Drugs used in Hypertension
This left ventricle is very thickened (slightly over 2 cm in
thickness), but the rest of the heart is not greatly enlarged.
This is typical for hypertensive heart disease. The
hypertension creates a greater pressure load on the heart
to induce the hypertrophy.
The left ventricle is markedly thickened in this patient
with severe hypertension that was untreated for many
years. The myocardial fibers have undergone
hypertrophy.
See below
Modulation of Renin Release
Natriuretic Peptide and ADH Signaling Pathways
Hypertension
• High bp assoc with decr LE, stroke, CAD, and
other end-organ diseases (e.g., retinopathy, renal
failure).
• Problem: Risk is graded.
• Lowering the bp is indicated in patients if the
diastole bp > 90 mm Hg and systole bp > 160 mm
Hg.
• Other risk factors for vascular disease may be
synergistic: smoking, obesity, hyperlipidemia, DM
and ventricular hypertrophy.
• In cases of mild hypertension, weight loss, decr
alcohol and salt may be sufficient, but…
• In more severe cases, drug treatment is indicated.
Drugs used for Hypertension
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β-adrenergic receptor antagonists
Thiazide diuretics
ACE inhibitors
Ca2+ antagonists
α 1-adrenergic receptor antagonists?
Centrally acting drugs: α 2-adrenergic receptor
agonists?
• Moderate hypertention usually requires just one
drug, but becoming incr more evident that >2
drugs will do the job better.
Thiazide Diuretics
• One of 2 1st-line of defense in treating hypertension
• Mechanism of decr arterial bp – not known.
• Initially, decr in blood vol, venous return, and cardiac
output  decr bp.
• Gradually, the cardiac output returns to normal, but
the hypotensive effect remains because the peripheral
resistance has, in the meantime, decreased.
• Diuretics have no direct effects on the vascular smooth
muscle.
• Rather, the small, but persistent decr in body Na+ 
decr in H2O  decr bp.
Thiazide Diuretics (cont’d)
• One possible mech: decreased smooth muscle
Na+  2° decr in [Ca2+]cyto so that the muscle
becomes less responsive.
• These drugs may cause hypokalemia, DM,
gout.
• Side-effects: impotence, libido loss.
• These drugs have a flat-dose response curve:
**What does this mean, both response-wise
and clinically? (possible exam question)
β-Adrenoreceptor Antagonists
• One of 2 1st-line of defense in treating hypertension.
• Decr bp by decr cardiac output (CO).
• With cont’d treatment, the CO returns to normal, but
the bp remains low (not known how) because the
peripheral vasc resistance is “reset” at a lower level.
• Centrally acting mechanism? Not likely because some
of these drugs do not cross the BBB.
• Block of β1-adrenoreceptors in renal JG cells that
secrete renin may be involved.
• Adverse side-effects: cold hands, fatigue, asthma
provocation, HF, or conductance block, incr serum TGs,
and decr HDL levels.
• All of these drugs decr bp, but at least some of these
side-effects can be averted (cardioselective hydrophillic
drugs (w/o liver metabolism or BBB penetration) (e.g.,
atenolol).
Vasodilator Drugs – ACE Inhibitors
• Recall angiotensin II – strong circulating
vasoconstrictor. So, inhibiting its synthesis in
hypertensive patients  decr in peripheral
resistance and bp.
• ACEIs don’t impair CV reflexes and share few of
the side-effects with diuretics and β-blockers.
• Side-effects: incr bradykinin  dry cough (ACE
also metabolizes bradykinin);
• More serious side effects: angioedema,
proteinurea, neutropenia.
• 1st dose may cause a very steep fall in bp (e.g., in
patients on diuretics bec. they are Na+-depleted)
• May cause renal failure in patients with
bilateral renal artery stenosis:
- Angiotensin II required to constrict
postglomerular arterioles and maintain
adequate GF.
- Inhibition of angiotensin II formation does
not seriously impair secretion and excessive K+
retention occurs only with K+ supplements or
K-sparing diuretics (recall that aldosterone
incr Na+ reabsorption and K+ excretion).
Vasodilator Drugs –
Angiotensin Receptor Antagonists
• Losartan (e.g.) lowers bp by blocking
angiotensin (AT1) receptors.
• Similar properties to the ACEIs, but do not
cause cough, because they do not prevent
bradykinin metabolism.
Vasodilator Drugs –
Ca-Channel Blockers (Ca antagonists)
• Vascular SM tone determined by [Ca2+]cyto.
• Increased by α1-adrenoceptor activation (recall
incr sympathetic tone?) that triggers Ca2+ release
from the SR via ins-1,4,5-P3 (IP3) signaling.
• Also, receptor-operated cation channels
depolariation  Ca2+ channels (L-type VG Ca2+
channels)  more Ca2+ enters cell.
• Nifedipine, amlopidine bind Ca2+ channels, block
Ca2+ entry  relaxation of arterial SM  decr
peripheral resistance and  decr bp.
• Efficacy similar to that of the thiazides, βblockers, and ACEIs
• Side-effects: excessive vasodilation  dizziness,
headaches, hypotension, flushing, ankle edema.
Vasodilator Drugs –
α1-Adrenoreceptor Antagonists
• Prazosin < doxazosin (longer-acting).
• Selectively block vascular α1-adrenoceptors 
vasodilation.
• Unlike non-selective α-blockers, these drugs
not likely to cause tach, but may cause
postural hypotension.
• May be severe after 1st dose.
Vasodilator Drugs –
Hydrazine
• Used in combination with a β-blocker and
diuretic.
• Side-effects: reflex tach, which may  angina,
headaches, fluid retention
– (2° hyperaldosteronism).
• In slow acetylators, hydrazine may produce
lupus syndrome  fever, arthralgia, malaise,
and hepatitis.
Vasodilator Drugs –
Minoxidil
• Potent vasodilator that  severe fluid retention
and edema.
• But, when given with a β-blocker and loop
diuretic, it is effective in severe hypertension
resistant to other drug combinations.
• Relaxes vascular SM cells by opening ATPsensitive K+ channels  hyperpolarization and
closing VG-Ca2+ channels.
• [These K+ channels are normally kept closed by
ATPintracell, which is antagonised by minoxidil
Centrally-Acting Drugs
• Methyldopa  in adrenergic nerve endings to
α-methylNE, which stimulates α2adrenoceptors in the medulla and decr
sympathetic outflow.
• Side-effect: drowsiness, hemoytic anemia.
• Clonidine  rebound hypertension if
suddenly withdrawn.
Acute Severe Hypertension
• Hydralazine in hypertension assoc with
eclampsia of pregnancy.
• Nitroprusside in malignant hypertension with
encephalopathy.
Kidneys
• Aldosterone stim Na+ reabsorption in the
distal tubule and incr K+ and H+ secretion.
• Cytoplasmic receptors.
• Induces synthesis of the Na+/K+-ATPase in the
basolateral membrane and Na+ channels in
the luminal membrane.
• Cell surface aldosterone receptors may
mediate a more rapid incr in Na+ channel
permeability.
Kidneys (cont’d)
• Diuretics increase the Na+ load in the distal tubules and
 incr K+ secretion and excretion (except for the K+sparing agents).
• This effect is greater if [aldosterone]plasma are high (e.g.,
vigourous diuretic therapy has depleted the body of
Na+ stores.)
• Vasopressin (ADH) released from the Post Pit.
• Incr the number of H2O channels in the collecting ducts
 passive reabsorption of H2O.
• In cranial diabetes insipidus, absence of ADH  large
vols of hypotonic urine: treated with vasopressin (or
desmopressin, a longer acting analogue)
Diuretics – Drugs Acting on the Kidneys
• Purpose: to incr the excretion of NaCl and H2O,
normally controlled by aldosterone and
vasopressin, respectively.
• Most work by decr the reabsorption of
electrolytes by the tubules.
• Accompanied by an incr in H2O excretion so that
osmotic balance is maintained.
[recall that diuretics are used to decr edema in
CHF]. But also used in some renal diseases and
hepatic cirrhosis.
• Some diuretics, esp thiazides, widely used in
treating hypertension, but their long-term
hypotension action is not only related to their
diuretic properties.
Thiazides
• Developed from carbonic anhydrase inhibitors.
• However, the diuretic effect of these drugs is not
related to their actions on this enzyme.
• Relatively safe, orally active, but relatively weak
diuretics
• Widely used for treatment for mild HF and
hypertension (also decr incidence of stroke).
• Many different thiazides exist, differing
significantly only in their duration of action.
• Bendoflumethiazide is widely used.
Thiazides - Mechanism
• Act mainly on the distal segments of tubules,
where they inhibit NaCl reabsorption by
binding to the symporter responsible for the
electroneutral cotransport of Na+/Cl-.
•  incr excretion of Na+, Cl-, and H2O.
• The increased Na+ in the distal tubule stim Na+
exchange with K+ and H+, increasing their
excretion and  hypokalema and metabolic
acidosis.
Thiazides – Adverse Effects
• Hypokalemia may ppt cardiac arrhythmias, esp in
patients on digitalis.
Can be prevented by giving K supplements, or by
combining therapy with K-sparing drugs.
• Hyperuricaemia. Uric acidblood are often
increased because thiazides are secreted by the
organic acid secretory system in the tubules and
compete for uric acid secretion. This may ppt
gout.
• Glc tolerance may be impaired and thiazides are
contraindicated in patients with NIDD.
• Lipids. Thiazides incr [cholesterol]plasma at least
during the 1st 6 mos of administration, but the
signif of this is uncertain.
Loop Diuretics (LDs) (high ceiling)
[Very Powerful]
• More effective than the thiazides.
• Act more rapidly, but shorter duration of action.
• Ususally furosemide – used orally to decr
peripheral and pulmonary edema in moderate
and severe HF.
• Given i.v. for pulmonary edema resulting from
acute ventricular failure.
• Effective in patients with decr renal function
(unlike the thiazides).
Loop Diuretics - Mechanism
• Inhibit NaCl reaborption in the thick ascending loop of
Henle.
This segment has a high binding capacity for absorbing NaCl
 diuresis produced at this site is much greater than at
other sites.
Act on the luminal membrane where they inhibit the
cotransport of Na+/K+/2Cl-.
[Recall that the Na+ is actively transported out of the cells into
the interstitium by an Na+/K+-ATPase-dependent pump at
the basolateral membrane].
• Specificity of these drugs due to their high concentration in
the renal tubules.
• However, at higher doses, these drugs may induce changes
in the electrolyte composition of the endolymph and cause
deafness.
Loop Diuretics – Adverse Effects
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Hyponatraemia
Hypotension
Hypovolemia
Hypokalemia – may be unimportant unless there are
additional risk factors for arrhythmia (e.g., digoxin).
• Can cause severe electrolyte imbalance and
dehydration.
• Ca2+ and Mg2+ excretion often increased ->
hypomagnesmia may occur.
• Over-enthusiastic use (high doses, i.v.) can cause
deafness, which may not be reversible.
Loop Diuretics (cont’d)
• Metalazone – thiazide-related drug with
activity between that of the LDs and thiazides.
• Synergistic with furosemide in treating
resistant edema and serious renal failure.
• Both thiazides and LDs incr K+ excretion.
• So, K+ supplements may be required to
prevent hypokalemia.
K+-Sparing Diuretics (KSDs)
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Weak when used alone.
Given to retain K+.
Often given with thiazides and LDs to prevent hypokalemia.
Act on aldosterone-responsive segments of the distal nephron,
where K+ homeostasis is controlled.
Aldosterone stim Na+ reabsorption  negative Ψ in the lumen,
which drives K+ and H+ into the lumen (and hence their excretion).
The KSDs decr Na+ reabsorption by either antagonizing aldosterone
(spironolactone) or blocking Na+ channels (amiloride, triamterene).
This causes the electrical Ψ across the tubular epithelium to fall,
decreasing the driving force for K+ secretion.
These drugs may cause severe hypokalemia, esp if renal impairment
exists.
Hypokalemia may also occur in the presence of ACEIs (e.g.,
catopril), because these drugs decr aldosterone secretion (and
therefore K+ excretion).
KSDs (cont’d) - Spironolactone
• Competitively blocks the binding of
aldosterone to its cytoplasmic receptor  incr
Na+ (Cl- and H2O) excretion and decr the
‘electrically coupled’ K+ secretion.
• Weak diuretic (only ~2 % of the total Na+
reabsorption is under aldosterone control).
• Used mainly in liver disease with ascites,
Conn’s syndrome (1° hyperaldosteronism) and
severe heart failure.
KSDs (cont’d) –
Amiloride and Triamterene
• Decrease the luminal membrane Na+
permeability in the distal nephron by blocking
Na+ channels on a 1:1 basis.
• This increases Na+ (Cl- and H2O) excretion and
decreases K+ excretion.
Carbonic Anhydrase Inhibitors
• Weak diuretics and rarely used for this purpose.
• Osmotic diuretics (e.g., mannitol) are filtered, but not easily
reabsorbed.
• Excreted with an osmotic equivalent of H2O and are used in
cerebral edema.
• Depress bicarbonate reabsorption in the prox tubule by
inhibiting the catalysis of CO2 hydration and dehydration
reactions.
• Thus, the excretion of HCO3-, Na+, and H2O are increased.
• The loss of HCO3-  metabolic acidosis  the effects of the
drug becomes self-limiting as the [HCO3-]blood falls.
• The incr Na+ delivery to the distal nephron incr K+ secretion.
• Acetazolamide used to treat glaucoma to decr intraocular P
(decr the secretion of HCO3- and assoc H2O into the AH.
Nephron anatomy and
the site of action of
Diuretics
Proximal Convoluted
Tubule Cell –
Note the
Action of
acetazolamide
Logical Combinations
Diuretic
b-blocker
CCB
Diuretic
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b-blocker
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*
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CCB
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-
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ACE inhibitor
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a-blocker
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-
*
* Verapamil + beta-blocker = absolute contra-indication
ACE inhibitor
a-blocker
Compelling and possible indications and contrindications for the major classes of
antihypertensive drugs
INDICATIONS
CONTRAINDICATIONS
CLASSS OF DRUG
COMPELLING
POSSIBLE
POSSIBLE
COMPELLING
a-blockers
Prostatism
Dyslipidaemia
Postural Hypotension
Unrinary incontinence
Angiotensin converting enzyme (ACE) inhibitors
Heart failure
Left ventricular dysfunction
Chronic renal disease *
Type II diabetic nephropathy
Renal impairment *
Peripheral vascular disease †
Pregnancy
Renovascular disease
Angiotensin II receptor antagonists
Cough induced by ACE inhibitor ‡
Heart failure
Intolerance of other antihypertensive drugs
Peripheral vascular disease
Pregnancy
Renovascular disease
Myocardial infarction
Heart failure
b-blockers
Angina
Heart failure
Dyslipidaemia
Peripheral vascular disease
Calcium antagonists (dihydropyridine)
Isolated systolic hypertension (ISH) in elderly patients
Angina
Elderly patients
Calcium antagonists (rate limiting)
Angina
Myocardial infarction
Thiazides
Elderly patients including ISH
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Asthma or COPD
Heart block
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Combination with b-blockade
Heart block
Heart failure
Dyslipidaemia
Gout
* ACE inhibitors may be beneficial in chronic renal failure but should be used with caution. Close supervision and specialist advice are needed when there is established and
significant renal impairment
† Caution with ACE inhibitors and angiotensin II receptor antagonists in peripheral vascular disease because of association
‡ If ACE inhibitor indicated
f b-blockers may worsen heart failure, but in specialist hands may be used to treat heart failure
with renovascular disease.