Antihypertension

Prajogo Wibowo
 ACE-I

Mechanism of Action:
▪ Inhibits peptidyl dipeptidase (Angiotensin Converting Enzyme or ACE). This prevents the
conversion of angiotensin I to angiotensin II. ACE also inactivates bradykinin, a potent
vasodilator that works in part by stimulating the release of nitric oxide and prostacyclin.
▪ ACE inhibition can thereby elevate bradykinin levels in addition to lowering Ang II levels. Ang
II is one of the most potent vasoconstrictors known.Mechanism of Action:
▪ Inhibits peptidyl dipeptidase (Angiotensin Converting Enzyme or ACE). This prevents the
conversion of angiotensin I to angiotensin II. ACE also inactivates bradykinin, a potent
vasodilator that works in part by stimulating the release of nitric oxide and prostacyclin.
▪ ACE inhibition can thereby elevate bradykinin levels in addition to lowering Ang II levels. Ang
II is one of the most potent vasoconstrictors known.
Side Effects:
▪ Acute renal failure can occur in patients with bilateral renal artery stenosis, heart failure or volume
depletion due to diarrhea or excessive diuretic effects.
▪ Hyperkalemia due to aldosterone suppression.
▪ Dry cough develops within 1 week to 6 months in 5-20% of patients, more frequently in women, (believed
to be caused by bradykinin & substance P).
▪ Angioedema (producing swelling around the mouth, nose, throat, glottis, lips and/or tongue occurs in 0.1-
0.5% of patients and is also attributed to bradykinin accumulation. It can be potentially life-threatening due
to airway swelling & obstruction). It usually develops within the first few hours after initiation of therapy.
▪ Severe hypotension in patients who are hypovolemic due to diuretics, salt restriction of GI fluid loss.
▪ Other side effects include: allergic response to sulfhydryl group on captopril, an alteration or loss of taste
(dysgeusia), skin rash & glycosuria. Neutropenia is a rare but serious side effect seen in hypertensive
patients with collagen-vascular or renal parenchymal disease.
Contraindications:
▪ Pregnancy: ACE inhibitors can cause fetal hypotension, renal failure & fetal malforations or
death when taken during the 2nd & 3rd trimesters. In addition, first trimester use of ACE
inhibitors, has also been associated with a potential risk of birth defects in retrospective data.
Once pregnancy is diagnosed, it is essential that ACE inhibitors be discontinued as soon as
possible, and another alternative antihypertensive drug regimen started, if necessary.
▪ Conditions where renal perfusion pressure is low, such as bilateral renal stenosis, or renal
stenosis in patients having only one kidney, heart failure or volume depletion caused by
diarrhea or excessive diuretic effect (Jackson 2006). This is because Ang II-mediated
vasoconstriction of the efferent arteriole helps maintain GFR when renal perfusion is low.
ACE-inhibitors and ARBs can cause acute renal failure in these situations.
Drug Interactions:
▪ Combination with potassium supplements or K-sparing diuretics can
result in hyperkalemia.
▪ NSAIDs may impair the hypotensive effect by blocking bradykinin-
mediated vasodilation (mediated at least in part by prostaglandins).
▪ NSAIDs can also reduce the production of prostaglandins which act
as renal vasodilators & are important for autoregulation of renal
blood flow. This is thought to be one mechanism by which NSAIDs
can cause nephrotoxicity
 ARBs

Mechanism of Action:
▪ Block AT1 receptors
▪ They have no effect on bradykinin metabolism & are
therefore more selective blockers on angiotensin effects
compared to ACE inhibitors
▪ They have the potential for more complete inhibition of Ang II
action compared to ACE inhibitors because there are
enzymes other than ACE that can generate Ang II
▪ Contraindications:
▪ Similar to ACE inhibitors, including contraindicated during 2nd &
3rd trimester of pregnancy. When used in pregnancy during the
second and third trimesters, drugs that act directly on the renin-
angiotensin system can cause injury and even death to the
developing fetus.
▪ Side Effects:
▪ Cough & angioedema can occur but are less common compared
to ACE inhibitors.
 Hydrazine

▪ Mechanism of Action:
▪ Hydralizine causes the relaxation of vascular smooth muscle by poorly understood
mechanism(s)
▪ It preferentially dilates arterioles vs. venous blood vessels, and thereby does not tend to
result in significant postural hypotension
▪ Its effect is abolished by endothelial denudation, suggesting an endothelial-dependent
mechanism (Maille et al, 2016).
▪ Hydralazine lowers blood pressure & promotes an increase in cardiac output via afterload
reduction
▪ Indications:
▪ Essential hypertension
▪ Hydralazine combination with nitrates is effective in heart failure & should be considered
an option in patients with both hypertension & heart failure, especially in African-American
patients
▪ Contraindications:
▪ Hypersensitivity to hydralazine
▪ Coronary artery disease
▪ Mitral valvular rheumatic heart disease
▪ Pharmacokinetics:
▪ Oral or parenteral administration
▪ Bioavailability is low (~25%)
▪ Plasma levels of hydralazine vary widely among individuals
▪ The half life is 1.5-3.0 hours, and 2-3 times per day dosing is needed to provide a
smooth control of blood pressure
▪ Hydralazine undergoes hepatic metabolism that is subject to polymorphic acetylation*
▪ Fast acetylators have lower plasma levels of hydralazine and require higher doses to
control blood pressure
▪ Side Effects:
▪ headache
▪ anorexia
▪ vomiting
▪ angina
▪ tachycardia
▪ Slow acetylators have a 10-20% incidence of a reversible lupus-like
syndrome characterized by arthralgia, myalgia, skin rash & fever (without
renal impairment)
▪ Drug interactions:
▪ MAO inhibitors should be used with caution in patients on hydralazine
 Minoxidil

Mechanism of Action:
▪ Minoxidil is a KATP potassium channel opener that increases K
conductance in arterial smooth muscle
▪ An increase in K conductance causes hyperpolarization, resulting in
deactivation of voltage-activated Ca channels and reduced Ca influx.
This causes relaxation of arterial smooth muscle (Mannhold 2003).
▪ Like hydralizine, it preferentially dilates arterioles vs. veins
▪ Arterial vasodilators lower blood pressure & promote an increase in cardiac
output via afterload reduction
ndications:
I

▪ Outpatient therapy of resistant forms of hypertension

▪ It has greater potential antihypertensive effect than
hydralazine, and is typically used as a replacement for
hydralazine if maximal doses of hydralazine are not effective in
patients with renal failure and severe hypertension, who do not
respond well to hydralazine (Benowitz, 2012)
Side Effects:
▪ Dermatologic: Hypertrichosis (increased hair growth) (common; 80%)
▪ hypertrichosis is particularly bothersome in women
▪ application of topical minoxidil to the scalp can stimulate hair growth
in balding men (but the effect disappears when topical application is
discontinued)
▪ CV: Reflex tachycardia, palpitations, angina, edema (if doses of beta
blockers & diuretics are inadequate)
▪ Headache, sweating
Pharmacokinetics:
▪ orally effective
▪ does not enter the CNS
▪ Mechanism of Action:
▪ blocks L-type calcium channels (cardiac & vascular)
▪ benzothiazepine class (has a different site of action on the Ca channel
compared to verapamil or dihydropyridines)
▪ Indications:
1 Vasospastic & Classic Angina (prophylactic treatment)
2 Hypertension
3 Control of ventricular rate in atrial fibrillation of flutter
Contraindications:
▪ Hypotension
▪ AV block (2nd- or 3rd-degree) or sick sinus syndrome,
except in the presence of a functioning ventricular
pacemaker
▪ Acute MI
▪ Pulmonary congestion
▪ Lactation
▪ Pharmacokinetics:
▪ Oral administration.
▪ Plasma elimination half-life is approximately 3.0 to 4.5 hours.
▪ Side Effects:
▪ Hypotension
▪ AV conduction block
▪ Bradycardia
▪ Constipation
▪ Major drug interactions:
▪ Diltiazem can produce additive effects with other antihypertensive drugs & with
cardiac effects of beta blockers
 verapamil

Mechanism of Action:
▪ phenylalkylamine class L-type Ca channel blocker (more
cardiac selective)
▪ Blocks L-type calcium channels (at a different site on the Ca
channel than diltiazem or dihydropyridines)
▪ Verapamil has slightly greater depressant effects on cardiac
tissue vs diltiazem, and much more than dihydropyridines
(which are vascular selective)
Indications:
1 Vasospastic & Effort-Associated angina (prophylactic treatment)
▪ Calcium channel blockers can be “tried” in refractory cases of unstable angina,
but otherwise are not drugs of first or second choice in this condition
2 Hypertension
3 Paroxysmal Supraventricular Tachycardia (PSVT)
▪ a drug of choice for prophylaxis
▪ a drug of 2nd choice after adenosine for acute treatment (adenosine has been
shown to produce better outcomes when used for acute conversion of PSVT to
sinus rhythm)
4 Control of ventricular rate in patients with chronic atrial fibrillation/flutter.
Contraindications:
▪ Severe hypotension
▪ 2nd or 3rd degree AV block
▪ Cardiogenic shock
▪ Severe CHF
▪ Sick sinus syndrome (unless client has artificial
pacemaker)
▪ Severe LV dysfunction
Pharmacokinetics:
▪ Oral administration
▪ A nonlinear correlation between the verapamil dose administered and verapamil
plasma levels does exist
▪ Estimated mean elimination half-life of 2.8 to 7.4 hours with single doses
▪ After repetitive dosing, the half-life has been observed to increase to 4.5 to 12.0
hours (after less than 10 consecutive doses given 6 hours apart)
▪ Bioavailability of verapamil is higher and half life longer in older (>65 yrs)
subjects
▪ Lean body weight also affects its pharmacokinetics inversely
▪ Side Effects:
▪ Constipation
▪ Bradycardia
▪ AV conduction block
▪ Asystole
▪ Major drug interactions:
▪ Verapamil undergoes biotransformation by predominantly CYP3A4,
however CYP1A2 and members of the CYP2C subfamily are involved in
its metabolism
▪ Verapamil can produce additive effects with other antihypertensive drugs
& with cardiac effects of beta blockers
 Propanolol

Mechanism of Action:
▪ Competitively blocks both β1 and β2 adrenergic receptors.
When access to β-receptor sites is blocked by Propranolol
HCl, the chronotropic, inotropic, and vasodilator responses
to beta-adrenergic stimulation are decreased
proportionately.
Indications:
1 the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a
thiazide diuretic.
2 the long-term management of patients with angina pectoris.
3 cardiac arrhythmias (atrial tachyarrhythmias induced by catecholamines, digitalis, thyrotoxicosis, or associated with Wolff-
Parkinson-White syndrome; for the control of ventricular rate in patients with atrial flutter or fibrillation when digoxin is ineffective or
contraindicated, ventricular arrhythmias caused by catecholamines or digoxin).
4 prevention of sudden death and reinfarction after an MI.
5 prophylactic treatment for the prevention of migraine headaches. (Not used for acute aborting of migraine attacks)
6 treatment of systolic & diastolic forms of heart failure
▪ Low doses of beta blockers reverse remodeling caused by chronic elevation of sympathetic tone in patients with systolic heart
failure. Ejection fraction typically increases significantly after several months of low dose beta blocker therapy.
▪ Beta blockers are also indicated for treating diastolic heart failure (heart failure with normal ejection fraction). Reducing the
heart rate assists diastolic filing, and reduced wall stiffness may help with diastolic filling.
7 management of hypertrophic subaortic stenosis
8 adjunct therapy with alpha blockers in treatment of pheochromocytoma
9 management of familial or hereditary essential tremor
▪ Contraindications:
▪ Cardiogenic shock
▪ Sinus bradycardia and greater than first degree block
▪ Bronchial asthma
▪ Side Effects:
▪ Bradycardia
▪ Congestive heart failure (a dose-dependent effect; low doses are used to treat heart
failure)
▪ Intensification of AV block
▪ Hypotension
▪ Paresthesia of hands
▪ Light-headedness
▪ Mental depression manifested by insomnia, lassitude, weakness, fatigue; sexual
dysfunction in men (see Refs 1, 4 & 5).
▪ Pharmacokinetics:
▪ Propranolol is almost completely absorbed from the gastrointestinal tract, but a portion is
immediately bound by the liver
▪ Peak effect occurs in one to one-and-one-half hours. The biologic half-life is approximately four
hours.
▪ There is no simple correlation between dose or plasma level and therapeutic effect, and the dose-
sensitivity range as observed in clinical practice is wide. The principal reason for this is that
sympathetic tone varies widely between individuals. Since there is no reliable test to estimate
sympathetic tone or to determine whether total beta blockade has been achieved, proper dosage
requires titration.
▪ Major drug Interactions:
▪ Patients receiving catecholamine-depleting drugs such as reserpine should be closely observed if
propranolol is administered.
▪ Caution should be exercised when patients receiving a beta blocker are administered a calcium-
channel blocking drug.
 Metoprolol

Mechanism of Action:
▪ a β1 selective (cardioselective) adrenoceptor blocking agent.
▪ This preferential effect is not absolute, however, and at higher
plasma concentrations, metoprolol also inhibits β2-
adrenoreceptors, chiefly located in the bronchial and vascular
musculature.
▪ Metoprolol has no intrinsic sympathomimetic activity, and
membrane-stabilizing activity is detectable only at plasma
concentrations much greater than required for beta-blockade.
▪ Indications:
▪ Hypertension
▪ Post-MI
▪ Angina Pectoris
▪ CHF (see Propranolol)
▪ Contraindications:
▪ Sinus bradycardia
▪ Heart block greater than first degree
▪ Cardiogenic shock & overt cardiac failure
▪ Pharmacokinetics:
▪ Oral and oral sustained-release formulations are available
▪ Side Effects:
▪ Fatigue
▪ Dizziness
▪ Depression
▪ Bradycardia
▪ For more information on beta-blocker CNS side effects (see
propranolol).Major drug Interactions:
▪ Reserpine or calcium channel blockers (additive effect)
Mechanism of Action:
▪ A racemic mixture of two pairs of isomers that produces both
selective β1 block & vasodilation.
▪ The d-isomer is a highly selective β1 blocker (the most selective
β1 blocker clinically available)
▪ the l-isomer causes the release of nitric oxide via β3 receptor-
mediated activation of endothelial NO production (Kamp et al,
2010).
▪ Nebivolol lacks agonist & Na channel blocking (membrane
stabilizing) actions at therapeutically relevant concentrations.
▪ Indications:
▪ Treatment of hypertension.
▪ Contraindications:
▪ Patients (especially those with coronary artery disease)
should avoid abrupt discontinuation of therapy due to an
increased risk of myocardial infarction & ventricular
arrhythmias.
▪ In general, patients with bronchospastic disease should
not receive beta blockers.
▪ Side Effects:
▪ Relatively few reported
▪ Pharmacokinetics:
▪ Oral formulations. Plasma half life of the active d-isomer
is ~12 hours.
▪ Metabolized by a number of routes, including CYP2D6.
Metabolites contribute to beta-blocking activity
 Prazosin

Mechanism of Action:
▪ Selectively blocks α1 adrenergic receptors (competitive)
▪ The peripheral vasodilator effect of prazosin is confined mainly
to the level of the resistance vessels (arterioles)
▪ Unlike conventional α-blockers, the antihypertensive action of
prazosin is usually not accompanied by a marked reflex
tachycardia (e.g. as compared to a non-selective α-blocker)
▪ Indications:
▪ Treatment of hypertension
▪ It can be used alone or in combination with other antihypertensive drugs
such as diuretics or beta-adrenergic blocking agents
▪ Side Effects:
▪ Dizziness
▪ Orthostatic hypotension
▪ Pharmacokinetics:
▪ Taken orally. Following oral administration, human plasma concentrations
reach a peak at about three hours with a plasma half-life of two to three hours.
▪ The drug is highly bound to plasma protein.
 Doxazosin

▪ Mechanism of Action:
▪ α-1 selective blocker (similar to prazosin)
▪ Indications:
▪ Benign Prostatic Hyperplasia (BPH) - treatment of urinary outflow obstruction
▪ Antagonism of alpha-1 receptors relaxes smooth muscle in the prostate and bladder neck,
which decreases urethral resistance & relieves outflow obstruction in patients with BPH.
▪ Optional drug for treatment of Hypertension, but more useful in those patients with both BPH and
hypertension.
▪ NOTE: Alpha blockers have not been shown to reduce morbidity and mortality in patients with
hypertension, in contrast to several other classes of antihypertensive medications (such as
thiazide diuretics, ACE inhibitors & calcium channel blockers).
▪ Pharmacokinetics:
▪ Long half life (22 hrs), once a day dosing.
 Terazosin

Mechanism of Action:
▪ Competitive α-1 blocker
▪ It has also been shown to induce prostate smooth muscle
cell apoptosis resulting in improvement of urinary
symptoms. It has a quinazoline structural nucleus which
may account for this effect.
▪ Indications:
▪ Treatment of hypertension & BPH
▪ Improves urinary flow rates & symptoms in patients with BPH
▪ Commonly prescribed along with finasteride (which has a different mechanism of
action) to control the progression & symptoms of BPH. When combined, a smaller
terazosin maintenance dose can be used, resulting in less dose-related side
effects (e.g. orthostatic hypotension & dizziness).
▪ Pharmacokinetics:
▪ Half life of 9-12 hrs
▪ Side Effects:
▪ Dizziness, syncope & orthostatic hypotension
 Aliskiren

Mechanism of Action:
▪ A direct inhibitor of renin
▪ Renin is secreted by the kidney in response to a reduction in renal perfusion
due to hypertension or reduction in blood volume. Renin cleaves
angiotensinogen to Ang I.
▪ Ang I is converted to the active Ang II by both angiotensin-converting enzyme
(ACE) & non-ACE pathways
▪ Ang II has multiple actions, including being a powerful vasoconstrictor, causing
the release of catecholamines from the adrenal gland & nerve endings,
promoting aldosterone secretion & subsequent Na reabsorption. These effects
in combination increase blood pressure.
▪ Indication:
▪ Treatment of Hypertension
▪ It has a clinical efficacy similar to ACE inhibitors (but is more expensive)
▪ The results of clinical trials have made it “not” a drug of first choice:
▪ In the AVOID & ALTITUDE clinical trials, combination of aliskiren plus either an ACE inhibitor
or an ARB increased the risk of adverse effects, but did not lower the risk of a serious
cardiovascular or renal event (Mann & Hilgers, 2013).
▪ Side Effects:
▪ Fetal/Neonatal Morbidity & Mortality when used in the 2nd & 3rd trimester of pregnancy. In
addition, first trimester use of ACE inhibitors, has also been associated with a potential risk of
birth defects in retrospective data
▪ Dose-related GI adverse effects (diarrhea, abdominal pain, dyspepsia)
 Methyldopa

Mechanism of Action:
▪ The antihypertensive effect of methyldopa is believed to be due to its
metabolism to α-methylnorepinephrine, which then lowers arterial
pressure by:
▪ false neurotransmission (by replacing vesicular norepinephrine
with α-methylnorepinephrine)
▪ activation of presynaptic α2 receptors in the brainstem reduces
sympathetic outflow, lowering blood pressure (similar to clonidine)
▪ reduction of plasma renin activity
▪ Indications:
▪ Treatment of hypertension during pregnancy as a
replacement for ACE inhibitors & ARBs (which are more
efficacious, but are strongly contraindicated in pregnancy).
▪ The patient can be switched back to an ACE inhibitor or
ARB once pregnancy is over
▪ Notes:
▪ Methyldopa is the L-isomer of alpha-methyldopa
 Clonidine

Mechanism of Action:
▪ α2 adrenoreceptor agonist that produces its main therapeutic
effect by stimulating α-2 receptors in the brain stem.
▪ This action results in reduced sympathetic outflow from the central
nervous system. This produces:
▪ decreased total peripheral resistance
▪ decreased renal vascular resistance
▪ reduced heart rate
▪ reduced blood pressure
▪ Indications:
▪ treatment of hypertension
▪ Contraindications:
▪ Hypersensitivity
▪ Side Effects:
▪ Dry mouth, dizziness, constipation
▪ Pharmacokinetics:
▪ Clonidine acts relatively rapidly. The patient’s blood pressure
declines within 30 to 60 minutes after an oral dose, the maximum
decrease occurring within 2 to 4 hours.
▪ Major drug Interactions:
▪ May potentiate the CNS-depressive effects of alcohol,
barbiturates or other sedating drugs.
▪ May produce bradycardia & depress sinus node function in
patients on digitalis, calcium channel blockers and beta-blockers.
Combination