (SA node)
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Nifedipine (depin, calcigard)
Dose- 5 mgm three times daily
15-60 mgm daily dose
Short acting nifedipine more likely to cause MI
Sustained release preparations – preferred
Sublingual preparations used in emergencies
Amlodipine
Most preferred drug in treatment of HTN
Long acting
Given once daily - better compliance
Cannot be used in emergencies
Dose 2.5-10 mgm/day
Nicardipine
• 20-60 mgm/day
Isradipine
• 2.5-10 mgm/day
• Both similar to nifedipine
• Lacdipine
• It is a longer acting newer CCB
• 2-6 mgm once daily
• Cilnidipine
• Recently approved
• Claimed to be a renoprotective CCB
• Benidipine
• Longer acting newer CCB
• Claimed to inhibit remodelling
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Diltiazem
Pharmacological properties in between verapamil &
nifedipine
↓↓ –ve ionotropic effects than verapamil
↓↓ vasodilatation than nifedipine
Dose – 60-120 mgm/day
Verapamil (isoptin, calaptin)
It is a potent –ve ionotropic agent
Causes suppression of SA node – anti-arrhythmic
effect
↓↓ potent coronary & vasodilator
Should not be combined with ß blockers & digitalis
Contraindicated in CHF
Dose – 80-240 mgm /day
Vasodilators
Hydrallazine
• Dilates only arterioles not veins
• Fall in blood pressure accompanied by
compensatory ↑↑ in heart rate, stroke volume
& cardiac output (CO)
• Well absorbed orally
• Metabolized by acetylation – can be fast
acetylators & slow acetylators
Dose – 40-200 mgm/day
ADRs
• High doses produce a syndrome similar to acute
rheumatoid arthritis or disseminated lupus
errythematosis (SLE)
• In IHD patients reflex tachycardia & sympathetic
stimulation
angina
ischemic arrhythmias
• ß blockers combined
Minoxidil
• Very effective oral vasodilator
• Dilates only arterioles not veins
• Acts by opening K+ channels
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↓ contractions in smooth muscle
Well absorbed orally – metabolized by conjugation
½ life is 4 hours
Hypotensive effect lasts due to active metabolite
minoxidil SO4
Associated with reflex tachycardia & sympathetic
stimulation ß blockers combined
Dose 5-10 mgm in two divided doses
Sodium nitroprusside
• It is a powerful parenterally administered
vasodilator
• Used in hypertensive emergencies & cardiac
failure
• Dilates both arterioles & venules
↓↓ peripheral resistance
↓↓ venous return
• It acts by releasing nitric oxide which relaxes
smooth muscle
• In HTN ↓ in blood pressure due to ↓↓ vascular
resistance while CO does not change
• In cardiac failure CO ↑↑ due to after load
reduction
• Nitroprusside is a complex of
Iron
Cyanide Nitroso moiety
• It is rapidly metabolized by uptake into RBCs with
liberation of - cyanide
metabolized by mitochondrial enzymes
Thiocyanate
distributed extracellulary
Eliminated by kidneys
• In renal failure thiocyanate accumulates
Toxicity
- weakness
- disorientation
- psychoses
- muscle spasms
- convulsions
• Nitroprusside rapidly lowers blood pressure
• Its effect disappears in 1-10 minutes of
discontinuation
• Given by infusion
• Na nitroprusside in aqueous solution is sensitive
to light
• Should be made fresh before each administration
& covered with opaque foil
Dosage - 0.5 μgm/kg/minute
• May be ↑10 μgm/kg/minute
• Blood pressure monitoring should be
continuously done when on Na nitroprusside
ADRs
• Most serious toxicity related to accumulation of
cyanide
metabolic acidosis
arrhythmias
excessive hypotension
Death
• Administration of Na thioSO4 as sulphur donor
facilitates metabolism of cyanide
Diazoxide
• It is chemically related to thiazides but has no diuretic
activity
• It is a parenterally administered arteriolar dilator used in
hypertensive emergencies
• Acts by opening K+ channels
vascular smooth muscle relaxation
• Injection of diazoxide
Rapid fall in blood pressure associated with tachycardia
& ↑ CO
• Hypotension occurs within 5 minutes & lasts for 4-12
hours
Dose
• Started with smaller doses 50-100 mgm
• Can also be given as infusion at a rate of
15-30 mgm/minutes
• ß blockers given to prevent reflex tachycardia
ADRs
• Most significant is excessive hypotension
• Reflex tachycardia can provoke angina, ischemia
& cardiac failure in IHD patients
Centrally acting drugs
• Methyl dopa decrease sympathetic outflow
• Clonidine
from vasopressor centers in
the brain
• The two drugs do not have identical sites of
action
• They act primarily on different populations of
neurons in vasomotor centers of the brain stem
• Clonidine ↓↓ heart rate & cardiac output more
than methyl dopa
• Methyl dopa
It is an analog of L-dopa
α methyl dopamine
stored in adrenergic nerve vesicles
released on nerve stimulation
false transmitter interacts with adrenergic
receptors (α2 presynaptic – bind more tightly to
α2 than α1 )
• Methyl dopa is useful in the treatment of mild to
moderate HTN
• Lowers blood pressure by ↓↓ peripheral
resistance
• Variable ↓↓ in heart rate & cardiac output
• Most cardiovascular reflexes remain intact
• Blood pressure ↓↓ not dependent upon
maintenance of upright posture
• It ↓↓ renal vascular resistance
• Postural hypotension is not a problem
Dose: 1-2 g in divided doses in pregnancy
Clonidine
• It acts at α adrenoreceptors in the medulla of the
brain
• It ↓↓ sympathetic
tone
↑↑ parasympathetic
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↓↓ in blood pressure & heart rate
It also ↓↓ circulating catecholamines
Binds more tightly to α2 than α1
It is lipid soluble & rapidly enters brain after oral
administration
Given twice daily
• Daily dosage:
- 0.2-1.2 mgm/day
Transdermal patch
• It ↓↓ blood pressure for 7 days after a single
application
• Postural hypotension is not a problem as
baroreceptor reflexes are intact
• It is usually given with a diuretic
ADRs
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Drowsiness due to central sedation
Dryness of mouth
GI disturbances
Allergic rash
Abrupt cessation
rebound HTN
Treated with α & ß blockers
Should be withdrawn slowly
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Diuretics
Lower blood pressure by depleting body Na+
stores
Initially ↓↓ blood pressure by ↓↓ blood
volume & cardiac output
Peripheral resistance (PR) may ↑↑
After 6-8 weeks cardiac output returns towards
normal
Peripheral resistance (PR) ↓↓
Na+ contributes to PR by ↑↑ vessel stiffness &
neural sensitivity
Possible relation - ↑↑ Na-Ca exchange
• Some diuretics have direct vasodilating activity eg.
indapamide, thiazides
• Diuretics effectively ↓↓ blood pressure by 10-15
mm
• Mild or moderate HTN can be treated by diuretics
alone
• In severe HTN they are combined with
vasodilators
sympathoplegic drugs
• Thiazide diuretics are appropriate for most
patients
• More potent loop diuretics are used
- in severe HTN
- when several drugs with Na+ retaining
properties are used
- when glomerular filtrate is ↓ 30-40 ml/minute
- in cardiac failure
where Na+
- cirrhosis
retention is marked
• K+ sparing diuretics useful to avoid excessive K+
loss particularly in patients taking digitalis
Dose
• Chlorthiazide - 100-250 mgm /day
• Hydrochlorthiazide – 12.5 – 50 mgm/day
• Furosemide – 20 -400 mgm/day IV, oral
ADRs
• Most common K+ depletion – may be hazardous in
- patients on digitalis
- cardiac arrhythmias
- in acute MI
- left ventricular dysfunction
• Mg+ depletion
Thiazides
- ↑↑ serum lipid concentration – hyperlipidemia
- ↑↑ uric acid concentration – gout
- Impaired glucose tolerance – hyperglycemia
- Hypercalcemia