PH1.27 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of antihypertensive drugs and drugs used in shock

1. PH1.27 Describe the mechanisms of action, types,
doses, side effects, indications and
contraindications of antihypertensive drugs and
drugs used in shock
Dr Pankaj Kumar Gupta, MD
Assistant Professor,
Department of Pharmacology,
ESIC Medical College & Hospital,
Faridabad (HARYANA) INDIA

2. Objectives
• Definition
• Blood pressure regulation
• Etiology of hypertension
• Classification of hypertension
• Prevalence of hypertension
• Classification of anti-hypertensive drugs
• Pharmacology of diuretics
• Pharmacology of ACE-I/ARBs
• Pharmacology of B & α blockers
• Pharmacology of CCBs
• Pharmacology of central sympatholytics
• Pharmacology of vasodilators

3. Hypertension
• Blood pressure is
a measurement of
the force exerted
against the walls
of arteries as
heart pumps
blood to body.

4. Blood Pressure
• A force exerted against the walls of arteries by
heart.
• Blood pressure is made up of two numbers:
– Systolic pressure is the pressure when the
ventricles pump blood out of the heart.
– Diastolic pressure is the pressure between
heartbeats when the heart is filling with blood.
• Normal blood pressure is when blood pressure
is lower than 120/80 mm Hg most of the time.
https://medlineplus.gov/ency/article/000468.htm
https://www.nhlbi.nih.gov/health/high-blood-pressure

5. Hydraulic equation of BP
BP = CO X PVR
Blood Pressure = Cardiac output (CO) X Resistance to passage
of blood through pre-capillary arterioles (PVR)

6. Normal Blood Pressure Regulation
• Physiologically CO and PVR is maintained minute to
minute by:
– Arterioles
– Post-capillary Venules
– Heart
– Kidney
• In hypertensives – Baroreflex and renal blood-
volume control system – set at higher level
• All antihypertensives act via interfering with
normal mechanisms
It is regulated by
 Baroreflex
 Humoral mechanism
 Renin-angiotensin-aldosterone
system
 Local agents like Nitric oxide

8. Baroreceptor reflex arc
• Postural baroreflex:

9. Etiology
Primary HTN/Essential Secondary HTN
•No identifiable cause
•90-95% of cases
•Caused by an underlying condition
•Sleep apnea
•Drug-induced
•Chronic kidney disease
•Primary aldosteronism
•Renovascular disease
•Chronic steroid therapy and
Cushing’s syndrome
•Pheochromocytoma
•Coarctation of the aorta
•Thyroid or parathyroid disease

10. Classification of Hypertension
Category Systolic
(mmHg)
Diastolic
(mmHg)
Normal < 120 AND < 80
Pre-hypertension 120-139 OR 80-89
Hypertension
Stage-I 140-159 OR 90-99
Stage-II ≥160 OR ≥100
JNC – 8 Classification of BP

11. Prevalence
• It is estimated that at least one in four adults
in India has hypertension, but, only about 12%
of them have their blood pressure under
control.
• Uncontrolled blood pressure is one of the
main risk factors for cardiovascular diseases
(CVDs) such as heart attacks and stroke, and
are responsible for one-third of total deaths in
India.
https://www.who.int/india/news/detail/02-06-2022-india-hypertension-control-initiative--a-high-impact-and-low-cost-
solution#:~:text=It%20is%20estimated%20that%20at,blood%20pressure)%20by%2020253.
https://www.who.int/india/health-topics/hypertension

12. Classification of Anti-hypertensive Drugs
SN Drug Class Drug Examples
1 Diuretics •Thiazides: Hydrochorothazide, Chlorthalidone, Indapamide
•High ceiling: Furosemide
•K+Sparing: Spiranolactone, Amiloride, Eplerenone
2 ACE inhibitors Captopril, Enalapril, Lisinopril, Ramipril, Fosinopril
3 Angiotensin (AT 1
receptor) blockers
Losartan, Candesartan, Valsartan, Telmisartan, Irbesartan,
Olmesartan
4 Direct renin inhibitor Aliskiren
5 Calcium channel
blockers
Phenylalkylamine: Verapamil
Benzothiazepine: Diltiazem
Dihydropyridines: Nifedipine, Amlodipine, Cilnidipine

13. Classification of Anti-hypertensive Drugs
SN Drug Class Drug Examples
6 β-Adrenergic blockers Propranolol, Metoprolol, Atenolol
7 β+α Adrenergic
blockers
Labetalol, Carvedilol
8 α-Adrenergic blockers Prazosin, Terazosin, Doxazosin, Phentolamine
9 Central
sympatholytics
Clonidine, Methyldopa, Phenoxybenzamine
10 Vasodilators Arteriolar: Hydralazine, Minoxidil, Diazoxide
Arteiolar +Venous: Sodium nitroprusside

14. Diuretics
• Used as initial therapy alone or in combination with
drugs from other groups
• MOA: acts on Kidneys to increase excretion of Na
and H2O – decrease in blood volume – decreased
BP
– Thiazides: chlorothiazide, hydrochorothiazide
– Loop Diuretics: furosemide, bumetanide, ethacrynic
acid
– Potassium sparing diuretics: spironolactone,
triamterene, amiloride

15. Ter Maaten JM, et al, Nat Rev Cardiol. 2015;12(3):184-192.

16. Effects
Mechanism of
action
Diuretics
•Urinary Na, K, Ca, Mg
•Na/K/2Cl transporter in
TAL the most effective
Loop diuretics
Furosemide
•Urinary Na, K, Mg
•BUT↓ urinary Ca (hypercalcemia)
•Metabolic alkalosis
•Na and Cl cotransporter in
DCT
Thiazide diuretics
Hydrochlorothiazide
•↑ Urinary Na
•↓ K, H secretion
•Metabolic acidosis
•Competitive antagonist of
aldosterone in CCT
K-sparing diuretic
Spironolactone
•Urinary Na HCO3, K
•Urinary alkalosis
•Metabolic acidosis
•Inhibition of NaHCO3
reabsorption in PCT
CA inhibitors
Acetohexamide
Dorzolamide
•Urine excretion
•Little Na
•Osmotic effect in PCT
Osmotic diuretic
Mannitol

17. Uses
Diuretics
•Acute pulmonary edema (Drug of choice)
•Heart failure
•Hyperkalemia, Hypercalcemia
Loop diuretics
Furosemide
•Hypertension
•Mild heart failure
•Nephrolithiasis
•Diabetes inspidus
Thiazide diuretics
hydrochlorothiazide
•Hepatic cirrhosis (Drug of choice)
K-sparing diuretic
Spironolactone
•Glaucoma
•Epilepsy
•Mountain sickness
•Alkalosis
•Phosphatemia
CA inhibitors
Acetohexamide
Dorzolamide (topically) for
glaucoma
•Cerebral edema
•Glaucoma
•Acute renal failure
•Drug toxicities
Osmotic diuretic
Mannitol

18. Side effects
Diuretics
•Water & Electrolyte Imbalance: Hypokalemia, Hyponatremia,
Hypovolemia, Hypomagnesemia, Hypocalcemia
•Metabolic: Precipitate gout (Hyperuricemia), Alkalosis
Loop diuretics
Furosemide
•Water & Electrolyte Imbalance: Hypokalemia, Hyponatremia,
Hypovolemia, Hypomagnesemia, Hypercalcemia
•Metabolic: Precipitate gout (Hyperuricemia), Alkalosis,
•Hyperlipidemia, Hyperglycemia
•Erectile dysfunction
Thiazide diuretics
hydrochlorothiazide
•Gynaecomastia
•Hyperkalaemia, Metabolic acidosis.
•GIT upset and peptic ulcer
K-sparing diuretic
Spironolactone.
•Metabolic acidosis , Urinary alkalosis
•Hypokalemia
CA inhibitors
Acetohexamide
Dorzolamide
•Extracellular water expansion
•Dehydration
•Hypernatremia
Osmotic diuretic
Mannitol

19. Pharmacology of ACE inhibitors Captopril
• Captopril, the first ACE
inhibitor to be
marketed, is a potent
ACE inhibitor. It is the
only ACE inhibitor
approved for use in
the U.S. that contains
a sulfhydryl moiety.
Mechanism of action

20. Pharmacokinetics
Absorption: •Given orally, absorbed rapidly
•Bioavailability 75%.
•Bioavailability is reduced by 25-30% with food, so Captopril
should be given 1 hour before meals.
Distribution •Peak concentrations in plasma occur within an hour
•Drug is cleared rapidly with a t1/2 2 hours.
Metabolism: •Partially metabolized.
Excretion: •Most of the drug is eliminated in urine,
•40-50% as captopril and the rest as captopril disulfide dimers
and captopril–cysteine disulfide
Dose: •6.25-150 mg orally, two to three times daily.

21. Adverse effects 1. Hypotension
2. Hyperkalaemia
3. Cough
4. Rashes, urticaria
5. Angioedema
6. Dysgeusia
7. Foetopathic
8. Headache, dizziness, nausea
9.Granulocytopenia & proteinurea
10.Acute renal failure
Interactions 1. Indomethacin increases hypotensive activity of Captopril
2. NSAID + Diuretics +ACE inhibitor incidence of renal failure
reported
3. Antacid+ Captopril = Reduced bioavailability of Captopril

22. Angiotensin (AT 1 receptor) blocker
Losartan
• Approximately 14% of
an oral dose of losartan
is converted to the 5-
carboxylic acid
metabolite EXP 3174,
which is more potent
than losartan as an AT1
receptor antagonist.

23. Pharmacokinetics
Absorption: •Oral absorption is not affected by food
•Bioavailability is only 33% due to first pass metabolism
Distribution •Peak plasma levels of losartan and EXP3174 (active metabolite)
occur~1-3 hours
•Plasma half-lives are 2.5 and 6-9 hours, respectively.
Metabolism: •The metabolism of losartan to EXP3174 and to inactive
metabolites is mediated by CYP2C9 and CYP3A4.
Excretion: •The plasma clearances of losartan and EXP3174 are due to
renal clearance and hepatic clearance
Dose: •Orally once or twice daily for a total daily dose of 25-100 mg.

24. Adverse effects 1. Hypotension
2. Hyperkalamia
3. Teratogenicity
Uses 1.Hypertension
2. CHF
3.Myocardial infarction
4. Diabetic nephropathy

25. Pharmacology of Calcium Channel
Blocker Verapamil
Mechanism of action
• Voltage-sensitive Ca++ channels (L type or slow channels)
mediate the entry of extracellular Ca++ into smooth muscle
and cardiac myocytes and sinoatrial (SA) and atrio-ventricular
(AV) nodal cells in response to electrical depolarization.
• In both smooth muscle and cardiac myocytes, Ca++ is a trigger
for contraction. Ca++ channel antagonists, also called Ca++
entry blockers, inhibit Ca++ channel function.
• In vascular smooth muscle, this leads to relaxation, especially
in arterial beds. These drugs also may produce negative
inotropic and chronotropic effects in the heart.

26. Pharmacokinetics
Absorption: •Absorption is nearly complete after oral administration.
•Bioavailability is reduced, in some cases markedly, by first pass
hepatic metabolism.
•Intravenous administration of diltiazem or verapamil leads to a rapid
therapeutic response.
Distribution •Plasma protein binding is 70-98% for all CCBs;
Metabolism: •A major metabolite of diltiazem is des acetyl diltiazem, which has
about one-half of diltiazem's potency as a vasodilator.
•N-Demethylation of verapamil results in production of norverapamil,
which is biologically active but much less potent than the parent
compound.
•The t1/2 of norverapamil is~10hours.
Excretion: Their elimination half-lives vary widely and range from 1.3-64 hours
Dose: Amlodipine- 2.5-10 mg OD

27. Adverse effects •Constipation, Pretibial edema, Nausea, Flushing, and
Dizziness.
•Heart failure, AV blockade, Sinus node depression; these
are most common with verapamil and least common with
the dihydropyridines.
Uses 1.Hypertension
2.Cardiac arrhythmias
3.Hypertrophic cardiomyopathy

28. Pharmacology of β-blocker
(Propranolol)
Mechanism of action
• The negative Chronotropic and Inotropic effects of these agents (and the
reductions in heart rate, stroke volume, and cardiac output that follow)
account for the initial anti-hypertensive effect of the ß-antagonists.
• Decreased vasomotor tone, with a consequent decrease in systemic
vascular resistance, with longer-term therapy.
• Antagonism of ß1-adrenergic receptors in the kidney decreases secretion
of renin and thereby decreases production of the potent vasoconstrictor,
angiotensin II.
• On acute use- little change in BP, no direct action on blood vessels
• On chronic use- gradual fall in BP (1-3 wk) due to ↓ tpr in response to
↓CO, both SBP & DBP falls.

30. Pharmacokinetics
Absorption: •Well absorbed orally
•Low bioavailability (BA) due to high first pass metabolism.
•Oral: Parenteral = 40:1
•BA is high when taken with meal as food ↓ first pass
metabolism
Distribution •>90% bound to plasma proteins.
•Lipophilic and penetrates in brain.
Metabolism: •Dependent on hepatic blood flow
•Repeat adm increases BA as propranolol ↓ HBF
•Many metabolites, Hydroxylated metabolite has ß-blocking
action.
Excretion: •Metabolites are excreted via urine mostly glucuronides.
Dose: •Oral-10 mg BD to 160 mg QID
•IV- 2-5 mg over 10 min
•IM/SC- no due to irritant property

31. Adverse effects •Cardiovascular adverse effects- bradycardia, atrio-ventricular
blockade and heart failure. (due to β-blockade)
•Patients with airway disease may suffer severe asthma attacks.
•Symptoms of hypoglycemia from insulin overdosage, for example,
tachycardia, tremor, and anxiety, may be masked.
•B-blockers block adrenergically induced lipolysis & glycogenolysis
resulting in hyperlipidemia, hypertryglyceridemia & hypoglycemia.
•Tiredness & reduced exercise capacity (due to blunting of B2
mediated blood flow to muscles)
•Cold hand & feet in winter (blunting of vasodilator B2 receptors
•Rebound hypertension in case of abrupt withdrawal
•CNS adverse effects include sedation, fatigue, and sleep alterations.
•Sexual dysfunction has been reported for most of the β-blockers in
some patients.
Interactions 1.Digitalis+Prpranolol=Depression of Sinus node and AV conduction,
cardiac arrest can occur
2.Delays recovery from hypoglyacemic effect of insulin
3.Indomethacin and other NSAIDs attenuate anti-hypertensive action.
4.Cimetidine inhibits its metabolism

32. Uses 1. Hypertension
2. Angina pectoris
3. Cardiac Arrhythmias
4. Myocardial Ischemia (MI)
5. Congestive Heart Failure (CHF)
6. Dissecting aortic aneurysm
7. Pheochromocytoma
8. Thyrotoxicosis
9. Migraine
10. Anxiety
11. Essential tremor
12. Glaucoma
13. Hypertrophic Obstructive Cardiomyopathy (HOCM)
Current Status •Mild anti-hypertensives
•Suffice in 30-40% of populations
•Response takes 1-3 weeks
•OD dosing is sufficient for most B-blockers (24 hrs action)

33. Pharmacology of α-Adrenergic
blockers (Prazosin)
Mechanism of action
• Blockade of α1 adrenergic receptors inhibits
vasoconstriction induced by endogenous
catecholamines; vasodilation may occur in both
arteriolar resistance vessels and veins.
• Blockade of α1 receptors also inhibits vasoconstriction
and the increase in blood pressure produced by the
administration of a sympathomimetic amine. The pattern
of effects depends on the adrenergic agonist that is
administered.

34. Pharmacokinetics
Absorption: •Well absorbed after oral administration, and
bioavailability is 50-70%.
•Peak concentrations in 1-3 hours after an oral dose.
Distribution •High plasma proteins bound (primarily α1-acid
glycoprotein)
•Only 5% of the drug is free in the circulation
Metabolism: •Extensively metabolized in the liver
Excretion: •Little unchanged drug excreted by the kidneys
•The plasma t1/2 is 3 hours (may be prolonged to 6-8
hours in congestive heart failure)

35. Adverse effects ‘First dose effect’ may cause dizziness and fainting.
Uses 1.Hypertension
2.Raynaud’sdisease
3.Benign Hypertrophy of Prostrate (BHP) Terazosin, Doxazosin and
Uroselective α1A & α1B blocker Tamsulosin is used
4.Pheochromocytoma

36. Pharmacology of β+α Adrenergic
blockers (Carvedilol)
Mechanism of action
• It blocks β1, β2, and α1 receptors similarly to labetalol, but
also has anti-oxidant and anti-inflammatory effects.
• It has membrane stabilizing activity but it lacks intrinsic
sympathomimetic activity. Carvedilol produces
vasodilation.
• Additional properties (e.g. anti-oxidant and anti-
inflammatory effects) may contribute to the beneficial
effects seen in treating congestive heart failure and in its
cardio protective effects.
• The drug is FDA-approved for use in hypertension,
congestive heart failure, and left ventricular dysfunction
following MI.

37. • Carvedilol is extremely liphophic and is able to
protect cell membranes from lipid peroxidation. It
prevents low density lipoprotein (LDL) oxidation.
• Carvedilol also inhibits ROS-mediated loss of
myocardial contractility, stress-induced
hypertrophy, apoptosis, and the accumulation
and activation of neutrophils.
• Labetalol is 5 times more potent in blocking β
than α receptor

38. Pharmacokinetics
Absorption: •Rapidly absorption
•Peak plasma concentrations in1-2 hours.
Distribution •Highly lipophilic and thus is extensively distributed into
extravascular tissues.
•>95%protein bound.
Metabolism: •Extensively metabolized in the liver, predominantly by
•CYP2D6 and CYP2C9.
•t1/2 is 7-10 hours
•Stereo selective first-pass metabolism results in more rapid
clearance of S(–)-carvedilol than R(+)-carvedilol.
•Because of carvedilol's extensive oxidative metabolism by
the liver, its pharmacokinetics can be profoundly affected by
drugs that induce or inhibit oxidation. These include the
inducer, rifampin, and inhibitors such as cimetidine,
quinidine, fluoxetine, and paroxetine
Excretion: Kidney

39. Adverse effects 1. Postural hypotension
2. Failure of ejaculations
Uses 1. Essential hypertension
2. CHF
3. Pheochromocytoma

40. Pharmacology of Central
Sympatholytics
Clonidine
• Clonidine is a α2 receptors agonist
Mechanism of action
• Activation of α2 receptors in the lower brainstem region.
• Decreases discharges in sympathetic pre-ganglionic fibers
in the splanchnic nerve and in postganglionic fibers of
cardiac nerves.
• Also, stimulates parasympathetic outflow thus, slowing of
heart rate as a consequence of increased vagal tone and
diminished sympathetic drive.
• Activation of pre-synaptic α-2 receptors that suppress the
release of NE from postganglionic sympathetic nerves.

41. Pharmacokinetics
Absorption: •Well absorbed
•Bioavailability is nearly 100%
Distribution •Peak concentration in plasma and maximal
hypotensive effect are observed 1-3 hours after
an oral dose.
Metabolism: t1/2 of the drug ranges from 6-24 hours, with a
mean of~12hours.
Excretion: •About half of an administered dose can be
recovered unchanged in the urine

42. Adverse effects •Dry mouth and sedation
•Sexual dysfunction
•Marked bradycardia
•About 15-20% of patients develop contact dermatitis when using
clonidine in the transdermal system
•Withdrawal reactions follow abrupt discontinuation of long-term
therapy
Uses •Hypertension
•Opioid withdrawal

43. Pharmacology of Vasodilators
Arteriolar: Hydralazine
• Hydralazine (1-hydrazinophthalazine) was one of the first orally
active antihypertensive drugs to be marketed in the U.S
Mechanism of action
• Hydralazine directly relaxes arteriolar smooth muscle.
• There is evidence suggesting that hydralazine inhibits IP3-induced
release of Ca++ from intracellular storage sites in arteries, leading to
diminished contraction.
• There is also evidence that hydralazine promotes arterial dilation by
opening high conductance Ca++ -activated K+ channels.
Uses
• Moderate to severe hypertension not controlled by first line drugs.
• Hypertension in pregnancy

44. Pharmacokinetics
• Well absorbed , but the systemic bioavailability is low (16%
in fast acetylators and 35% in slow acetylators).
• Hydralazine is N-acetylated in the bowel and/or the liver.
• t1/2 of hydralazine is 1 hour, and systemic clearance of the
drug is ~50 mL/kg/min.
Averse effects
• Headache, nausea, flushing, hypotension, palpitations,
tachycardia, dizziness, and angina pectoris.
• Myocardial ischemia
• Lupus syndrome is the most common.
• Illness that resembles serum sickness, hemolytic anemia,
vasculitis, and rapidly progressive glomerulonephritis.

45. Pharmacology of Vasodilator
Arteiolar+Venous: Sodium nitroprusside
Mechanism of action
• Nitroprusside is a nitrovasodilator that acts by releasing NO.
• NO activates the guanylylcyclase-cGMP PKG pathway, leading to
vasodilation, mimicking the production of NO by vascular endothelial cells,
which is impaired in many hypertensive patients.
Pharmacokinetics
• Sodium nitroprusside is an unstable molecule that decomposes under
strongly alkaline conditions or when exposed to light.
• It is given by continuous intravenous infusion to be effective.
• The metabolism of nitroprusside by smooth muscle is initiated by its
reduction, which is followed by the release of cyanide and then NO.
• Cyanide is further metabolized by liver rhodanase to form thiocyanate,
which is eliminated almost entirely in the urine.

46. Adverse effects
• Due to excessive vasodilation, with hypotension.
• Less commonly, toxicity may result from conversion of
nitroprusside to cyanide and thiocyanate.
• Toxic accumulation of cyanide leading to severe lactic
acidosis.
Uses
• Used to produce controlled hypertension in CHF, pump
failure, etc.
Brands
• SONIDE, PRUSIDE, 50 mg in 5 ml inj.

47. References
• https://medlineplus.gov/ency/article/000468.htm
• https://www.nhlbi.nih.gov/health/high-blood-pressure
• https://academic.oup.com/bjaed/article/4/1/2/356873
• https://www.who.int/india/news/detail/02-06-2022-india-hypertension-control-
initiative--a-high-impact-and-low-cost-
solution#:~:text=It%20is%20estimated%20that%20at,blood%20pressure)%20by%2
020253.
• https://www.who.int/india/health-topics/hypertension

49. Thanks