OBAT ANTIHYPERTENSI

DR MED dr.WIDHARTO PH,SpFK

FARMAKOLOGI DAN TERAPI
FAK.KEDOKTERAN UGM
• Table 11–1. Pharmacokinetic Characteristics and Dosage of Selected Oral Antihypertensive Drugs.

Drug Halflife(h) Bioavailability(%) Suggested Initial Dose Usual Maintenance Dose Range
Atenolol 6 60 50 mg/d 50–100 mg/d
Captopril 2.2 65 50–75 mg/d 75–150 mg/d
Clonidine 8–12 95 0.2 mg/d 0.2–1.2 mg/d
Guanethidine 5 50 10 mg/d 25–50 mg/d
Hydralazine 1 25 100 mg/d 40–200 mg/d
Hydrochlorothiazide 12 70 25 mg/d 25–50 mg/d
Lisinopril 12 25 10 mg/d 10–80 mg/d
Losartan 1–22 36 50 mg/d 2.5–100 mg/d
Methyldopa 2 25 1 g/d 1–2 g/d No
Minoxidil 4 90 5–10 mg/d 40 mg/d No
Nifedipine 2 50 30 mg/d 30–90 mg/d
Prazosin 3–4 70 3 mg/d 10–30 mg/d
Propranolol 3–6 25 80 mg/d 80–480 mg/d
Reserpine 24–48 NA 0.25 mg/d 0.25 mg/d
Verapamil 4–6 22 180 mg/d 240–480 mg/d
 Centrally Acting Sympathoplegic Drugs
Mechanisms & Sites of Action
• These agents reduce sympathetic outflow from
vasopressor centers in the brainstem but allow
these centers to retain or even increase their
sensitivity to baroreceptor control. Accordingly,
the antihypertensive and toxic actions of these
drugs are generally less dependent on posture
than are the effects of drugs that act directly on
peripheral sympathetic neurons
 Methyldopa (L- -methyl-3,4-dihydroxyphenylalanine)
• is an analog of L-dopa and is converted to –
methyl-dopamine and -methylnorepinephrine;
• this pathway directly parallels the synthesis of
norepinephrine from dopa illustrated in Figure
6–5. Alpha-methylnorepinephrine is stored
inadrenergic nerve vesicles, where it
stoichiometrically replaces norepinephrine,
and is released by nerve stimulation to
interact with postsynaptic adrenoceptors
 clonidine, a 2-imidazoline derivative
• The antihypertensive action of, was discovered in the course of testing the drug
for use as a topically applied nasal decongestant.
• After intravenous injection, clonidine produces a brief rise in blood pressure
followed by more prolonged hypotension.
• The pressor response is due to direct stimulation of -adrenoceptors in arterioles.
• The drug is classified as a partial agonist at -receptors because it also inhibits
pressor effects of other -agonists.
• Considerable evidence indicates that the hypotensive effect of clonidine is
exerted at -adrenoceptors in the medulla of the brain. In animals, the
hypotensive effect of clonidine is prevented by central administration of
-antagonists. Clonidine reduces sympathetic and increases para-sympathetic
tone, resulting in blood pressure lowering and bradycardia.
• The reduction in pressure is accompanied by a decrease in circulating
catecholamine levels.
 Guanabenz and guanfacine
• are centrally active antihypertensive drugs
that share the central - adrenoceptor-
stimulating effects of clonidine. They do not
appear to offer any advantages over clonidine.
 Pharmacokinetics & Dosage

• Pharmacokinetic characteristics of methyldopa are

listed in Table 11–1. Methyldopa enters the brain
via an aromatic amino acid transporter. An oral
dose of methyldopa produces its maximal
antihypertensive effect in 4–6 hours, and the effect
can persist for up to 24 hours. Because the effect
depends on accumulation and storage of a
metabolite ( -methylnorepinephrine) in the vesicles
of nerve endings, the action persists after the
parent drug has disappeared from the circulation.
 Toxicity

• The most frequent undesirable effect of methyldopa is

overt sedation, particularly at the onset of treatment.
With long-term therapy, patients may complain of
persistent mental lassitude and impaired mental
concentration. Nightmares, mental depression,
vertigo, and extrapyramidal signs may occur but are
relatively infrequent. Lactation, associated with
increased prolactin secretion, can occur both in men
and in women treated with methyldopa. This toxicity
is probably mediated by inhibition of dopaminergic
mechanisms in the hypothalamus.
 Clonidine

Toxicity
Dry mouth and sedation are frequent and may be severe. Both effects are centrally mediated
and dose-dependent and coincide temporally with the drug's antihypertensive effect.
The drug should not be given to patients who are at risk for mental depression and should be
withdrawn if depression occurs during therapy
Reserpine
 Adrenoceptor Antagonists

• The pharmacology of drugs that antagonize

catecholamines at - and -adrenoceptors is
presented in Chapter 10: Adrenoceptor
Antagonist Drugs. This chapter will
concentrate on two prototypical drugs,
propranolol and prazosin, primarily in relation
to their use in treatment of hypertension.
Other adrenoceptor antagonists will be
considered only briefly.
 Propranolol

• Propranolol was the first -blocker shown to be effective in

hypertension and ischemic heart disease. It is now clear
that all -adrenoceptor-blocking agents are very useful for
lowering blood pressure in mild to moderate hypertension.
• In severe hypertension, -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 in
patients with heart failure, and they are particularly
advantageous for treating hypertension in that population
 BETA BLOCKERS
Labetalol, carvedilol->Beta1 =Beta 2
- Alfa1 >Alfa2
Antagonists
• Metoprololol, acebutolol, alprenolol, atenolol,
betaxolol, celiprolol, esmolol:-> B 1 >>>B 2
• Propranolol, carteolol, penbutolol, pindolol,
timolol: B 1 =B 2
• Butoxamine: B 2 >>> B 1
• Prazosin is a piperazinyl quinazoline effective in the management
of hypertension:(Antihypertensive Agents).
It is highly selective for 1 receptors, having relatively low affinity for
2 receptors (typically 1000-fold less potent).
This may partially explain the relative absence of tachycardia seen
with prazosin as compared to what is reported with phentolamine
and phenoxybenzamine.
• Prazosin leads to relaxation of both arterial and venous smooth
muscle due to blockade of 1 receptors.
• Prazosin is extensively metabolized in humans; because of metabolic
degradation by the liver, only about 50% of the drug is available
after oral administration. The halflife is normally about 3 hours.
• Terazosin is another reversible 1-selective
antagonist that is effective in hypertension
(Chapter 11:Antihypertensive Agents); it has
also been approved for use in men with urinary
symptoms due to benign prostatic hyperplasia
(BPH). Terazosin has high bioavailability but is
extensively metabolized in the liver, with only a
small fraction of unchanged drug excreted in the
urine. The half-life of terazosin is 9–12 hours
• Doxazosin is efficacious in the treatment of
hypertension and BPH. It differs from
prazosin and terazosin in having a longer half-
life of about 22 hours. It has moderate
bioavailability and is extensively metabolized,
with very little parent drug excreted in urine
or feces. Doxazosin has active metabolites,
although their contribution to the drug's
effects is probably small
• Tamsulosin is a competitive 1 antagonist with a structure quite different from that of most other
• 1-receptor blockers. It has high bioavailability and a long half-life of 9–15 hours. It is metabolized
• extensively in the liver. Tamsulosin has higher affinity for 1A and 1D receptors than for the 1B
• subtype. The drug's efficacy in BPH suggests that the 1A subtype may be the most important
• subtype mediating prostate smooth muscle contraction. Evidence suggests that tamsulosin has
• relatively greater potency in inhibiting contraction in prostate smooth muscle versus vascular
• smooth muscle, compared with other 1-selective antagonists, which have equal or greater effects in
• vascular smooth muscle. This finding suggests that 1A receptors are less important in mediating
• contraction in human arteries and veins. Furthermore, compared with other antagonists,
tamsulosin
• has less effect on standing blood pressure in patients. Nonetheless, caution is appropriate in using
• any antagonist in patients with diminished sympathetic nervous system function.
• Members of the prazosin family of 1-selective antagonists are efficacious drugs in the treatment of
• mild to moderate systemic hypertension
• Alfuzosin is an 1-selective quinazoline derivative that has also
been shown to be efficacious in BPH. It has a bioavailability of
about 60%, is extensively metabolized, and has an elimination
halflife of about 5 hours. This drug is not currently available in the
USA.
• Indoramin is another 1-selective antagonist that also has efficacy
as an antihypertensive. Urapidil is an 1 antagonist (its primary
effect) that also has weak 2-agonist and 5-HT1A-agonist actions
and weak antagonist action at 1 receptors. It is used in Europe as
an antihypertensive agent and for benign prostatic hyperplasia.
• Labetalol has both 1-selective and -antagonistic effects; it is
discussed below
 Pharmacokinetic Properties of the Beta-Receptor Antagonists

• Absorption:Most of the drugs in this class are

well absorbed after oral administration; peak
concentrations occur 1–3 hours after ingestion.
Sustained-release preparations of propranolol
and metoprolol are available.
• Bioavailability: Propranolol undergoes extensive
hepatic (first-pass) metabolism; its bioavailability
is relatively low (Table 10–2). The proportion of
drug reaching the systemic circulation increases
as the dose is increased, suggesting that hepatic
extraction mechanisms may become saturated
 Properties of Several Beta-Receptor-Blocking Drugs
Selectivity PartialAgonistActi LocalAnestheticActi LipidSolubility EliminationHalf-Life Approxi ioavailability

Acebutolol 1 Yes Yes Low 3–4 hours 50

Atenolol 1 No No Low 6–9 hours 40
Betaxolol 1 No Slight Low 14–22 hours 90
Bisoprolol 1 No No Low 9–12 hours 80

Carteolol None Yes No Low 6 hours 85

Carvedilol 1 None No No No data 6–8 hours 25–35
Celiprolol 1 Yes 2 No No data 4–5 hours 70

Esmolol 1 No No Low 10 minutes –0

Labetalol 1 None Yes 1 Yes Moderate 5 hours 30
Metoprolol 1 No Yes Moderate 3–4 hours 50
Nadolol None No No Low 14–24 hours 33
Penbutolol None Yes No High
 Alpha1 Blockers
• Prazosin :
• Mechanism & Sites of Action:
• Prazosin, terazosin, and doxazosin produce
most of their antihypertensive effect by
blocking 1- receptors in arterioles and venules.
Selectivity for 1-receptors may explain why
these agents produce less reflex tachycardia
than do nonselective -antagonists such as
phentolamine
 Angiotensin converting enzyme inhibitors (ACE inhibitors)

Drugs in this class:

• Captopril
• Enalapril*
• Lisinopril
• Ramipril*
• Trandolapril*
• Fosinopril*
• Cilazapril*
• Imidapril*
• Moexipril*
• Quinapril*
• Perindopril*
British Hypertension Society guidelines suggest that
an ACE inhibitor, beta-blocker, calcium channel
blocker, or thiazide diuretic should be first-line
choices for the treatment of hypertension
ACE inhibitors are less likely to be effective in low-
renin hypertension, which is common among
Afro-Caribbean patients.
An ACE inhibitor may be a particularly good choice
for patients with diabetes
 Treatment and prevention of diabetic nephropathy

• ACE inhibitors have a beneficial effect in delaying

the progression of nephropathy in patients with
type I diabetes. This effect seems to be
independent of their effects on blood pressure,
but this is controversial.
• There is debate about the extent to which these
results also apply to patients with type II diabetes.
Trials of angiotensin receptor blockers have shown
efficacy in type II diabetes. Most clinicians do not
distinguish between type I and type II diabetes,
because the cause of the damage is thought to be
very similar.
• Dry cough is common (about 20% of patients). It is
thought to result from reduced breakdown of bradykinin
in the bronchial mucosa. This may be intolerable
Safety:
• Measure renal function 4 days and 2 weeks after starting
these drugs.
• Measure renal function 1 week after increasing the dose.
• Measure the plasma potassium if the patient is also
taking a potassium-sparing drug. See interactions above.
• Measure the blood pressure.
 Prescribing information: Angiotensin
converting enzyme inhibitors
Captopril:
• By mouth, initial dose 6.25 mg.
• Needs to be given three times daily to give 24-hour cover.
• May be increased to 12.5 mg tds, 25 mg tds, and a maximum of 50 mg
tds.
• Consider a once-daily drug for long-term treatment.

Enalapril:
• By mouth, inital dose 2.5 mg
• Should be given twice daily for 24-hour cover.
• May be increased to 5 mg, 10 mg, 20 mg, and a maximum of 40 mg
daily, in divided doses.
Lisinopril:
• By mouth, initially 2.5 mg daily.
• May be increased to 10 mg, 20 mg, and a maximum of 40 mg daily(in
hypertension).
• Usual maintenance dose 10–20 mg daily.

Ramipril:
• By mouth, initially 2.5 mg daily.
• May be increased to 5 mg, then to a maximum of 10 mg daily .
 Angiotensin receptor antagonists/blockers (ARBs)

Antagonists at the angiotensin II receptor (type 1)

Drugs in this class
• Candesartan
• Eprosartan
• Irbesartan
• Losartan
• Telmisartan
• Valsartan
Contraindicated in pregnancy; blocking the effect of angiotensin can
cause birth defects.
ARBs cause vasodilatation and can precipitate a fall in blood pressure
in patients with a fixed cardiac output: aortic stenosis, mitral
stenosis, and hypertrophic cardiomyopathy. Seek expert advice
before using in these groups.
ARBs are less likely to be effective in low-renin
hypertension
An ACE inhibitor or ARB may be a particularly
good choice for patients with diabetes
 Prescribing information: Angiotensin receptor antagonists

Losartan:
• By mouth, 50 mg daily.
• May be increased in increments of 25 mg daily to a maximum of 100 mg daily.
• Reduce the initial dose to 25 mg daily in renal or hepatic insufficiency .

Irbesartan
• By mouth, 150 mg daily.
• May be increased to a maximum of 300 mg daily.
• Reduce the initial dose to 75 mg daily in renal insufficiency.
Candesartan
• By mouth, initially 4 mg daily; increase to 8 mg daily if tolerated.
• May be increased to a maximum of 16 mg daily.
• Reduce the initial dose to 2 mg daily in renal or hepatic insufficiency.
Valsartan
• By mouth, initially 80 mg daily.
• May be increased to a maximum of 160 mg daily.
• Reduce the initial dose to 40 mg daily in renal or hepatic insufficiency.
 Calcium channel blockers
The contraction of vascular smooth muscle cells
depends on influx of calcium into the cell in
response to depolarization. Inhibition of this
influx of calcium causes vasodilatation.
These drugs have differential effects on the
heart and peripheral vasculature, depending
on their chemical structures
 Groups of calcium channel blockers

Dihydropyridines
• Typified by nifedipine
• Principally affect the peripheral vasculature
Phenyalkylamines
• Typified by verapamil
• Principally affect the heart
Benzthiazepines
• Typified by diltiazem
• Affect the heart and peripheral vasculature
 Dihydropyridines (nifedipine-like)

Drugs in this class

• Amlodipine
• Felodipine
• Isradipine
• Lacidipine
• Nicardipine
• Nifedipine
• Nimodipine
• Nisoldipine
Avoid in pregnancy and breastfeeding (teratogenic in animals; excreted in
breast milk).
Amlodipine
• Treatment of hypertension or angina.
– By mouth, initially 5 mg once daily; increase to a maximum of 10 mg once daily.
Felodipine
• Treatment of hypertension
– By mouth, initially 5 mg (elderly 2.5 mg) daily in the morning.
– The usual maintenance dose is 5–10 mg daily.
– Dosages above 20 mg daily are rarely needed.
• Prophylaxis of angina.
– By mouth, initially 5 mg daily in the morning; increase if necessary to 10 mg daily
 Benzthiazepines (diltiazem)

Avoid in pregnancy and breastfeeding

(experimental evidence of teratogenicity;
enters breast milk).
• Diltiazem is negatively inotropic; avoid using in
patients with heart failure.
• Diltiazem also affects cardiac conduction;
avoid using it in patients with 2nd or 3rd degree
heart block or sick sinus syndrome
 Phenylalkylamines (verapamil)

Take care in pregnancy and breastfeeding (but no clear

evidence of harm
• Verapamil is negatively inotropic; avoid it in patients with
known left ventricular impairment or heart failure (even if
they are currently stable).
• The major action of verapamil is on cardiac conduction;
avoid using it in patients with 2nd or 3rd degree heart block
or sick sinus syndrome.
• Do not co-prescribe verapamil with beta-blockers; there is
a risk of severe reduction of cardiac output (see drug
interactions below for details).
• Reduce the dose in severe liver impairment