Antihypertensive Drugs
Dr. Kaukab Azim. MBBS, PhD
Drug List *
Diuretics
Sympathoplegic
Vasodilators
drugs
Inhibitors and antagonists of the reninangiotensin system
ACE
inhibitors
Captopril
Hydrochlorothiazide
Indapamide
Clonidine
Hydralazine
Methyldopa
Nitroprusside Enalapril
Furosemide
Prazosin
Minoxidil
Spironolactone Propranolol
Enalaprilat
Diazoxide
Labetalol
Fenoldopam
Esmolol
CCBs
* More drugs have been mentioned in other slides
ARBs
Losartan
Renin
inhibitors
Aliskiren
Hypertension Epidemiology
It is estimated that, in industrialized countries, some kind of hypertension (HTN)
affects 25 % of subjects over 20.
HTN is a main risk factor for stroke, coronary and renal diseases, heart failure and
sudden death.
In about 95% of cases, the etiology of HP is unknown (essential or primary
hypertension) but is thought to be multifactorial.
Heredity is a predisposing factorial. Environmental factors (i.e. dietary Na+, obesity,
stress) seem to act only in genetically susceptible persons.
In most cases the disease lacks subjective symptoms.
The medical treatment of HP is usually long-lasting (often for life).
It is estimated that today 50% of hypertensive patients lacks an effective treatment.
Other definitions
Isolated systolic hypertension is defined as a systolic blood
pressure of greater than 140 mm Hg and a diastolic pressure
of < 90 mm Hg and staged appropriately (e.g. 170/85 mm Hg
is defined as stage 2 isolated systolic pressure).
Hypertensive crisis can be defined as a severe elevation in
blood pressure (diastolic BP >120 mm Hg), and is classified
further as
a) hypertensive emergency (immediately life-threatening,
with end-organ damage)
b) hypertensive urgency (non immediately life-threatening,
without end-organ damage)
The terms accelerated hypertension or malignant
hypertension are used to define a severe hypertension
accompanied by end organ damage.
Pathophysiology of HTN
1) Disorder of sodium metabolism (likely the main factor)
The extracellular fluid volume increases in hypertensive patients when
exposed to high dietary sodium intake, in spite of the expected natriuretic
response
2) Imbalance of the renin-angiotensin system
a. 20 % have lower than normal renin values
b. 20 % have higher than normal renin values
c. 60 % have normal renin values
3) Sympathetic overactivity (hyperdynamic state).
Increased sympathetic activity leads to increases in cardiac output, heart
rate, plasma renin concentration and peripheral vascular resistance.
[all the above mentioned mechanisms are probably secondary to a genetic
predisposition]
4) Mosaic theory: Multiple factors sustain hypertension even though
aberration of only one could be initially responsible.
Classification of Antihypertensive
Drugs
1) Diuretics
• Thiazides and congeners.
• Loop diuretics.
• Potassium-sparing
diuretics.
2) Sympatholytic drugs
• Centrally acting
antiadrenergic agents.
• Alpha adrenergic blockers.
• Beta adrenergic blockers.
• Alpha-beta adrenergic
blockers.
3) Vasodilators
• Nitric oxide releasers.
• Potassium channel
openers.
• Calcium channel blockers
• D1-dopamine receptor
agonists.
4) Angiotensin inhibitors and
antagonists
• Angiotensin Converting
Enzyme (ACE) inhibitors.
• Angiotensin receptor
antagonists.
Diuretics
 Diuretics lower blood pressure but there is no strict
correlation between diuretic efficacy and
antihypertensive efficacy.
 The fact points out that diuretics do not reduce blood
pressure only by increasing diuresis.
 The initial hypotensive effects of diuretics is associated
with a reduction in plasma volume and cardiac
output. Peripheral vascular resistance is usually
unaffected (or sometimes increased).
 After 4-8 weeks of continuous therapy intravascular
volume and cardiac output return towards normal
while peripheral vascular resistance decreases, due to
arteriolar vasodilation.
Diuretics
Mechanisms of this vasodilation are still poorly
understood, but are probably related to:
a) Depletion of body Na+ stores (likely the main
mechanism) which leads to a fall in smooth muscle
Na+ concentration. This in turn decreases
intracellular Ca++ concentration by activating the
Ca/Na exchanger.
b) Induction of renal prostaglandin biosynthesis.
c) Opening of K channels.
Diuretics
 Thiazides and thiazide-like drugs are first choice antihypertensive
agents. They are the most effective diuretics to reduce blood
pressure in patients with normal renal function.
 The antihypertensive doses are lower that those required for
diuretic effect.
 Loop diuretics are preferable to thiazides only in some well
recognized clinical situations (malignant hypertension, concomitant
chronic kidney disease etc.)
 Potassium sparing diuretics are only used in combination with
thiazides to counteract hypokalemia. Spironolactone is used in
hypertension due to hyperaldosteronism.
 Diuretics can enhance the hypotensive effects of many
antihypertensive agents.
Drugs that alter sympathetic
nervous system function
Centrally acting sympathoplegic
Drugs
Drugs
• Alpha-2 receptor agonists: clonidine
• Indirect acting adrenergic drugs: methyldopa
Mechanisms of antihypertensive action
a) Alpha-2 receptor agonists:
• Activation of alpha-2 receptors in Nucleus Tractus Solitarius and in
rostral ventrolateral medulla (the main mechanism).
• Activation of peripheral alpha-2 receptors (after high doses).
b) Indirect acting adrenergic drugs:
Methyldopa acts as a false neurotransmitter. It is taken up by the
adrenergic neurons where it is transformed into methylnorepinephrine,
the alpha-2 receptor agonist, which acts as described above.
The final effect common to all these drugs is a decreased firing of the
reticulospinal tract, that is a decrease of central adrenergic tone
Therapeutic uses in hypertension
• Clonidine and methyldopa (usually given
together with a diuretic) are second choice
drugs for therapy of hypertension.
• Methyldopa is often preferred for the
treatment of hypertension in pregnancy (long
experience has shown that it is not harmful to
the fetus).
Toxicity of centrally acting
sympathoplegic drugs
Central Nervous Ssytem
• Sedation and drowsiness (up to 50%), mental clouding.
• Weakness, headache, dizziness, nightmares (up to 15%)
• Risk for depression
Cardiovascular system
• Clonidine (and rarely methyldopa) can cause a hypertensive crisis, when the drug
is suddenly withdrawn.
• Bradycardia, A-V block (in risk patients).
Gastrointestinal system
• Xerostomia (clonidine up to 50%, methyldopa up to 10%) (the effect is centrally
mediated).
Other systems
• Sexual dysfunction (up to 20%).
• Skin eruption (up to 20% with clonidine, when given transdermally).
• Methyldopa can cause positive Coombs’ test (up to 30%, after longterm therapy).
Alpha Blockers
Drugs
Prazosin, doxazosin, etc.
Mechanism of action
Selective blockade of alpha-1 receptors. (They reduce blood pressure
by dilating both resistance and capacitance vessels)
Adverse effects
1) Cardiovascular system
• Postural hypotension, mainly after the first dose (the so called
"first-dose phenomenon"). It can lead to myocardial and cerebral
ischemia (syncope). The mechanism is uncertain.
• Tachycardia, palpitations (.5%).
• Nasal stuffiness
• Peripheral edema, after chronic treatment (due to sodium and
water retention).
2) Central nervous system
Fatigue, dizziness, vertigo, drowsiness (up to 10%)
3) Other systems
• Urinary frequency, urinary incontinence.
• Sexual dysfunction (up to 20%, it includes
priapism and inhibition of ejaculation).
- (second choice drugs), often associated with
other antihypertensive drugs.
Beta-blockers (the “olols”)
Proposed mechanisms of action
(the mechanisms are listed in order of decreasing importance)
① Decrease in cardiac output (blockade of cardiac beta-1
receptors)
② Inhibition of renin release (blockade of beta-1 receptors
of juxtaglomerular cells)
③ Inhibition of norepinephrine release from presynaptic
adrenergic terminals (blockade of presynaptic beta
receptors)
④ Reduction of central adrenergic tone (blockade of
hypothalamic and bulbar beta receptors?)
Classes of Beta Blockers
Non-selective
• Propranolol
• Carteolol
• Penbutolol
• Pindolol
• Timolol
Selective (at Beta 1)
• Acebutolol
• Atenolol
• Betaxolol
• Bisoprolol
• Metoprolol
Hemodynamic actions
Beta-blockers (Propranolol)
Alpha-beta blockers (Labetalol)
• Heart rate: decreased.
• Heart rate: unchanged.
• Cardiac output: unchanged or
decreased.
• Venous tone: decreased.
• Postural hypotension: evident.
• Renal blood flow: unchanged.
• Cardiac output: decreased.
• Venous tone: unchanged.
• Postural hypotension: negligible.
• Renal blood flow: decreased
(early) normal (late).
• Efficacy of antihypertensive
effect: good.
• Peripheral vascular resistance:
increased (early), decreased
(late)mainly in hypertensive
patients (the mechanism of this
decrease is uncertain).
• Efficacy of antihypertensive
effect: high.
• Peripheral vascular resistance:
decreased.
Guidelines for use of Beta-blockers
Patients most likely to benefit from a betablocker drug therapy are those who have:
1. young age.
2. supraventricular arrhythmias.
3. hypertrophic obstructive cardiomyopathy.
4. exertional angina.
5. post myocardial infarction.
6. hypertensive emergency (labetalol).
Points to remember about BBs
All beta-blockers give equivalent results in the treatment of
hypertension. The choice is therefore mainly dictated by the
tolerability of the treatment.
In this regard it is worth remembering that:
①
Compounds which are partial agonists appear to depress heart
function less than other beta-blockers.
②
Selective compounds increase airway resistance less than
nonselective compounds.
③
Nonselective compounds devoid of partial agonist activity are
most prone to cause peripheral vascular disturbances (because
of a decreased cardiac output associated with a blockade of
vasodilation in skeletal muscle).
Adverse Effects
CVS: Bradycardia, hypotension, rebound
hypertension when withdrawn abruptly
Respiratory: Bronchoconstriction
CNS: Insomia, depression, nightmares,
constipation
Hepatic: Impaired ability of the liver for
gluconeogenesis and glycogenolysis causing
hypoglycemia
Sexual dysfunction
Vasodilators used in treatment of
hypertension
Drug
Site of action
Mechanism of action
Nitropursside
Arterioles and veins
Production of nitric oxide
Hydralazine
Arterioles
Uncertain
(Perhaps inhibition of Ca++
release from sarcoplasmic
reticulum, and stimulation
of NO release)
Minodoxil
Diazoxide
Arterioles
Arterioles
K+ channel opening
K+ channel opening
Fenoldopam
Arterioles
D1- receptor activation
Nitroprusside Pharmacology
Pharmacokinetics
• Rapidly metabolized by red blood cells with liberation of cyanide, which in turn is metabolized to
thiocyanate.
• The half life is about 2 minutes, so the drug must be given by continuous infusion to be effective.
Adverse effects
• Excessive vasodilation, rebound hypertension, palpitations
• Nausea and vomiting, substernal pain
• Accumulation of:
a) cyanide (with too high doses)
b) thiocyanate (over prolonged administration)
Contraindications and precautions
• Impaired cerebral circulation
• Compensatory hypertension (i.e., stenosis of aorta)
Therapeutic uses
• Hypertensive emergencies.
• Severe heart failure (cardiac output can increase owing to afterload reduction).
• To induce a controlled hypotension, during surgery.
Hydralazine Pharmacology
Adverse effects
a) Due to extension of pharmacological effects:
• Asthenia, headache, nausea, dizziness.
• Palpitations, sweating and flushing.
• Myocardial ischemia, angina (in risk patients)
b) Due to immunological reactions
• Lupoid syndrome (up to 20% incidence, with very high doses).
• Fever, serum sickness, hemolytic anemia, vasculitis.
Contraindications and precautions
• Coronary artery disease
• Cerebrovascular disease
• Collagen disease
Therapeutic uses
• Hypertension (second choice drug).
• Heart failure (combined with isosorbide mononitrate in AfricanAmerican patients)
Minodoxil Pharmacology
Pharmacokinetics and administration
• Minoxidil is a prodrug which is transformed by the liver into the active
molecule.
• The half life is about 4 hours but the duration of action is 24-48 hours
probably because of the formation of the active metabolite.
• Administration: oral.
Adverse effects
• Salt and water retention (can be pronounced) (7%).
• Tachycardia, palpitations, flushing, nasal stuffiness angina.
• Cardiac failure (mainly in patients with left ventricular hypertrophy and
diastolic dysfunction, who respond poorly to volume overload)
• Hypertrichosis (Hair growth > 95% of patients, if used for more than a
month).
Therapeutic uses
(Not very commonly used because of its toxicity)
• Severe hypertension that responds poorly to other antihypertensive
medications.
• Locally used to treat baldness.
Diazoxide Pharmacology
Chemistry
The drug is similar to thiazide diuretics, but it does not cause diuresis
Adverse effects
• Salt and water retention, edema.
• Hyperglycemia (50% of patients)
• Excessive hypotension (may lead to stroke, angina and myocardial infarction)
• Flushing and headache (all vasodilators cause this)
• Hypertrichosis (Hair growth in 20% of patients).
Contraindication and precautions
• Compensatory hypertension (i.e., stenosis of aorta)
• Impaired cerebral circulation
• Coronary disease
• Sulfa drug hypersensitivity (a sulfur atom is present in diazoxide molecule)
• Diabetes mellitus
Therapeutic uses
• Hypertensive emergencies.
• To treat hypoglycemia secondary to insulinoma.
Dopamine D1-Receptor Agonist
Fenoldopam is the only drug on the market.
Pharmacodynamics
• Vasodilation, mainly in renal and mesenteric vascular beds.
• Increased natriuresis (activation of D1 receptors causes an inhibition of NA+
reabsorption in the proximal tubule)
Pharmacokinetics
• Half-life: about 10 minutes.
• Administration: IV infusion
Adverse effects
• Reflex tachycardia, flushing
• Dose-dependent increase in intraocular pressure
• Decrease in serum potassium levels (likely due to natriuresis-induced aldosterone
release).
Contraindications
• Angina (tachycardia can trigger an anginal attack)
• Glaucoma.
• Hypokalemic states.
Therapeutic uses
• Hypertensive emergencies.
• To induce a controlled hypotension, during surgery.
Calcium Channel Blockers
as Antihypertensives
Drugs
All calcium channel blockers (verapamil, diltiazem, dihydropyridines) are
equally effective in lowering blood pressure.
Hemodynamic actions
• Heart rate: increased (dihydropyridines); unchanged or decreased
(verapamil, diltiazem)
• Cardiac output: increased (dihydropyridines); unchanged (verapamil,
diltiazem)
• Venous tone: unchanged.
• Peripheral vascular resistance: decreased.
• Postural hypotension: negligible.
• Renal blood flow: unchanged or increased.
• Efficacy of antihypertensive effect: moderate.
• Duration of antihypertensive effect: variable (nifedipine . 2-6 hours;
amlodipine 24-36 hours)
Calcium Channel blockers
Uses in hypertension
• Hypertension (first choice drugs, more effective in African
patients).
• Hypertensive emergencies (nicardipine).
Long term epidemiological studies have reported an increased
risk of mortality when short-acting nifedipine is used in
hypertension. Slow release formulations apparently do not
increase this risk. While there is still debate about causation, it
seems that the sudden decrease in blood pressure causes a
pronounced reflex tachycardia which can precipitate a
myocardial infarction in patients at risk].
Renin Inhibitors
Drugs
• Aliskiren is the only drug on the market
Mechanism of action
• Competitive inhibition of renin, the enzyme that converts
angiotensinogen into angiotensin I (the rate limiting step in
angiotensin II biosynthesis).
• The inhibition of renin activity causes a decrease of angiotensin I, II,
and aldosterone and an increase (up to 10 fold) of plasma renin.
Pharmacodynamics
• Dose-dependent decrease in blood pressure.
Pharmacokinetics
• Oral bioavailability: . 2.5%
• Mainly eliminated unmetabolized by biliary excretion.
• Half-life: 24 hours.
Renin Inhibitors
Adverse effects
(usually well tolerated)
• Dizziness, fatigue
• Diarrhea (up to 10%, dose-related )
• Hyperkalemia (when given with ACE inhibitors or angiotensin
antagonists)
• Severe hypotension (rare)
• Angioedema (rare)
Contraindications
• Pregnancy (because of the known teratogenic effects from blocking
the renin-angiotensin-aldosterone system)
Therapeutic uses
• Hypertension (second choice drugs)
ACE inhibitors
Drugs
• Captopril, lisinopril and enalaprilat are active drugs. All other
compound (enalapril, benazepril, fosinopril, etc.) are prodrugs.
Mechanism of action
• The converting enzyme peptidyl dipeptidase hydrolyzes angiotensin
one to angiotensin II and inactivates bradykinin.
• By inhibiting this enzyme, ACE-inhibitors lead to:
1) inhibition of the renin-angiotensin system
2) increased plasma levels of bradykinin
Both actions lead to a relaxation of vascular smooth muscle, but the
first action is the most important.
All drugs of this class have the same actions and similar patterns of
adverse effects.
(i.e. by inhibiting angiotensin II formation ACE inhibitors decrease the
negative feed-back so causing an increase in renin release. This may
attenuate the antihypertensive effect of these drugs).
ACE inhibitors
Pharmacokinetics
• Oral bioavailability: variable (enalapril 95%, benazepril
40%)
• Distribution in peripheral tissues (most compounds do
not cross the blood-brain barrier)
• All compounds that are prodrugs are transformed by
the liver into active metabolites.
• Half-lives are variable (captopril . 2 hours: benazepril .
20 hours)
• All compounds, except enalaprilat, are administered by
oral route only .
ACE inhibitors: Adverse effects
Cardiovascular system
• Hypotension and postural hypotension (mainly after
the initial doses, in 3-5% of patients who are salt and
water depleted, or who have congestive heart failure).
Respiratory system
• Dry and disturbing cough (up to 20%) (it may be
mediated by accumulation in the lungs of bradykinin
and prostaglandins or, more likely, substance P).
Urinary system
• Renal insufficiency (in patients with bilateral renal
artery stenosis or with stenosis of the renal artery of a
solitary kidney)
Other systems
• Hyperkalemia (mainly when given in
conjunction with other drugs or diseases that
alter K+ homeostasis).
• Angioneurotic edema. It is rare (up to 0.3%),
but may be fatal (inhibition of bradykinin
metabolism can be involved).
Prenatal effects
• ACE inhibitors are pregnancy categoty D
ACE inhibitors: Therapeutic uses
Hypertension (first choice drugs) (thiazide diuretics can increase
substantially the antihypertensive effect)
 Hypertensive emergencies (enalaprilat IV)
 Myocardial infarction (overall mortality is reduced when treatment
is begun during periinfarction period).
 Chronic congestive heart failure (they decrease the progression of
heart failure, the incidence of sudden death and myocardial
infarction, and they improve the quality of life)
 Diabetic glomerulopathy, hypertensive nephroangiosclerosis (they
decrease the progression of the disease by preventing the
angiotensin II induced vasoconstriction on the efferent glomerular
arteriole).
 Primary or secondary hyperaldosteronism (when resistant to
conventional therapy).
Angiotensin II Receptor antagonists
Drugs
• Losartan, eprosartan, irbesartan, etc.
Mechanism of action
• Competitive antagonism at angiotensin II receptors (these drugs selectively block
AT1 receptors)
Pharmacodynamics
• They can prevent and reverse most known actions of angiotensin II, including:
1. Rapid and slow hypertensive responses
2. Stimulant effect on the peripheral sympathetic nervous system.
3. All CNS effects (thirst, vasopressin release, etc.)
4. Release of adrenal catecholamines
5. Secretion of aldosterone
6. All direct and indirect effects of angiotensin II on the kidney
7. All growth-promoting actions
• They exert a more complete inhibition of angiotensin actions compared with ACE
inhibitors (enzymes other than ACE are capable of generating angiotensin II)
• They have no effect on bradykinin and leukotriene metabolism.
Main actions are:
• a) Vasodilation
• b) Increased salt and water secretion
Angiotensin II Receptor antagonists
Pharmacokinetics
• Losartan: - Oral bioavailability:. 33%. Half-life: . 2 hours.
• All compounds are administered by oral route only.
Adverse effects
[all adverse effects that result from inhibiting angiotensin II related functions should be
expected]
• Hypotension (mainly in patients in whom hypertension is highly dependent on
angiotensin II)
• Hyperkalemia (in conjunction with other factors that alter K+ homeostasis)
Main Contraindications
• Bilateral renal artery stenosis, severe stenosis of abdominal aorta.
• Pregnancy [these drugs are classified by FDA in the pregnancy risk category D
because of their substantial teratogenic risk].
Therapeutic uses
• Hypertension (first choice drugs)(thiazide diuretics can increase substantially the
antihypertensive effect)