Hypertension B.Pharm Pharmacology notes (Dr. Monu Yadav)

1. Anti Hypertensive Drugs
Prepared by: Dr. Monu

2. Hypertension
• Hypertension is defined as systolic blood pressure (SBP) of
140 mmHg or greater, diastolic blood pressure (DBP) of
90 mmHg or greater.
Normal BP: <120/<80
Prehypertension: 120-139/80-89
Hypertension stage1 140-159/90-99
Hypertension stage 2 160/100
Emergency >210/>120
Resistant hypertension Failure of BP control with drugs

8. • Renin is a proteolytic enzyme and also called angiotensinogenase
• It is produced by juxtaglomerular cells of kidney
• It is secreted in response to:
– Decrease in arterial blood pressure
– Decrease Na+ in macula densa
– Increased sympathetic nervous activity
• Renin acts on a plasma protein – Angiotensinogen (a glycoprotein synthesized and
secreted into the bloodstream by the liver) and cleaves to produce a decapeptide
Angiotensin-I
• Angiotensin-I is rapidly converted to Angiotensin-II (octapeptide) by ACE (present in
luminal surface of vascular endothelium)
• Furthermore degradation of Angiotensin-II by peptidases produce Angiotensin-III
• Both Angiotensin-II and Angiotensin-III stimulates Aldosterone secretion from Adrenal
Cortex (equipotent)
• AT-II has very short half life – 1 min

9. Diuretics
• Thiazide diuretics: Lower blood pressure initially by increasing sodium and water
excretion.
• Side effects: Thiazide diuretics can induce hypokalemia, hyperuricemia and
hyperglycemia in some patients.
• Loop diuretics: The loop diuretics act promptly by blocking sodium and chloride
reabsorption in the kidneys. Side effects of the loop diuretics include dizziness,
headache, gastrointestinal upset, hyponatremia, hypokalemia and dehydration.
• K+ Sparing: Potassium-sparing diuretics (spironolactone, and eplerenone), a type
of diuretic that helps eliminate excess sodium and water from the body while
retaining potassium at the same time. Hyperkalemia (increased levels of potassium
in the blood) side effects Abdominal discomfort, Ataxia (loss of control on bodily
movements due to lack of coordination between muscles and brain), Kidney
stones.

11. Potassium Sparing Diuretics
• Spironolactone (a synthetic steroid that
antagonizes aldosterone at intracellular
cytoplasmic receptor site).
• Triamterene & Amiloride (blocks Na transport
channels resulting in a decrease in Na/K
exchange).

12. ACE inhibitors
• ACE is also responsible for the breakdown of bradykinin, a peptide that increases the
production of nitric oxide and prostacyclin by the blood vessels. Both nitric oxide and
prostacyclin are potent vasodilators.
• ACE inhibitors • ACE inhibitors decrease angiotensin II and increase bradykinin levels.
• Vasodilation is result of decreased vasoconstriction (from reduced levels of angiotensin II)
and enhanced vasodilation (from increased bradykinin).
• By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of
aldosterone, resulting in decreased sodium and water retention.
• ACE inhibitors reduce both cardiac preload and afterload, thereby decreasing cardiac
work.
• The ACE inhibitors, are recommended as first-line treatment of hypertension in patients
with a variety of indications, including high coronary disease risk or history of diabetes,
stroke, heart failure, myocardial infarction, or chronic kidney disease.

14. ACE inhibitors in Hypertension Captopril
• Sulfhydryl containing dipeptide and stops conversion
of Angiotensin-I to Angiotensin-II.
• It does not block AT receptors
– Food interferes with its absorption

15. Captopril – Adverse effects
• Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID
and beta blockers (routine check of K+ level)
• Hypotension – sharp fall may occur – 1st dose
• Angioedema: swelling of lips, mouth, nose etc.
• Rashes
• Dysgeusia: loss or alteration of taste
• Contraindications: Pregnancy, hypersensitivity and hyperkalaemia

16. ACE inhibitors - Enalapril
• It is a prodrug – converted to enalaprilate
• Advantages over captopril:
– Longer half life – OD (5-20 mg OD)
– Absorption not affected by food
– Rash and loss of taste are less frequent
– Longer onset of action
– Less side effects
– Enalapril is not recommended in pregnancy. It can reduce the level of fluid around
baby, particularly if take it in the second and third trimesters. This can result in
long-term damage to your baby's kidneys and lungs and a number of other
problems.

17. ACE inhibitors – Ramipril
• It is a popular ACEI now
• It is also a prodrug and convert into ramiprilat with long
half life
• Tissue specific – Protective of heart and kidney
• Ramipril is not recommended in pregnancy.

18. ACE inhibitors – Lisinopril
• It is a lysine derivative
• Not a prodrug
• Absorption not affected by food and not metabolized
– excrete unchanged in urine
• Long duration of action – single daily dose
• Lisinopril is not recommended in pregnancy

19. ACE inhibitors and hypertension
• 1st line of Drug:
– No postural hypotension or electrolyte imbalance (no fatigue or
weakness)
– Safe in asthmatics and diabetics
– No rebound hypertension

20. Angiotensin antagonists (ARBs)
• ARBs produce arteriolar and venous dilation and block
aldosterone secretion, thus lowering blood pressure
and decreasing salt and water retention.
• ARBs do not increase bradykinin levels.

21. Angiotensin Receptor Blockers (ARBs)
Losartan
• Competitive antagonist of AT1 receptor
• Blocks all the actions of A-II
Like vasoconstriction, sympathetic stimulation, aldosterone release and renal
actions of salt and water reabsorption
• No inhibition of ACE
Side effects
• Fetopathic like ACEIs – not to be administered in pregnancy
• Rare 1st dose effect hypotension
• Low dysgeusia and dry cough

22. Direct renin inhibitor
• Aliskiren: A selective renin inhibitor .
• Directly inhibits renin and, thus, acts earlier in the renin– angiotensin–
aldosterone system than ACE inhibitors or ARBs.
• It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and
thiazides.
• Aliskiren should not be routinely combined with an ACE inhibitor or ARBs.
• Aliskiren can cause diarrhea, especially at higher doses, and can also cause cough
and angioedema, but probably less often than ACE inhibitors.
• Aliskiren is contraindicated during pregnancy.

24. Beta Blockers
• Non-selective(β1/β2): Propranolol,Timolol Nadolol,Pindolol,
propranolol.
• Selectiveβ1: Atenolol, Acebutalol.

28. Beta-adrenergic blockers
• Non selective: Propranolol (others: nadolol, timolol, pindolol, labetolol)
• Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol)
• Side effects:
– Fatigue, lethargy
– decreased work capacity
– Loss of libido – impotence
– Cognitive defects – forgetfulness
– Difficult to stop suddenly
– Therefore cardio-selective drugs are preferred now

29. Αlpha-adrenergic blockers
• Non selective alpha blockers are not used in chronic essential
hypertension (phenoxybenzamine, phentolamine).
• Specific alpha-1 blockers like prazosin, terazosin and doxazosine are
used
• PRAZOSIN is the prototype of the alpha-blockers
• Adverse effects:
– Prazosin causes postural hypotension
– Fluid retention in monotherapy
– Headache, dry mouth, weakness, dry mouth, blurred vision, rash, drowsiness
and failure of ejaculation in males

30. 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
• Highest smooth muscle relaxation and vasodilator action followed by verapamil
and diltiazem

31. Calcium Channel Blockers
– 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 and angina patients
– No renal and male sexual function impairment
– No adverse fetal effects and can be given in pregnancy
– Minimal effect on quality of life

32. Vasodilators - Hydralazine
• Directly acting vasodilator
• MOA: hydralazine molecules combine with receptors in the endothelium of
arterioles – NO release – relaxation of vascular smooth muscle – fall in BP
• Uses: 1) Moderate hypertension when 1st line fails – with beta-blockers and
diuretics 2) Hypertension in Pregnancy

33. Vasodilators - Minoxidil
• Powerful vasodilator, mainly 2 major uses – antihypertensive and alopecia
• Prodrug and converted to an active metabolite which acts by
hyperpolarization of smooth muscles
• More often in alopecia to promote hair growth
• MOA of hair growth:
– Enhanced microcirculation around hair follicles and also by direct stimulation
of follicles
– Alteration of androgen effect of hair follicles

34. Sodium Nitroprusside
• Rapidly and consistently acting vasodilator
• MOA: nitroprusside to NO – relaxation also by non-enzymatically to NO
by glutathione
• Uses: Hypertensive Emergencies
• Adverse effects: Palpitation, pain abdomen, psychosis, weakness and lactic
acidosis.

35. 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.
– Various adverse effects – cognitive impairment, postural hypotension.
– 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