1.
PHARMACOTHERAPY OF
HYPERTENSION
BY
DR. ARUN. S
POST GRADUATE - 1ST YEAR
DEPT OF PHARMACOLOGY
GMC, ANANTHAPURAMU

2.
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
• 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?

3.
1. List the Classification of Anti-hypertensive drugs according to the site
of action
2. Describe the pharmacological basis for use of thiazides and other
diuretics in hypertension
3. Describe the MOA, pharmacologic effects, ADR and indications for
ACEIs and ARBs
4. List out the use of following drugs to treat hypertension ( CCB,
Ganglion blocking drugs, Adrenergic neuron blocking drugs, Beta
receptor antagonists, alpha receptor antagonists, vasodilators)
5. List out the Advantages and limitations of combining
antihypertensives
6. Describe the Pharmacological agents used in PIH and ISH

4.
DEFINING HYPERTENSION
• Hypertension, also known as high or
raised blood pressure, is a condition
in which the blood vessels have
persistently raised pressure.
• Hypertension is diagnosed if, when it
is measured on two different days,
the systolic blood pressure readings
on both days is ≥140 mmHg and/or
the diastolic blood pressure readings
on both days is ≥90 mmHg

5.
A BRIEF HISTORY
• 1950s
Veratrum and Sodium thiocyanate - toxic and difficult to use
Ganglion blockers - effective but varied side effects
Reserpine - Very effective but caused Mental depression
Hydralazine - Marked side effects when used alone
• 1960s
Methyldopa, Beta blockers, Thiazides, Loop diuretics, Clonidine
1961 - Guanithidine - improvement on ganglion blockers

6.
Contd..
• 1970s
Alpha 1 blocker - prazosin introduced
• 1980 - 1990s
ACE inhibitors, ARBs, CCB
• 1995
Imidazolines, Neutral endopeptidase inhibitors
• 2007
Direct renin inhibitors - Aliskiren
• Nov 2022
Baxdrostat - AAldosterone synthesis inhibitor for resistant hypertension
https://www.sciencedaily.com/releases/2022/11/221107192302.htm
Currently in Phase 2 trials

7.
• 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)

8.
ABSORPTION, FATE AND
EXCRETION:
• 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.

9.
Anti-hypertensive action
of thiazides is lost when
1. salt intake is high
2. NSAID intake

10.
Actions of thiazides

11.
• No effect on capacitance vessels, sympathetic reflexes are not
impaired.
• Postural hypotension is rare
• Average fall in MAP - 10 mm Hg
• Potentiate other Anti-hypertensives except DHP CCB.
• Hence prevents tolerance to other agents by not allowing expansion
of plasma volume

12.
Thiazides should be used at low doses only because by increasing
the dose, antihypertensive effect does not increase but adverse
effects tend to increase.
Indapamide:
• Effective as an antihypertensive at lower doses than those
required for the diuretic effect (due to its direct vasodilatory
action).
• It also produces less metabolic adverse effects (hypokalemia,
hyperglycemia, hyperuricemia etc.) and can be used as an
antihypertensive in diabetic patients (whereas other thiazides
are contra-indicated).

13.
• Once a day dosing, flat dose-response curve
• No fluid retention, No tolerance
• No CNS side effects
• No postural hypotension
• More effective in patients with Isolated systolic hypertension
• Reduces risk of osteoporosis in older women and post-menopausal
women
• Low cost

14.
• 1960s -70s Thiazides were used as monotherapy - dosage was 50mg/day of
HCZ / Chlorthalidone
Side effects noted were:
• Hypokalemia - muscle pain, fatigue, loss of energy, Torsedes de pointes
resulting in sudden cardiac death
• Erectile dysfunction in males
• Carbohydrate intolerance, precipitation of diabetes ( due to inhibition of
insulin release because of hypokalemia)
• Dyslipidemia - rise in total and LDL cholesterol, lowering of HDL - increases
risk of atherogenesis
• Hyperuricaemia - Inhibition of urate excretion - precipitates gout

15.
ALLHAT (2002) - The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial - Thiazides are first choice anti-hypertensive.
Low dose Thiazides <25mg/day were very effective. Side effects were only
because of increasing the dose.
Advantages of low dose thiazides:
1. Significant hypokalemia doesn’t occur
2. Continuous ECG monitoring - no incidence of increase in arrhythmias
3. Very minimal effects on blood glucose and lipid profile - so can be used in
diabetes
4. Reduces Fatal and non fatal MI risk by 27-44%
5. Reduces stroke risk by 31-49%
6. Reduces left ventricular hypertrophy

16.
• Potent, oral diuretic.
• Not recommended for long term Rx
• 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).

17.
• Rapidly absorbed (60-100%) from the GI
tract.
• Food reduces its bioavailability.
• The onset of action is quick and the
duration short.
• Given IV, the diuresis begins within 2
minutes and lasts for 2-3 hours.
• Excreted within 4 hours by kidney
• Fifty per cent of the dose is excreted
unchanged in urine; the rest is conjugated
with glucuronide in the kidney.
• Hence, in patients with renal insufficiency
the plasma t½ is prolonged.

18.
36

19.
DRUGS PROPRIETA
RY NAMES
INITIAL
ORAL
DOSAGE
DOSAGE
RANGE
ADVERSE EFFECTS COMMENTS
FUROSEMIDE LASIX 20MG BD 40-320MG IN
2-3 DIVIDED
DOSES
SAME AS
THIAZIDES. BUT
HIGHER RISK OF
EXCESSIVE
DIURESIS AND
ELECTROLYTE
IMBALANCE,
INCREASES
CALCIUM
EXCRETION
SHORT DURATION OF
ACTION. SHOULD BE
RESERVED FOR
PATIENTS WITH
KIDNEY DISEASE OR
FLUID RETENTION.
POOR ANTI-
HYPERTENSIVE
ACTION.
ETHACRYNIC
ACID
EDECRIN 50MG OD 50-100MG
OD OR BD
BUMETANIDE 0.25 MG
BD
0.5 - 10 MG
IN 2 OR 3
DOSES
TORSEMIDE DEMADEX,
DYTOR
5MG OD 5 - 10 MG OD EFFECTIVE BLOOD
PRESSURE
MEDICATION AT LOW
DOSAGE
37

20.
DOSAGE FORMS:

21.
(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.

22.
SPIRONOLACTONE:
• Acts by competitive antagonism of aldosterone, in the distal part of the nephron
• Prevents potassium secretion and thus decreases sodium reabsorption.
• Given orally, its full response is observed after 3-5 days.
• Short t½ of 1.6 hrs.
• Major action is due to an active metabolite, canrenone (t½ 17 hr).
• When combined with thiazide or loop diuretics it prevents loss of potassium.
• Metabolised to several inactive compounds.

23.
PHARMACOLOGICAL USES OF SPIRONOLACTONE:
• By itself it is not an antihypertensive agent.
• As an add-on drug, it may be particularly useful in hypertensive patients with significant
hypokalemia
• Drug of choice in primary hyperaldosteronism.
• Add-on drug in congestive heart failure.
ADVERSE REACTIONS OF SPIRONOLACTONE
• Hyperkalemia
• Endocrine effects: decreased libido, gynecomastia, impotence and menstrual
irregularity.
• Miscellaneous effects: lethargy and drowsiness.
• It may increase blood urea nitrogen and serum uric acid levels.
• Gastritis
Preparation and dosage:
Spironolactone is supplied as a microcrystalline preparation, 25 mg tablet. Dose :
100-200 mg per day (maximum 400 mg) in divided doses.

24.
44

25.
EPLERENONE
• Blocks the mineralocorticoid receptors in the kidney, heart, blood vessels and brain more
selectively than spironolactone.
• Metabolised by the liver - t½ of 4 -6 hours.
• Adverse reactions: GI intolerance, dizziness, hyperkalemia and
hypertriglyceridemia.
• Advantage over spironolactone is the lower incidence of endocrine side effects.
It is used to treat:
(a)Hypertension, in the dose of 50 mg OD, increased to 100 mg OD (maximum dose)
within 4 weeks, as required,
(b) Post MI CHF, in one half of the above dosage.
(c) It is also used in the combined oral contraceptive pill, Yasmin

26.
Absorption:
Oral Bioavailability: ~3%
Peak Plasma Time: 1-3 hr
Onset of action: Optimum effect achieved within 2 weeks
Effects are decreased when taken with a high fat meal
Metabolism:
In liver by CYP3A4
In preclinical studies, P-gp was found to be the major efflux system involved in
intestinal absorption and elimination via biliary excretion of aliskiren
Excretion:
Half-life: 24 hr
Excretion: Urine (~25%)

27.
Pharmacokinetics:
53

28.
AKISKIREN + HCT
AKISKIREN

29.
ACE INHIBITORS: (Prototype drug - captopril)

30.
• All ACEI are prodrugs except captopril and
lisinopril
• Bioavailability of about 65%.
• Absorption is reduced by food and so it is
given 1 hour before a meal.
• Metabolism: liver (50%)
• Metabolites: captopril-cysteine disulfide
(inactive)
• Renal excretion (95%)
Dosage Forms & Strengths of captopril:
Tablet - 12.5mg, 25mg, 50mg, 100mg

31.
PHARMACOKINETICS:
INTRAVENOUS FORM
59

32.
• Dry cough - possibly due to increase in bradykinin levels
• Hyperkalemia, particularly in patients with renal insufficiency and in
those taking a potassium sparing diuretic.
• Skin rashes, disturbances of the sense of taste, vitiligo
• Headache, GI disturbances, muscle cramps and rarely leucopenia.
• Proteinuria (>1 g/day) has been described.
• Angioedema.
• Foetal toxicity in animals and should be avoided in pregnancy.

33.
63

34.
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 (90%)
CLINICAL TRIALS:
1. AIRE (1993) - Acute Infarction Ramipril Efficacy Study
2. HOPE (2000) - Heart Outcomes Prevention Evaluation
3. ALLHAT (2002) - The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial
All the prospective studies confirmed the anti-hypertensive and
cardioprotective effects of ACE inhibitors.
They are more effective in younger hypertensives (<55 yrs)

35.
INDICATIONS:
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

36.
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.

37.
ENALAPRIL:
• It is a prodrug and is converted in the body to the active metabolite enalaprilat.
• Food does not interfere with its absorption.
• It is more potent.
• Its action is slower but lasts longer.
• It is less liable to cause taste disturbances, leucopenia and glomerulopathy
• Enalaprilat is the only drug in this class available intravenously.

38.
• 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

39.
• Pharmacokinetics are similar to ACEIs
• All indications, adverse effects and contra-
indications of ACEI also apply to ARB
except that incidence of cough and
angioedema is less with ARB.
• Metabolized by hepatic P450 enzyme
CYP2C9.

40.
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.

41.
1. LIFE (2002) - LCZ696 In Advanced Heart FailurE
2. VALUE (2004) - Valsartan Antihypertensive Long-term Use Evaluation
Outcomes in hypertensive patients with valsartan or amlodipine.
3. SCOPE (2004) - Study on COgnition and Prognosis in Elderly
Stroke prevention with candesartan in elderly with ISH.
4. JLIGHT (2004) - Japanese Losartan therapy Intended for Global renal
protection in HyperTensive patients.
All these trials attested the favourable effects of ARBs on morbidity and
mortality in hypertensive patients.

42.
CCB belong to 3 chemically distinct classes:
1. Phenylalkylamines e.g., Verapamil
• Least selective
• Has significant effects on both cardiac and vascular smooth muscle cells.
2. Dihydropyridines (DHP) e.g., Nifedipine, Amlodipine, etc.
Greater affinity for vascular calcium channels than the calcium channels in the heart.
They are beneficial in treating hypertension. They show little interaction with other
cardiovascular drugs, such as digoxin or warfarin.
3. Benzothiazepines e.g., Diltiazem.
Affects both cardiac and vascular smooth muscle cells.

43.
82

44.
83

45.
• Most of these agents have short half-lives (3 to 8
hours) following an oral dose.
• Sustained-release preparations are available and
permit once-daily dosing.
• Amlodipine has a very long half-life and does not
require a sustained-release formulation
• As these drugs are metabolised by liver, dose
adjustment in patients with renal disease is less
critical.
• They are potent vasodilators.
• Calcium channel blockers do not dilate veins.

46.
• Nifedipine - hypertensive emergencies.
• Nifedipine and other short half-life dihydropyridines are not
recommended for long term treatment of hypertension.
• CCB are useful in impaired renal function or asthma, and in acute
hypertension during pregnancy.
• As a monotherapy particularly in moderately hypertensive patients
with diabetes mellitus.
• Diltiazem and amlodipine are as effective as diuretics, beta-blockers
or their combination, in the long term treatment of essential
hypertension.

47.
VERAPAMIL - 1st degree AV block, constipation.
Verapamil and diltiazem - avoided in patients with heart failure or
with atrioventricular block due to their negative inotropic and
dromotropic effects.
DIHYDROPYRIDINES - Dizziness, headache, feeling of fatigue
caused by a decrease in blood pressure, Peripheral edema, gingival
hyperplasia.
CCB have no significant CNS effects. Edema of feet may be observed.

48.
90

49.
DOSAGE FORMS:

50.
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.
95

51.
1. HINT, TRENT, SPRINT I & II - Increased mortality / re-infarction
in patients treated with standard nifedipine or other short acting DHPs.
Possibly because of repeated surges of adrenergic discharge and marked
swings of BP due to short action of rapidly acting DHP.
2. These were not seen in long acting DHP and Verapamil / diltiazem -
DAVIT I & II

52.
contd..
3. Syst-EUR - Systolic hypertension in Europe shows that Nitrendipine
reduces cardiovascular morbidity and mortality in elderly hypertensives
4. ACCOMPLISH (2008) and ASCOT-BPLA (2005) - Superior
efficacy of amlodipine both as monotherapy and when combined with
an ACEI for reducing CVS events in high risk HTN patients
5. ALLHAT and Syst-EUR - Stroke prevention by CCB
• CCBs are next to ACEI in slowing diabetic nephropathy
• Most useful anti-hypertensives in cyclosporine induced Hypertension
in renal transplant recipients.

53.
PHARMACOKINETICS:
• It is well absorbed after oral and parenteral administration.
• Maximal blood levels are reached within 3 to 4 hours after oral
administration.
• The drug is acetylated in the liver.
Fast acetylators → drug levels → less drug effect
Slow acetylators→ drug levels → ADR: SLE
• Elimination of the drug is almost complete within 24 hours.
• Less than 5% of an oral dose is excreted unchanged in urine. Hence, it
can be used even in the presence of renal damage.

54.
PHARMACOLOGICAL ACTIONS:
• Direct relaxation of the arteriolar wall.
• The effect is slow in onset but prolonged. Even on
its IV administration, the BP falls only after 15-20
minutes.
• The fall in BP → decrease in the total peripheral
resistance
↓
compensatory tachycardia (↑ CO and SV)
• The splanchnic, coronary, cerebral and renal blood
flow may increase.
• It causes increase in plasma renin activity and
fluid retention.
• It can be given in hypertension during pregnancy
(2nd and 3rd trimesters).

55.
ADVERSE REACTIONS:
• Gastrointestinal irritation producing nausea, vomiting, gastric
hypersecretion, anorexia and diarrhoea.
• Cardiac effects: These include palpitation, tachycardia and anginal
attacks.
• Others like headache, nasal congestion, flushing, tremors and
dizziness.
• It causes secondary salt and water retention.
• Intolerance: The manifestations are fever, skin rash and
polyneuritis.
• GI haemorrhage and pancytopenia are serious manifestations.
• Acute rheumatoid arthritis or SLE like syndrome may develop
with large doses (over 600 mg/day) given for prolonged periods.

56.
Preparations and dosage:
• 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.

57.
2. SODIUM NITROPRUSSIDE:
This drug, known since 1850, has been used as a colour
indicator for acetone and aldehydes. It was regarded as a
poison because of its cyanide group.
Given by IV infusion, it is metabolised to active
compound NO which causes relaxation of arterioles and
veins.
• This results in the reduction in peripheral resistance
and venous tone, lowering the after load and the
preload.
• The myocardial oxygen consumption is reduced with
improvement in myocardial function in low output
states.
• Heart rate and the regional blood flow are little
affected.
• It increases plasma renin activity.
• It is rapidly metabolised to thiocyanate.
• The action is of rapid onset but of very short duration

58.
THERAPEUTIC USES:
• Hypertensive emergencies.
• It is infused IV slowly in the dose
of 0.5-5 mcg/kg/min.
• In the treatment of severe
hypertension, if the BP is not
adequately controlled after 10
minutes of infusion at the maximal
rate, the drug should be stopped
immediately for fear of toxicity.
• Nitroprusside must not be stopped
abruptly during treatment of heart
failure because of the danger of
rebound hypertension.

59.
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.

60.
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.

61.
AVAILABLE FORMS
• 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.

62.
114

63.
DOSAGE AND AVAILABLE
FORMS:
Minoxidil is used with a diuretic as a
reserve drug in patients with severe
hypertension who do not respond to
other drugs.
Minoxidil is started with a low dose of 5
mg daily and is gradually increased to
40–50 mg.
BALDNESS:
Activates the gene that controls the
protein of hair shaft by this it stimulates
the maturation and growth of cells of the
hair shaft. Hence it is used topically (2%
solution) for the correction of alopecia.

64.
DIAZOXIDE:
Related to thiazide diuretics and is a potent arteriolar dilator.
MOA - similar to minoxidil
ADR: Hyperglycaemia, salt and water retention, palpitation and myocardial
ischaemia.
THERAPEUTIC USE: It is used intravenously in hypertensive
emergencies where monitoring of infusion is not possible.
Diazoxide has a long duration of action (24 hours) and is suitable in such
situations.

65.
119

66.
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.

67.
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.

68.
NON SELECTIVE ALPHA BLOCKERS
PHENOXYBENZAMINE
Cyclizes spontaneously to highly reactive
ethyleniminium intermediate.
Competitive block:
Blockade is slow onset & longer duration
(3-4 days). Also inhibits reuptake of NE. Shifts blood
from pulmonary to systemic circuit. Shift fluid from
extravascular to vascular compartment - relaxation of
postcapillary vessels.
PHARMACOKINETICS - Preferred ROA- i.v.
Lipid soluble -penetrates brain. Mainly excreted
through urine in 24 hrs. Accumulates in adipose
tissue on chronic administration.
Dose - 20-60 mg/d oral; 1mg/kg/1hr slow i.v
infusion.
Uses - Pheochromocytoma, occasionally 2° shock,
PVD
PHENTOLAMINE
More potent α-blocker
Duration of action is shorter (min).
Equally blocks α1 & α2 receptors- NA
release ↑sed.
Uses - Δsis & intraop.management of
pheochromocytoma.
HTN due to clonidine withdrawl, cheese
reaction.
Dermal necrosis due to extravasated i.v
NA/DA.
Given S.C as local infiltration.

69.
ALPHA 1 BLOCKER
Prazosin
• Highly selective α1-blocker , α1: α2 selectivity 1000:1
• Fall in BP with only mild tachycardia.
• Dilates arterioles more than veins
• Postural hypotension occurs as 1st dose effect, minimized by starting with low
doses at bed time.
• Also inhibits PDE- ↑se cAMP in smooth muscle.
PK
• Effective orally, BA- 60%.
• Highly bound to plasma proteins (α1 acid glycoprotein).
• Metabolized in liver, excreted in bile.
• t1/2 – 2-3hrs, effect lasts for 6-8hrs.
Uses
• Primarily as antihypertensive.
• LVF not controlled by diuretics & digitalis.
• Raynaud’s disease
• BPH
• Scorpion sting

70.
FIRST DOSE EFFECT
• Occurs in 1% patients
• Due to profound postural hypotension
• Lose consciousness 30-60 min after receiving 1st dose
• Minimized by given first dose of the drug at bedtime or in very low
initial doses (less than 1mg)
• Adviced patients not to drive or do any hazardous activities after
taking the dose for 12-24hrs.

71.
BETA BLOCKERS

72.
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.

73.
Atenolol is the preferred β-blocker because of the advantages like once
a day dosing, absence of CNS side effects and β1 selectivity.
β-blockers should always be tapered while withdrawing.
Metoprolol may be given as a sustained release preparation for twice
daily use. It is particularly preferred in patients with concurrent
hypertension and heart failure.
Esmolol is a short-acting β1-blocker with a half life of about 10 min. It
is given intravenously as a loading dose of 0.5–1 μg/kg followed by an
infusion (50–300 μg/kg/min). Esmolol is suited for use in intraoperative
and postoperative hypertension and in hypertensive emergencies.

74.
ALPHA + BETA BLOCKERS
Labetalol and carvedilol block
α1- and β- receptors. They are
used IV in the treatment of
hypertension in
pheochromocytoma and in
hypertensive emergencies.

75.
TO SUMMARIZE

76.
155

77.
ANTI HYPERTENSIVE DRUGS TARGETING
THE SYMPATHETIC SYSTEM

78.
CLONIDINE
MECHANISM OF ACTION:
It is a selective α2-agonist. Stimulation
of α2 autoreceptors in the CNS (in the
vasomotor centre and hypothalamus)
decreases central sympathetic outflow,
blocks the release of noradrenaline from
the nerve terminals leading to a fall in BP
and bradycardia

79.
Pharmacological actions:
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

80.
Other Uses
1. In opioid withdrawal: Most withdrawal symptoms in opioid addicts
are of sympathetic overactivity and can be benefited by treatment with
clonidine.
2. Diabetic neuropathy: Clonidine controls diarrhoea by improving
absorption of NaCl and water in the gut by stimulation of α2 receptors
in the intestines.
3. With anaesthetics: Clonidine given preoperatively reduces the dose
of the general anaesthetic needed due to its analgesic effects.

81.
Preparations:
Clonidine hydrochloride 0.1 mg tablets. A transdermal preparation is
also available; its effect lasts for 7 days.
Guanfacine and Guanabenz are related to clonidine and have actions
similar to clonidine. Their duration of action, however, is prolonged.
New drugs like moxonidine and rilmenidine are congeners of
clonidine with longer half lives. These drugs are selective for
imidazoline receptors that modulate the central α2 receptor activity.

82.
AVAILABLE DOSAGE FORMS:
Abrupt discontinuation of clonidine therapy can lead to
rebound hypertension - Rx with phentolamine

83.
ALPHA METHYL DOPA
• An analog of dopa, is a prodrug.
• It is metabolised in the body to alpha
methyl norepinephrine which is an α2-
agonist and acts like clonidine.
• It reduces central sympathetic outflow
leading to a fall in BP.
• Renin levels also fall but renal blood flow
is well maintained.
• Onset of action is about 4–6 hr
• Duration of action 12–24 hr.
• Left ventricular hypertrophy is reversed in
about 12 weeks of treatment.

84.
USES:
Methyldopa is used in mild to moderate hypertension along with a diuretic.
It is safe in hypertension during pregnancy and is the preferred antihypertensive
in such patients. Started with 250 mg twice daily, the dose may be increased to a
maximum of 750 mg BD.
ADVERSE EFFECTS:
Sedation, dryness of mouth and nose, nightmares, depression, vertigo,
extrapyramidal signs, raised prolactin levels, headache, postural hypotension,
impotence, hemolytic anemia
On prolonged use, salt and water retention may blunt the antihypertensive effect
(called pseudotolerance) and needs a diuretic to be added.

85.
• These drugs inhibit the NN type of nicotinic receptors that
are present on the autonomic ganglia (both sympathetic and
parasympathetic).
• The therapeutic effect (decrease in blood pressure) is due to
the decrease in neurotransmission through sympathetic
ganglia whereas decreased transmission through
parasympathetic ganglia is responsible for the adverse
effects like urinary retention and dry mouth.
• Hexamethonium and trimethaphan are the drugs in this
group and are used as antidotes for nicotine poisoning.

86.
• Trimethaphan is given intravenously to produce controlled
hypotension during certain surgical procedures due to its rapid and
short action (15 minutes)
• Trimethapan is used along with nitroprusside as a slow i.v. infusion for
hypertensive emergencies in aortic dissection.

87.
Guanethidine:
depletes the stores of
noradrenaline in the
adrenergic neurons and also
blocks its release.
Because of the adverse
effects like postural
hypotension, diarrhoea and
sexual dysfunction,
guanethidine is not used.

88.
Reserpine
It is an alkaloid obtained from Rauwolfia
serpentina (Sarpagandhi) that grows in India.
MECHANISM OF ACTION:
• In the adrenergic neurons, it binds to the
vesicles that store monoamines like
noradrenaline, dopamine and 5-HT and
destroys these vesicles.
• Reserpine thus depletes the stores of these
monoamines and reduces BP.
• Depletion of monoamines particularly
dopamine is thought to be responsible for
the antipsychotic effects of reserpine

89.
USES:
Hypertension
Initial - 0.5 mg daily for 1 or 2 weeks
Maintenance - 0.1-0.25 mg PO OD
Use higher dosages cautiously occurrence of mental depression
or other adverse reactions may increase
Psychiatric Disorders
0.5 mg daily, but may range from 0.1 to 1 mg; titrate dose
according to patient response
Tardive Dyskinesia
0.25 mg q6hr; may increase by 0.1-0.25 mg to a total of 5 mg
daily

90.
ADVERSE EFFECTS:
drowsiness, depression,
nightmares, parkinsonism, postural
hypotension, oedema, weight gain,
gynaecomastia and sexual
dysfunction
AVAILABLE FORMS AND
DOSAGES:
tablet - 0.1mg, 0.25mg
It is not currently in clinical
practice

91.
181

92.
182

93.
183
Major determinant - Aorta

94.
187

95.
189

96.
190

97.
191

98.
192

99.
WHO guidelines 2021

100.
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.
198

101.
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.
199

102.
200

103.
201

104.
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, slideshare, Osmosis videos, Pubmed
202