PHARMACOTHERAPY OF

HYPERTENSION

BY
DR. ARUN. S
POST GRADUATE - 1ST YEAR
DEPT OF PHARMACOLOGY
GMC, ANANTHAPURAMU
A CASE SCENARIO...
• A 35-year-old man presents with a blood pressure of 150/95 mm Hg.
• He has been generally healthy, is sedentary, drinks several cocktails per day, and does not
smoke cigarettes.
• He has a family history of hypertension, and his father died of a myocardial infarction at
age 55.
• Physical examination is remarkable only for moderate obesity.
• Total cholesterol is 220 mg/dL
• High-density lipoprotein (HDL) cholesterol level is 40 mg/dL.
• Fasting glucose is 105 mg/dL.
• Chest X-ray is normal.
• Electrocardiogram shows left ventricular enlargement.
• How would you treat this patient?
SPECIFIC LEARNING OBJECTIVES:

BY THE END OF THE INTEGRATED SEMINAR THE POST GRADUATE

STUDENT WILL BE ABLE TO
1. List the Classification of Anti-hypertensive drugs
2. Describe the pharmacological basis for their anti-
hypertensive action
3.List out the Advantages and limitations of combining
antihypertensives
4. List out the 1st line, 2nd line and 3rd line drugs used in
hypertension.
CLASSIFICATION OF
ANTI-HYPERTENSIVE DRUGS
DIURETICS - THIAZIDES

• THIAZIDES - Diuretic of choice for

uncomplicated hypertension; have
similar efficacy.

• Enhance the effect of other

antihypertensive agents.

• Chlorthalidone has longer t1/2 - 48hrs

compared to hydrochlorothiazide (<
24 hours)
PROTOTYPE DRUG -
HYDROCHLOROTHIAZIDE
PHARMACOKINETICS:

• well absorbed from the intestine

• effect starts within one hour.
• distributed throughout the ECF and
are relatively concentrated in the
kidney.
• crosses the placental barrier.
• excreted in urine.
DRUGS PROPRIETAR INITIAL DOSAGE ADVERSE COMMENTS
Y NAMES ORAL RANGE EFFECTS
DOSAGE
HYDROCHLORTHIAZIDE EZIDRIX, 12.5 OR 12.5 - ↓K+, ↓Mg2+, LOW DOSES
MICROZIDE, 25MG OD 50MG OD ↑Ca2+, ↓ Na+, EFFECTIVE IN
HYDRAZIDE ↑URIC ACID, ↑ MANY
GLUCOSE, ↑ PATIENTS
LDL, ↑ TGL, WITHOUR
RASH, METABOLIC
ERECTILE ABNORMALITI
DYSFUNCTION ES,
CHLORTHALIDONE THALITONE 12.5 OR 12.5 - METOLAZONE
25MG OD 50MG OD MORE
EFFECTIVE IN
METOLAZONE ZAROXOLYN 1.25 OR 1.25 - 5 MG KIDNEY
2.5MG OD OD DISEASE,
INDAPAMIDE
DOES NOT
INDAPAMIDE LOZOL, 2.5MG OD 2.5 - 5MG USE: ALTER SERUM
DAPAMIDE OD antihypertensive in LIPID LEVELS
diabetic patients
BENDROFLUMETHIAZIDE APRINOX 2.5MG OD 2.5 - 5MG
NEO OD
NACLEX
LOOP DIURETICS:
PROTOTYPE DRUG - FUROSEMIDE
• Potent, oral diuretic.
• Not recommended for long term Rx of hypertension
• Indicated in severe hypertension with CHF and renal
dysfunction.
• Indacrinone can be used in patients of gout because it
inhibits reabsorption of uric acid in the nephron (other loop
diuretics and thiazides cause hyperuricemia).
MECHANISM OF
ACTION AND ADR
DRUGS PROPRIETA INITIAL DOSAGE ADVERSE EFFECTS COMMENTS
RY NAMES ORAL RANGE
DOSAGE
FUROSEMIDE LASIX 20MG BD 40-320MG IN SAME AS SHORT DURATION OF
2-3 DIVIDED THIAZIDES. BUT ACTION. SHOULD BE
DOSES HIGHER RISK OF RESERVED FOR
EXCESSIVE PATIENTS WITH
DIURESIS AND KIDNEY DISEASE OR
ELECTROLYTE FLUID RETENTION.
IMBALANCE, POOR ANTI-
INCREASES HYPERTENSIVE
CALCIUM ACTION.
EXCRETION

ETHACRYNIC EDECRIN 50MG OD 50-100MG

ACID OD OR BD
BUMETANIDE 0.25 MG 0.5 - 10 MG
BD IN 2 OR 3
DOSES
TORSEMIDE DEMADEX, 5MG OD 5 - 10 MG OD EFFECTIVE BLOOD
DYTOR PRESSURE
MEDICATION AT LOW
DOSAGE
DOSAGE FORMS:
RENIN ANGIOTENSIN
ALDOSTERONE SYSTEM
INHIBITORS

MECHANISM OF
ACTION
DIRECT RENIN INHIBITORS
• Inhibition of renin decreases Angiotensin I and Angiotensin II levels
and hence produces a fall in BP
ALISKIREN: (Tekturna)
• Oral non-peptide drug
• It should not be used along with ACEI or ARBs or in pregnancy.
• Dosage Forms & Strengths:
1. Tablet - 150mg, 300mg
2. Oral pellets in capsules - 37.5mg
• Indications: Hypertension in adults and children ≥6 years
• Adverse effects: diarrhoea, abdominal pian, angioedema, headache
Pharmacokinetics:
ACE INHIBITORS: (Prototype drug -
captopril)
PHARMACOKINETICS:
INTRAVENOUS FORM
Contraindication for ACEI:
(1) Severe bilateral renal artery stenosis as they reduce GFR and may cause renal failure,
(2) Aortic stenosis,
(3) Coarctation of the aorta; and
(4) Pregnancy.
Status in Hypertension:
• Presently the first-line antihypertensives.
• ACE inhibitors are useful in the treatment of hypertension of all grades due to all causes.
• Addition of a diuretic potentiates their antihypertensive efficacy.

They are specially indicated as antihypertensives in:

a. Hypertension with left ventricular hypertrophy - because hypertrophy is gradually
reversed by ACE inhibitors.
b. Patients with diabetes mellitus - because ACE-I slow the development of nephropathy.
c. Renal diseases with hypertension - ACE inhibitors slow the progression of chronic renal
diseases like glomerulosclerosis.
d. Patients with co-existing IHD including post-MI patients.
e. In severe hypertension, they may be combined with other antihypertensives like β-
blockers, CCBs or diuretics
 ANGIOTENSION RECEPTOR BLOCKERS
PROTOTYPE DRUG - LOSARTAN

• block the AT1 receptors,

• Pharmacologic effects are similar to those of ACE inhibitors
• ARBs do not increase bradykinin levels.
• Used as first-line agents for the treatment of hypertension, especially in
patients with a compelling indication of diabetes, heart failure, or
chronic kidney disease.
• ARBs should not be combined with an ACE inhibitor for the treatment
of hypertension due to similar mechanisms and adverse effects.
• teratogenic
Special features of losartan:
– Produce active metabolite - 5-Carboxylic acid (E-3174) (active
metabolite; 40 times as potent as losartan in angiotensin II-blocking
activity)
– Has anti-platelet action due to competitive antagonism of TXA2.
– Mild uricosuric effect
Telmisartan has additional PPAR-δ agonistic activity. This activity can
help in patients with dysglycemia. Telmisartan is longest acting whereas
eprosartan is shortest acting ARB.
POTASSIUM SPARING DIURETICS

(1) Aldosterone antagonist: Spironolactone, eplerenone.

(2) Direct inhibitors of renal epithelial sodium
channels: Triamterene and Amiloride - They have no
anti-hypertensive action.

These drugs are combined with loop or thiazide diuretics

to prevent or correct hypokalemia.
ALDOSTERONE
ANTAGONISTS
CALCIUM CHANNEL BLOCKERS
DOSAGE FORMS:
CLEVIDIPINE
Clevidipine is a dihydropyridine L-type calcium channel blocker, highly selective for
vascular smooth muscle.
It reduces mean arterial blood pressure by decreasing systemic vascular resistance.
Used in patients with acute hypertension who cannot take drugs orally.
Pharmacokinetics:
• Onset: 2-4 minutes
• Protein Bound: 99.5%
• Metabolized in blood and extravascular tissues
• Half-Life: Initial 1 minute; terminal 15 minutes
• Excretion: Urine (63-74%); feces (7-22%)
Dosage forms:
Intra venous emulsion - 1–2 mg/hour IV infusion.
ADVERSE EFFECTS:
• Hepatic dysfunction
• Thiocyanate toxicity -
Prolonged administration of
sodium nitroprusside either in high doses
or in the presence of renal insufficiency.
This results in fatigue, anorexia,
nausea, vomiting, sweating, disorientation,
psychotic behavior and muscle twitching.
Larger doses may cause ataxia,
rigidity, convulsions and metabolic
acidosis.
• Nitrates have a synergistic effect with
vasodilator drugs and can lead to sudden
fall in BP and collapse.
PREVENTION OF TOXICITY:
• Administration of sodium
thiosulphate along with nitroprusside
prevents the accumulation of cyanide.
• Alternatively, hydroxocobalamin
may be given which combines with
cyanide to form cyanocobalamin
which is a nontoxic compound.
• Methaemoglobinaemia is also known
following infusion of nitroprusside. It
should be avoided in pregnancy.
Preparations and dosage of
hydralazine:
• Hydralazine hydrochloride tablets 10,
25, and 50 mg. Maximum dose 100 mg
daily.
• Dihydralazine sulphate 25 mg tablet.
• Injection 20 mg for IM/IV use.
AVAILABLE FORMS OF
NITROPRUSSIDE
• Sodium nitroprusside is supplied as 50 mg
powder to be dissolved in 500 ml of 5%
dextrose in water, just prior to
administration.
• When it is exposed to light, it is converted
to cyanide; hence a brown or black paper
bag over the IV fluid container is necessary.
• Translucent plastic tubing may need taping.
• Only freshly prepared solution should be
used.
Fenoldopam:
It is a D1 dopamine receptor agonist, brings about dilation of
peripheral arteries and also loss of sodium.
It has a short t½ of 10 minutes and is given as an IV infusion.
USES:
Useful in hypertensive emergencies and postoperative
hypertension, particularly when there is impaired renal function.
Started with a low dose of 0.1 μg/kg/min, it is gradually increased
every 20 minutes till adequate response is attained. (maximum dose
1.6 μg/kg/min).
Adverse effects: include flushing, headache, palpitation and
hypotension. It should be avoided in patients with glaucoma since it
can raise the intraocular pressure.
Fenoldopam has efficacy similar to sodium nitroprusside but is
devoid of thiocyanate-related complications.
ALPHA ADRENERGIC
BLOCKERS
ALPHA RECEPTORS
Peripheral vascular alpha-
receptors are of two types
• Postsynaptic α1 receptors
which are stimulatory in
nature; their activation causes
vasoconstriction and
• Presynaptic α2 receptors
(auto-receptors), which are
inhibitory in nature; their
activation inhibits NA release.
BETA BLOCKERS
BETA BLOCKERS
• They are the first-line antihypertensive drugs in mild to moderate
hypertension with cardiac problems.
• β-blockers are effective and well-tolerated and are of special value in
patients who also have arrhythmias or angina.
• They should not be used alone.
• Suitable for combination with other antihypertensives, particularly
with drugs that cause tachycardia as their side effect (e.g.
vasodilators).
• Beta blockers are avoided in patients with peripheral arterial disease.
MECHANISM OF ACTION
Pharmacological actions of clonidine:
Given IV it produces a transient hypertensive response followed by a prolonged fall in both
systolic and diastolic BP accompanied by bradycardia. Initial hypertensive effect is not seen
after its oral administration.
PHARMACOKINETICS:
Bioavailability: Immediate release (75-85%)
Protein bound: 20-40%
Duration: 6-10 hr.
Metabolism in Liver.
Elimination Half-life: 12-16 hr.
Excretion: Urine
WHO guidelines 2021
A CASE SCENARIO...
• A 35-year-old man presents with a blood pressure of 150/95 mm Hg.
• He has been generally healthy, is sedentary, drinks several cocktails per day, and does not
smoke cigarettes.
• He has a family history of hypertension, and his father died of a myocardial infarction at
age 55.
• Physical examination is remarkable only for moderate obesity.
• Total cholesterol is 220 mg/dL
• High-density lipoprotein (HDL) cholesterol level is 40 mg/dL.
• Fasting glucose is 105 mg/dL.
• Chest X-ray is normal.
• Electrocardiogram shows left ventricular enlargement.
• How would you treat this patient?
CASE SCENARIO ANSWER
The patient has Joint National Committee stage 1
hypertension.

The strong family history suggests that this patient has

essential hypertension.
Need to do ECHO, LFT, RFT, Sr. electrolytes

Non-Pharmacological management - behavioral,

including dietary changes and aerobic exercise.
CONTD..
Thiazide diuretics in low doses are inexpensive, have relatively few
side effects, and are effective in many patients with mild hypertension.
Other first-line agents include angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers, and calcium channel
blockers.
A single agent should be prescribed and the patient reassessed in a
month.
If a second agent is needed, one of the two agents should be a
thiazide diuretic. Once blood pressure is controlled, patients should be
followed periodically to reinforce the need for compliance with both
lifestyle changes and medications.
REFERENCES:
1. Goodman and Gilman’s Pharmacological basis of
therapeutics 13th edition
2. Katzung Clinical Pharmacology 15th edition
3. KD Tripathi Essentials of Medical Pharmacology 8th edition
4. RS Satoskar Pharmacology and Pharmacotherapeutics 26th
edition

Web references - Google and slideshare