Medication in hypertension

DR. RASHIDI NOOSHABADI
4/20/2021

Antihypertensive
Agents
ASSO. PROF. OF PHARMACOLOGY
JUNDISHAPUR UNIVERSITY OF MEDICAL SCIENCES, AHVAZ, IRAN
4/20/2021

What Is Blood Pressure ?
Blood pressure is the amount of force on the walls of the arteries as the
blood circulates around the body

Hypertension
The most common cardiovascular disease
oThe prevalence increases with advancing age
oElevated arterial pressure causes pathological changes
in the vasculature and hypertrophy of the left ventricle
oHypertension is defined conventionally as a sustained
increase in blood pressure 140/90 mm Hg
•Isolated systolic hypertension
• systolic BP >140-160 mm Hg with diastolic BP <90 mm Hg)
• largely confined to people older than 60 years of age
4/20/2021

Korotokof sound
4/20/2021 DR. RASHIDI NOOSHABADI

Treatment of Hypertension: 7 classification
CATEGORIES
BP Systolic Diastolic
Normal >120 <80
Prehypertension 120-139 80-89
Stage1 149-159 90-99
Stage2 >160 >100
RISK FACTORS
1. Age above 55 and 65 in Men and Woman
respectively
2. Family History
3. Smoking
4. DM and Dyslipidemia
5. Hypertension
6. Obesity
7. Microalbuminuria

Etiology of Hypertension
Essential or primary hypertension
Secondary hypertension (10–15%)
4/20/2021
> 140 mmHg > 90 mmHg
• ~80–95% of hypertensive
:"essential" hypertension
(primary or idiopathic
hypertension).
• 5–20% : "secondary"
hypertension(a specific
underlying disorder causing the
elevation of blood pressure can
be identified ).

UNDERSTANDING RAAS SYSTEM
Angiotensin II
AT1 receptors
Vasoconstriction
(PVR)
Aldosterone release
salt & water
retention
(preload)
Stimulation
of SNS
Cell growth
AT2 receptors
ACE
Pathway
Non ACE
Pathway
Angiotensinogen
Renin(kidney)
Angiotensin I

BP = CO . PVR
arterioles, postcapillary venules (capacitance vessels), and heart
the kidney (intravascular fluid)
◦ RAS (direct constriction of resistance vessels, aldosterone
synthesis)
◦ Vasopressin
Baroreflexes (inhibits central sympathetic discharge)
local release of vasoactive substances from vascular endothelium
◦ endothelin-1 , NO
Hypertension
4/20/2021

factors may contribute hypertension prevalence
Both environmental and genetic
factors
Obesity and weight gain are strong,
independent risk factors for
hypertension
dietary NaCl intake
Low dietary intakes of
calcium and potassium
alcohol consumption
psychosocial stress
and low levels of physical activity.
blood pressure heritabilities are in
the range of 15–35%.

Therapy of Hypertension
oVery high blood pressures (systolic 210 mm Hg and/or diastolic 120 mm Hg)
othe syndrome of immediately life-threatening hypertension
oPharmacological treatment : Decreases morbidity and mortality from cardiovascular disease
◦ markedly reduces the risk of strokes, cardiac failure, and renal insufficiency due to hypertension
Reduction in risk of MI may be less impressive
4/20/2021

dr. Rashidi Nooshabadi
4/20/2021

Principles of Antihypertensive Therapy
oNonpharmacological therapy
oArterial pressure is the product of cardiac output and peripheral vascular
resistance
oDecreaseing the cardiac output
• by inhibiting myocardial contractility
• or by decreasing ventricular filling pressure (Venous tone , blood volume)
oDecreaseing peripheral resistance
• by acting on smooth muscle to cause relaxation of resistance vessels
oisolated systolic hypertension
◦ complex
◦ drug effects may be mediated by changes in peripheral resistance but also via effects on
large artery stiffness
4/20/2021

Diuretics
• Act on kidneys-Increase excretion
of sodium & water
• Reduce Blood Volume [Preload]
Reduce B.P
• Often used in combination with
other antihypertensive agents -e.g.
ACEIs, AT1 Blockers, beta blockers

Nephron sites of action of diuretics
convoluted

Inhibitors of Carbonic Anhydrase
extrarenal tissues containing carbonic anhydrase
◦ eye, gastric mucosa, pancreas, CNS, erythrocytes
Carbonic anhydrase inhibitors :
oReduction of the rate aqueous humor formation and consequently intraocular pressure
◦ in the CNS
◦ Paresthesias and somnolence
o Improving of epilepsy
◦ interference with carbonic anhydrase activity in erythrocytes
◦ increase CO2 levels in peripheral tissues and decrease CO2 levels in expired gas
oReduction of gastric acid secretion
ovasodilation by opening vascular Ca2+-activated K+ channels
4/20/2021

Inhibitors of Carbonic Anhydrase - Adverse Effects
oThese drugs are sulfonamide derivatives
Adverse effects secondary to urinary alkalinization or metabolic acidosis,
including:
1. induce or worsen hepatic encephalopathy
◦ contraindicated in patients with hepatic cirrhosis
2. calculus formation and ureteral colic
3. worsening of metabolic or respiratory acidosis
4. reduction of the urinary excretion rate of weak organic bases
4/20/2021

Inhibitors of Carbonic Anhydrase - Therapeutic Uses
oEdema
◦ The combination of acetazolamide with diuretics that block Na+ reabsorption at more distal sites in the nephron
causes a marked natriuretic response in patients with low basal fractional excretion of Na+ (<0.2%) who are
resistant to diuretic monotherapy
◦ their long-term usefulness often is compromised by the development of metabolic acidosis
o Open-angle glaucoma (Dorzolamide and Brinzolamide)
o Epilepsy (Acetazolamide)
oSymptomatic relief in patients with high-altitude illness or mountain sickness (Acetazolamide)
oFamilial periodic paralysis (Acetazolamide)
oOther off-label clinical uses
◦ for correcting a metabolic alkalosis, especially one caused by diuretic-induced increases in H+ excretion
4/20/2021

Osmotic Diuretics
Glycerin, Isosorbide, Mannitol, Urea
oOsmotic diuretics act both in proximal tubule and loop of Henle
◦ The major site of action : the loop of Henle
oexpand extracellular fluid volume, decrease blood viscosity, and inhibit renin
release
◦ By extracting water from intracellular compartments
increase urinary excretion of nearly all electrolytes
◦ including Na+, K+, Ca2+, Mg2+, Cl–, HCO3–, and phosphate
4/20/2021

Loop Diuretics
Furosemide, Bumetanide, Ethacrynic acid, Torsemide
oInhibitors of Na+-K+-2Cl– Symport in the thick ascending limb of the loop
of Henle
◦ Highly efficacious
◦ they sometimes are called high-ceiling diuretics (‫باال‬ ‫سقف‬)
1.approximately 25% of the filtered Na+ load normally is reabsorbed by the thick ascending limb
2.nephron segments past the thick ascending limb do not possess the reabsorptive capacity to rescue
the flood of rejectated exiting the thick ascending limb
4/20/2021

Loop Diuretics - Adverse Effects
Most adverse effects : abnormalities of fluid and electrolyte balance
•Serious depletion of total-body Na+
•Hypochloremic alkalosis
•Hypokalemia
•Hypomagnesemia
•Hypocalcemia
•Hyperuricemia
•Ototoxicity
4/20/2021

Thiazide and Thiazide-Like Diuretics
Hydrochlorothiazide, Chlorthalidone, Indapamide
oInhibitors of Na+-Cl– Symport in DCT
Increase Na+ and Cl– excretion
◦ moderately efficacious (i.e., maximum excretion of filtered Na+ load is only 5%)
◦ because ~90% of the filtered Na+ load is reabsorbed before reaching the DCT
Increase K+ and titratable acid excretion : Like inhibitors of Na+-K+-2Cl– symport, by the same mechanisms
oAcute thiazide administration increases uric acid excretion
◦ However, uric acid excretion is reduced following chronic administration
Thiazide diuretics decrease Ca2+ excretion (when administered chronically)
◦ Increased proximal reabsorption and direct effects to increase Ca2+ reabsorption in the DCT
Mild magnesuria
4/20/2021

K+-Sparing Diuretics
Triamterene , Amiloride
Inhibitors of Renal Epithelial Na+ Channels
Small increases in NaCl excretion
usually are employed for their antikaliuretic actions to offset the effects of other diuretics that
increase K+ excretion
the late distal tubule and collecting duct have a limited capacity to reabsorb solutes
◦ Na+ channel blockade in this part of the nephron only mildly increases Na+ and Cl– excretion rates (~2%
of filtered load)
Amiloride, at concentrations higher than needed to elicit therapeutic effects, also blocks the
Na+-H+ and Na+-Ca2+ antiporters and inhibits Na+, K+-ATPase
The most dangerous adverse effect : hyperkalemia
4/20/2021

Antagonists of Mineralocorticoid Receptors
Spironolactone, Eplerenone
oMineralocorticoids cause salt and water retention and increase K+ and H+ excretion
◦ Epithelial cells in late distal tubule and collecting duct contain cytosolic MRs with a high aldosterone affinity
◦ Liddle syndrome
oSpironolactone has some affinity toward progesterone and androgen receptors
eplerenone has very low affinity for progesterone and androgen receptors (<1% and <0.1%,
respectively) compared with spironolactone
life-threatening hyperkalemia
4/20/2021

Centrally acting Drugs
• Alpha-Methyldopa: a prodrug
• Precursor of Dopamine and NA
• MOA: Converted to alpha methyl noradrenaline which acts on alpha-2
receptors in brain and causes inhibition of adrenergic discharge in medulla –
fall in PVR and fall in BP
• Various adverse effects – cognitive impairement, postural hypotension,
positive coomb`s test etc. – Not used therapeutically now except in
Hypertension during pregnancy
• Clonidine: Imidazoline derivative, partial agonist of central alpha-2 receptor
• Not frequently used now because of tolerance and withdrawal hypertension
• Read it yourself
4/20/2021 dr. Rashidi Nooshabadi

DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM
FUNCTION
Adrenergic Receptor Antagonists
CENTRALLY ACTING SYMPATHOPLEGIC DRUGS
◦ Methyldopa : chiefly by reducing peripheral vascular
resistance
◦ The most common undesirable effect : sedation
◦ positive Coombs test
4/20/2021

CLONIDINE
◦ Reduction of cardiac output due to decreased heart rate
◦ relaxation of capacitance vessels
◦ reduction in peripheral vascular resistance
◦ Dry mouth and sedation are common
should not be given to patients who are at risk for mental depression
should be withdrawn if depression occurs during therapy
Concomitant treatment with tricyclic antidepressants may block the antihypertensive effect
of clonidine
◦ The interaction is believed to be due to α-adrenoceptor-blocking actions of the tricyclics
Withdrawal of clonidine after protracted use, particularly with high dosages (more than 1 mg/d),
can result in life-threatening hypertensive crisis mediated by increased sympathetic
nervous activity
4/20/2021

FUNCTION
GANGLION-BLOCKING AGENTS
◦ The adverse effects of ganglion blockers are direct extensions of their pharmacologic effects
◦ These effects include both sympathoplegia (excessive orthostatic hypotension and sexual dysfunction)
◦ and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc).
Guanethidine (no longer available in the USA)
Reserpine (Rauwolfia serpentina)
ADRENOCEPTOR ANTAGONISTS
BETA-ADRENOCEPTOR-BLOCKING AGENTS
◦ Propranolol
◦ Metoprolol & Atenolol
◦ Nadolol, Carteolol, Betaxolol, & Bisoprolol
◦ Labetalol, Carvedilol, & Nebivolol
◦ Esmolol
4/20/2021

receptors present in
• Block Beta
heart :
• Decrease CO  decrease heart rate &
force of contraction  negative
chronotropic & negative inotropic effects
• Decrease in Renin release from the
Kidneys
• Central action - reduction in
Sympathetic tone
Beta Blockers

β-adrenergic blockers
• β-adrenergic blockers are mild antihypertensives and
do not significantly lower BP in normotensives. In
stage 1 cases of hypertensive patients (30 - 40%), β-
adrenergic blockers are used alone.

Propranolol
• Propranolol is a first β blocker showed effective in
hypertension and ischemic heart disease.
• Propranolol has now been largely replaced by
cardioselective β blockers such as metoprolol and
atenolol, bisoprolol…
• All β-adrenoceptor-blocking agents
lowering blood pressure in mild
hypertension.
• In severe hypertension, β blockers
are useful for
to moderate
are especially
useful in preventing the reflex tachycardia that often
results from treatment with direct vasodilators.

Metoprolol & Atenolol
• Metoprolol and atenolol, which are cardioselective,
are the most widely used β blockers in the treatment
of hypertension.
• Metoprolol and atenolol is inhibiting stimulation of β1
adrenoceptors.
• Sustained-release metoprolol is effective in reducing
mortality from heart failure and is particularly useful
in patients with hypertension and heart failure.
to be less effective than
• Atenolol is reported
metoprolol in preventing the complications of
hypertension.

Other beta blockers
• Nadolol and carteolol, nonselective
antagonists
β-receptor
• Betaxolol and bisoprolol are β1-selective blockers
and penbutolol are partial
• Pindolol, acebutolol,
agonists, ie, β
sympathomimetic
particularly beneficial for patients
blockers with some intrinsic
activity. These drugs are
with
bradyarrhythmias or peripheral vascular disease.

Other beta blockers
• Labetalol, Carvedilol, & Nebivolol have
blocking and vasodilating effects.
• Esmolol is a β1-selective blocker that
both β-
is rapidly
metabolized via hydrolysis by red blood cell esterases.
Esmolol is used for management of intraoperative
and postoperative hypertension, and sometimes for
hypertensive emergencies, particularly when
hypertension is associated with tachycardia or when
there is concern about toxicity such as aggravation
of severe heart failure.

α-Adrenergic blockers
Prazosin, terazosin, and doxazosin
• Prazosin is a prototype α1-adrenergic blocking agent.
• Terazosin and doxazosin are long-acting congeners of
prazosin
• Alpha blockers reduce arterial pressure by dilating
both resistance and capacitance vessels.
Other alpha-adrenoceptorblocking agents
• phentolamine (reversible nonselective α-adrenergic
antagonist) and phenoxybenzamine (non-selective,
irreversible alpha blocker) are useful in diagnosis and
treatment of pheochromocytoma.

FUNCTION
ALPHA BLOCKERS
◦ Blocking α1 receptors in arterioles and venules
◦ reduce arterial pressure by dilating both resistance and capacitance vessels
◦ blood pressure is reduced more in the upright than in the supine position
◦ Retention of salt and water
◦ more effective when used in combination with other agents, such as a β blocker and
a diuretic
Prazosin, terazosin, doxazosin
◦ Less reflex tachycardia when lowering blood pressure than do nonselective α
antagonists such as phentolamine
oPhentolamine and phenoxybenzamine
◦ Diagnosis and treatment of pheochromocytoma and in other clinical situations
associated with exaggerated release of catecholamines
4/20/2021

VASODILATORS
oRelax smooth muscle of arterioles
◦ Decreasing systemic vascular resistance
◦ Sodium nitroprusside and the nitrates also relax veins
Hydralazine , Minoxidil
Nitroprusside , fenoldopam
Calcium channel blockers
Nitrates
4/20/2021

VASODILATORS
HYDRALAZINE
◦ Dilates arterioles but not veins
◦ The most common adverse effects : headache, nausea, anorexia, palpitations, sweating, flushing
◦ In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke
angina or ischemic arrhythmias
MINOXIDIL
◦ Very efficacious orally active vasodilator
◦ Dilates arterioles but not veins
◦ Greater potential antihypertensive effect
oSODIUM NITROPRUSSIDE
◦ Releases nitric oxide
◦ Dilates both arterial and venous vessels (reduced peripheral vascular resistance and venous return)
◦ The most serious toxicity is related to accumulation of cyanide; metabolic acidosis, arrhythmias, excessive
hypotension, and death have resulted
4/20/2021

oDIAZOXIDE
◦ parenterally to treat hypertensive emergencies
◦ hypoglycemia in hyperinsulinemia
◦ The most significant toxicity from parenteral : excessive hypotension
◦ Hyperglycemia
FENOLDOPAM
agonist of dopamine D1 receptors
dilation of peripheral arteries and natriuresis
for hypertensive emergencies and postoperative hypertension
4/20/2021

CALCIUM CHANNEL BLOCKERS
inhibition of calcium influx into arterial -
smooth muscle cells
Reduce peripheral resistance and blood pressure
Verapamil, diltiazem
Dihydropyridine family
◦ amlodipine, felodipine, isradipine, nicardipine,
◦ nifedipine, nisoldipine, Clevidipine
4/20/2021

Calcium Channel Blockers – Mechanism of
action
■ Three types Ca+ channels in smooth muscles – Voltage sensitive, receptor operated
and leak channel
■ Voltage sensitive are again 3 types – L-Type, T-Type and N-Type
■ Normally, L-Type of channels admit Ca+ and causes depolarization – excitation-
contraction coupling through phosphorylation of myosin light chain – contraction of
vascular smooth muscle – elevation of BP
■ CCBs block L-Type channel:
■ Smooth Muscle relaxation
■ DHPs have highest smooth muscle relaxation and vasodilator action followed by
verapamil and diltiazem
■ Other actions: DHPs have diuretic action
4/20/2021

Calcium Channel Blockers
■ Advantages:
■ Unlike diuretics no adverse metabolic effects but mild adverse
effects like – dizziness, fatigue etc.
■ Do not compromise haemodynamics – no impairment of work
capacity
■ No sedation or CNS effect
■ Can be given to asthma, angina and PVD patients
■ No renal and male sexual function impairment
■ No adverse fetal effects and can be given in pregnancy
■ Minimal effect on quality of life
4/20/2021

ACE inhibitors
Renin Inhibitors
ACE Inhibitors
Angiotensin
blockers

INHIBITORS OF ANGIOTENSIN
4/20/2021
• The ACE inhibitors, are recommended as
• first-line treatment of hypertension in patients
with a variety of compelling indications,
including high coronary disease risk
or history of diabetes, stroke,
heart failure, myocardial infarction,
or chronic kidney disease.

ACE INHIBITORS
Captopril, Enalapril, Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and
trandolapril
Particularly useful role in treating patients with chronic kidney disease
◦ diminish proteinuria and stabilize renal function
◦ valuable in diabetes, and these drugs are now recommended in diabetes even in the absence of
hypertension
extremely useful in the treatment of heart failure and as treatment after MI
Severe hypotension can occur after initial doses in patients who are hypovolemic
acute renal failure, hyperkalemia, dry cough sometimes accompanied by wheezing, and angioedema
contraindicated during the second and third trimesters of pregnancy
◦ the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or
death
Important drug interactions
◦ potassium supplements or potassium-sparing diuretics
◦ Nonsteroidal anti-inflammatory drugs
4/20/2021

ACE inhibitors
Comparative features of some ACE inhibitors

ARB AGENTS
Losartan , valsartan
Azilsartan, candesartan, eprosartan, irbesartan, olmesartan,
telmisartan
have no effect on bradykinin metabolism
4/20/2021

Possible combination of antihypertensive drugs: Continuous green line
(preferential combinations); dotted green line (acceptable combinations); dotted black
line (less usual combinations); red line (unusualcombinations).
Ref: Póvoa R, Barroso WS, Brandão AA, et al. I brazilian position paper on antihypertensive drug
combination. Arq Bras Cardiol. 2014;102(3):203-10.

Combinations to be avoided
Combination Possible effects
An α or β adrenergic blocker
with clonidine
Apparent antagonism of
clonidine action has been
observed.
Hydralazine with a
dihydropyridine (DHP) or
prazosin
haemodynamic action
Verapamil or diltiazem with β
blocker
bradycardia, A-V block can
Methyldopa with clonidine or any two drugs of the same class

Antihypertensives & pregnancy
Antihypertensives to be avoided
during pregnancy
Antihypertensives found safer
during pregnancy
ACE inhibitors, ARBs: Risk of foetal
damage, growth retardation.
Hydralazine
Methyldopa
Diuretics: increase risk of foetal
wastage, placental infarcts,
miscarriage, stillbirth.
Dihydropyridine CCBs: if used, they
should be discontinued before
labour as they weaken uterine
contractions.
Nonselective β blockers: Propranolol
cause low birth weight, decreased
placental size, neonatal bradycardia
and hypoglycaemia.
Cardioselective β blockers and those
with ISA, e.g. atenolol, metoprolol,
pindolol, acebutolol: may be used if
no other choice.
Sod. nitroprusside: Contraindicated
in eclampsia.
Prazosin and clonidine-provided that
postural hypotension can be
avoided.

Treatment of hypertension
• Resistant hypertension:
pressure that remains
It is defined as blood
elevated despite
administration of an optimal three-drug regimen that
includes a diuretic. The most common causes of
resistant hypertension
– poor compliance
– excessive ethanol intake
– concomitant conditions (diabetes, obesity, sleep apnea,
hyperaldosteronism, high salt intake, metabolic syndrome)
– concomitant medications (sympathomimetics,
nonsteroidal anti-inflammatory drugs, or antidepressant
medications)
– insufficient dose/ drug

Treatment of hypertension
• Hypertensive emergency: It is rare but life-
threatening condition (systolic BP >180 mm Hg or
diastolic BP >120 mm Hg with evidence of impending
or progressive target organ damage such as stroke,
myocardial infarction).
• A variety of medications are used, including calcium
channel blockers (nicardipine and clevidipine), nitric
oxide vasodilators (nitroprusside and nitroglycerin),
adrenergic receptor antagonists (phentolamine,
esmolol, and labetalol), the vasodilator hydralazine,
and the dopamine agonist fenoldopam.

Thank you

Plasma Kinins
(Bradykinin and Kallidin)
• Kinins are generated by
proteolytic reactions triggered
by tissue injury, inflammation,
allergic reaction, etc., and play
important mediator roles.
• Kininogens are α2 globulins
present in plasma which also
contains inactive kininogenase
prekallikrein, which is
activated by Hageman factor
(factor XII) during tissue injury.
Reference:
Hereditary angioedema. Available in
https://www.immunology.org/public-
information/bitesized-
immunology/immune-
dysfunction/hereditary-angioedema
Last accessed on 30/08/2017

Plasma Kinins
(Bradykinin and Kallidin)
Bradykinin and kallidin have similar actions.
• Cardiovascular system: Kinins are more potent
• vasodilators than ACh and histamine. The dilatation is medi
through endothelial NO and PGI2 generation, and involves mainly
arterioles.
• Smooth muscle: Action on other smooth muscles is not promin
some may be relaxed also. Bradykinin causes ma
bronchoconstriction in asthmatic patients.
• Kidney: Kinins increase renal blood flow as well as facilitate salt
water excretion by action on tubules.

Medication in hypertension

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