ANTI-
HYPERTENSIVE
DRUGS
PREVALENCE
TYPES& ETIOLOGY
TREATMENT
Non Pharmacological
Pharmacological
Normal regulation of blood pressure
BP=CO x PVR
Postural Baroreflex
Renal Response to Decreased BP
CLASSIFICATION
DIURETICS
SYMPATHOPLEGICS
CALCIUM CHANNEL BLOCKERS
DRUGS ACTING ON RENIN ANGIOTENSIN
SYSTEM
ACE INHIBITORS
ANGIOTENSIN RECEPTOR BLOCKERS
VASODILATORS
A. DIURETICS
Thiazides & related agents
Hydrochlorothiazide
Chlorthiazide
Benzthiazide
Chlorthalidone
Indapamide
Loop diuretics
Furosemide
Bumetanide
Ethacrynic acid
Potassium Sparing Diuretics
Triamterene
Spironolactone
Amlioride
B. SYMPATHOPLEGICS
1. Centrally acting drugs
Methyldopa
Clonidine
Guanabenz
Guanfacine
2. β-Adrenergic receptor antagonists
Propranolol
Metoprolol
Atenolol
3. α-Adrenergic receptor antagonists
Prazosin
Terazosin
Doxazosin
Phenoxybenzamine
Phentolamine
4. Alpha & Beta Blockers
Labetalol
Carvedilol
5. Adrenergic Neuron Blockers
Guanethidine
Reserpine
Trimethaphan
6. Ganglion Blocking Agents
Trimetaphan
C. CALCIUM - CHANNEL
BLOCKERS
Dihydropyridines
Nifedipine (Adalat)
Nicardipine
Nimodipine
Amlodipine
Nisoldipine
Nitrendipine
Felodipine
Isradipine
Phenylalkylamines
Verapamil (Calan)
Gallopamil
Diphenylpiperazines
Flunarizine
Trimetazidine
Ranolazine
Benzothiazepines
Diltiazem (Herbessor)
Diarylaminopropylamine
Bepridil
D. DRUGS ACTING ON RENIN
ANGIOTENSIN SYSTEM
Angiotensin Converting Enzyme (ACE)
Inhibitors
Captopril
Enalapril
Lisinopril
Benzapril
Perindopril
Quinapril
Angiotensin II Receptor Blockers
(Competitive antagonists):
Losartan
Valsartan
Candesartan
Eprosartan
Irbesartan
telmisartan
Sarasalin
E. VASODILATORS
1. Arterial
Oral
Hydralazine
Minoxidil
Parenteral
Diazoxide
Fenoldopam
2. Venodilators
Nitroglycerine
3. Aterial and Venous
Sodium Nitroprusside
A. DIURETICS
Thiazides & related agents
Hydrochlorothiazide
Chlorthiazide
Benzthiazide
Chlorthalidone
Indapamide
Loop diuretics
Furosemide
Bumetanide
Ethacrynic acid
Potassium Sparing Diuretics
Triamterene
Spironolactone
Amlioride
Drugs that alter sodium & Water
Balance
Dietary control of B.P by sodium restriction preventive
& Non Toxic Therapeutic Measure.
Diuretics
M.O.A & Haemodynamic Effects:
B.P by Primarily Because of Sodium Depletion
Initially : Because of Blood volume & C.O P.R May
After 6-8 Wks: C.O Returns to Normal P.R
(Sodium B.V Stiffness & Neuronal Reactivity
P. Resistance)
Sodium B.V Stiffness & Neuronal
Reactivity P.Resistance
Because of Na+ & Ca++ Exchange
Diuretics Reverse this.
Some diuretics have direct vasodilator
Activity.
Diuretic B.P by 10-15mn
Used alone in mild or moderate HTN
Used in combination with
sympathoplegics & vasodilators in more
severe HTN (they counteract the
compensatory mechanisms Sodium
B. SYMPATHOPLEGICS
1. Centrally acting drugs
Methyldopa
Clonidine
Guanabenz
Guanfacine
2. β-Adrenergic receptor antagonists
Propranolol
Metoprolol
Atenolol
3. α-Adrenergic receptor antagonists
Prazosin
Terazosin
Doxazosin
Phenoxybenzamine
Phentolamine
4. Alpha & Beta Blockers
Labetalol
Carvedilol
5. Adrenergic Neuron Blockers
Guanethidine
Reserpine
Trimethaphan
6. Ganglion Blocking Agents
Trimetaphane
C. CALCIUM - CHANNEL
BLOCKERS
Dihydropyridines
Nifedipine (Adalat)
Nicardipine
Nimodipine
Amlodipine
Nisoldipine
Nitrendipine
Felodipine
Isradipine
Phenylalkylamines
Verapamil (Calan)
Gallopamil
Diphenylpiperazines
Flunarizine
Trimetazidine
Ranolazine
Benzothiazepines
Diltiazem (Herbessor)
Diarylaminopropylamine
Bepridil
Type of Voltage gated or voltage
Dependent Calcium Channels
L Type
• Muscle
• Neurons
• Heart more sensitive to Verapamil
T Type
Neurons
• Heart
N Type
Neurons
P Type
Cerebellar purkinje neurons
Mechanism of action
In Blood Vessels
Blocking of voltage gated-calcium channels
Reduced Ca++ in smooth muscle cells
Reduced formation of Ca++ / Calmodulin complex
No activation of myosin light chain kinase
No Phosphorylation of myosin light chain
Vasodilatation
Reduced after & Preload in heart
Reduced O2 requirement
On Heart
Blockade of voltage gated calcium channels
Reduced Ca++ influx into cardiac cells
No breaking of troponin bridge
Less contraction
Less O2 consumption
Ph. Kinetics :
Nifedipine
Complete oral absorption
Peak plasma levels 20-45 Min
Detectable plasma levels 6 Min D.O.A 8-12 hrs
Orally active, almost complete absorption verapamil
extensive P.P.B (80-90%)
Diltiazem
Elimination half life 3-6 hrs.
Extensive metabolism in liver.
Verapamil and Nifedipine excreted in urine Diltiazem
excreted in faeces.
Pharmacological Actions / Effects
Group Actions On Heart
Anti Anginal
Anti hypertensive
Anti arrhythmic
Useful in Myocardial infarction
Other Effects
Anti-Platelet effect
Effect on other smooth muscles
Action on Skeletal muscles
Decreased release of insulin
Decrease secretion of exocrine glands.
Verapamil blocks reverse transporter p-
170 glycoprotein
THERAPEUTIC USES
Hypertension
Angina
Supraventricular arrhythmias
Hypertorophic cardiomyopathy
Prevent increase in infarct size
Migraine Prophylaxis
Raynaud’s phenomenon
Atherosclerosis
Subarachnoid haemorrhage
Toxicity
Cardiodepression, AV blocks, Cardiac
failure, Hypotension.
Constipation
Edema of dependent parts
Skin rashes
DRUGS ACTING ON RENIN
ANGIOTENSIN SYSTEM
ACE INHIBITORS
ANGIOTENSIN RECEPTOR BLOCKERS
Angiotensin converting enzyme (ACE)
inhibitors
Captopril
Enalapril
Lisinopril
Benzapril
Perindopril
Quinapril
Angiotensin II Receptor Blockers
(Competitive antagonists)
Losartan
Valsartan
Candesartan
Eprosartan
Irbesartan
telmisartan
Sarasalin
INHIBITORS OF RENIN-ANGIOTENSIN
SYSTEM
ACE Inhibitors
M.O.A.
Renin is released from JGA
Renin acts upon Angiotensinogen, to split off
the inactive decapeptide. Angiotensin I .
AngiotensinI is then converted primarily by
endothelial angiotensin converting
enzyme(ACE) to Octapeptide, angiotensin II.
Angiotensin II is the most powerful
vasoconstrictor.
It also stimulates the synthesis and secretion of
aldosterone which retains sodium & water.
ACEI inhibit the converting enzyme peptidyl
dipeptidase & prevents formation of
Angiotensin II. The same enzyme (under the
name of plasma kininase)inactivates
PHARMACOLOGICAL EFFECTS
Antihypertensive effect
Due to inhibitory action on the Renin - Angiotensin
System
Decreased Angiotensin II less vasoconstriction,
hence Vasodilatatio Decreased PR.
Due to increased bradykinin
Bradykinin degradation is prevented, accumulation of
bradykinin – a potent vasodilator
So B.P principally by P.R.
CO & H.R. not significantly changed
No reflex tachycardia (Safe in patients ē I.H.D) due to
• Downward resetting of baroreceptors OR
• Parasympathetic activity.
Effective in Patients ē High Renin level & Normal Renin
Levels
Effect on Nephropathy in D.M.
Proteinuria
Stabilize Renal Function.
Improve intra renal hemodynamics
Effect on Heart
Useful in C.C.F
After Load & Preload.
Useful after Myocardial Infarction
Post Myocardial Infarction
Remodeling
Pharmacokinetics
Orally active
Absorption : Rapidly absorbed from GIT (B.A=70%)
B.A ē Food.
Metabolism : By conjugation in liver
Distribution : Well distribution but not to C.N.S
Excretion : By kidneys
Pro -drugs are converted to active drugs by
hydrolysis in Liver.
Enalapril Deesterified Enalaprilat
Most of ACEI excreted by kidneys so dosage should
be in renal insufficiency.
Adverse Effects
Altered Taste
Allergic Skin Rashes
Drug Fever
Marked Hypotension ē First Dose in hypovolaemic
patients
Acute Renal Failure In Renal Artery Stenosis.
Hyperkalemia
Dry-cough, sometimes with wheezing because of
Bradykinin
Angioedema because of Bradykinin
Neutropenia serious but rare, in Autoimmune
diseases
Proteinuria In Renal insufficiency ē High Doses of
Captopril.
Teratogenc Effects:
In 2nd & 3rd Trimester Fetal Hypotension, Anuria & Renal
Failure, Sometimes Fetal malformations/Death.
Drug Interactions
With K+ Supplements /K+ Sparing Diuretics
(Marked hyperkalemia)
Non Steroidal Anti. Inflammatory Drugs may
impair the effect which is mediated through
Bradykinin.
Contraindications Pregnancy
Therapeutic Uses
• Hypertension.
Usually given with a thiazide diuretic. May be
given with beta blockers
• Congestive Cardiac Failure
• Diabetic Nephropathy
• Myocardial Infarction
Angiotensin Receptor Blockers
M.O.A : Competitive Blockers of Angiotensin-II
Receptors
Saralasin also has weak agonistic activity.
Useful tool for research
Given by IV infusion.
Not used as anti H.T other drugs are used
No Effect on Bradykinin, so no dry cough and no
angioedema
More effective than ACE I (Angiotensin - II also
generated by other Enzymes
Adverse . Effects: Like ACE I except Dry cough &
Angioedema.
VASODILATOR DRUGS
Drugs that dilate B.Vs by acting
directly on smooth muscles through non
autonomic mechanisms. They include:
Arterial vasodilators: Hydralazine,
Minoxidil, Diazoxide, Fenoldopam.
Arterial & Venous vasodilator: Sodium
Nitroprosside.
Calcium Channel Blockers : Nifedipine,
Diltiazem.
COMPENSATORY RESPONSES TO
VASODILATOR DRUGS & BASIS FOR
COMBINATION THERAPY
Hydralazine
Oral vasodilator
Hydrazine derivative
M.O.A: Direct arteriolar dilator. Does not dilate veins
Acts through release of nitric
oxide.
Phk :
Well abs. From G.I.T. Rapid first pass metabolism in liver.
So B.A is low.
Metabolised by Acetylation _ Due to genetic factors
,may be Slow or Rapid Acetylators
Rapid Acetylators Greater First pass metabolism.
Less B.A
Slow Acetylators Less First Pass metabolism.
More B.A.
Half Life : 2 - 4 hrs.
Ph. Effects:
Arteriolar dilatation leads to decreased
peripheral
resistance & hence decreases blood pressure.
Postural hypotension is uncommon.
The hypotensive effect elicits compensatory
responses.
Vasodilatation Hypotension which causes:
Increased sympathetic out flow &increased
rennin release.
Increased HR.Cardiac contractility--------
Increased CO, Increased PR----- Increased BP
Increased Renin ------Increased
Angiotensinogen---- Increased Aldosterone----
Decreased renal sodium excretion------
Increased plasma volume-----Increased BP
Therapeutic use
Anti H.T.V.
In severe H.T.N. in combination therapy.
Toxicity
Headache,
Nausea Anorexia,
Palpitation, Dizziness Angina /
arrhythmias (in Pt. ē I.H.D)
Syndrome like systemic Lupus
Erythematosis in slow acetylators
( reversible). With high doses (Arthralgia,
Myalgia, Skin rashes, Fever)
Rare side effects: Peripheral Neuropathy,
MINOXIDIL
Oral Arteriolar vasodilator.
MOA
Pro drug, converted to Minoxidil sulphate,
an active metabolite which is K+ channel
opener. This action stabilizes the
membrane at its RMP, and makes
contraction less likely & hence relaxation
of vascular smooth vasodilation
Decreased PR decreased BP
Compensatory responses are elicited, so
combined with Diuretic or a Beta blocker.
Ph. Kinetics
Well absorbed from GIT.
Metabolised by conjugation.
DOA: 24 Hrs
Only given orally
Toxicity
Tachycardia, palpitations, angina,
Edema---When doses of beta blockers &
diuretics are inadequate.
Headache, sweating & hirsuitism
(Topically used for baldness).
Sodium Nitroprusside
Powerful parenteral vasodilator of
Arterioles & Veins
Complex of Iron, Cyanide, Nitroso Group.
Given by I/V infusion.
Rapidly metabolised by uptake in to RBCS
With liberation of cyanide .
Cyanide metabolised to thiocynate in
presence of sulphur donor by
mitochondrial enzyme.
Thiocynates excreted by kidneys
M.O.A It activate guanylyl cyclase,
either via release of nitric oxide or by
direct stimulation of the enzyme.
Increase intracellular cGMP,
Relaxation of S.M of Arterioles +
Veins
Vasodlatation
P.R
B.P
Ph. Effects
Rapid in B.P
In Supine position &Upright position More
marked in upright position.
Effect disappears within 1-10min on stopping
infusion
Hypotension is due to decreased PR,
C.O- normally no change / slight
C.O – In CCF & Low C.O.
Because Of:
After Load.
Preload.
Toxicity Of Cyanide:
Metabolic Acidosis
Arrhythmias
Excessive hypotension
Death
Prevented By Soduim Thiosulphate or
Hydroxycobolamine.
Because Of thiocyanate:
Weakness, Disorientation, Psychosis,
Muscle Spasm & convulsions. Delayed
Hypothyroidism
Methemoglobinaemia during infusion may
occur.
Diazoxide
Long Acting arteriolar vasodilator
M.O.A:
Prevents Vascular Sm. muscle contraction
by
opening ATPase sensitive K+ Channel
Stabilization of Membrane Potential at RMP
No Contraction Relaxation
P.R B.P
Ph. Effects: only dilates Arterioles P.R Rapid in
B.P
H.R C.O (Of Compensatory Mechanisms)
Ph.K: Given I/V. Bound To P.Proteins & Vascular Tissue
Exc-30% unchanged
70% Metabolites
Ad. Effects:
• Excessive Hypotension
• Salt & Water Pretension
• Hyperglycemia
(Secretion of insulin from β -cells is inhibited)
Th. Uses:
• Hypertension – Severe
With β Blocker / Diuretics
• In Insulinoma to Treat Hypoglycaemia
Fenoldopam
Recently discovered peripheral arteriolar
dilator
Acts primarily as an agonist of D1-dopamine
receptors, resulting in dilatation of
peripheral arteries
Used for hypertensive emergencies and
postoperative hypertension.
Given by intravenous infusion
Major toxicities are reflex tachycardia,
headache, and flushing. Hypokalemia may
occur.
TREATMENT OF HYPERTENSIVE
EMERGENCIES (Hypertensive Crisis)
B.P. 200/120 mm Hg.
If not treated
- Cerebral Haemorrhage
- Epistaxis
- Acute Heart Failure
- Retinal Haemorrhages.
Pt. is monitored in an intensive care unit with
continuous recording of arterial B.P.
Fluid in-take & out-put monitoring.
Daily measurement of body weight.
Anti H.T Drugs
I/V Sodium Nitroprusside/fenoldopan as
infusion.
Nifedipine sublingually
Methyl Dopa I/V
ACE inhibitors (Captopril). Hydralazine. Orally
Prazosin (α Blockers) & β- Blockers. Orally
Labetalol Orally
Diuretics to prevent volume expansion-
Furosemide is the drug of choice.
Dialysis may be a necessary alternative to
the loop diuretics in patients with oliguric
renal failure.
Clonidine is contraindicated.
The Diastolic B.P should not be
normalized but kept at 100-110mmHg in
first few hours to prevent cerebral Hypo
perfusion, Brain injury.
Because chronic hypertension is
associated ē Auto regulatory changes in
cerebral Blood Flow.
Subsequently B.P. is normalized by
Oral Antihypertensive drugs over several
Weeks.
Monoamine Oxidase in hibitors:
Inhibit MAO enzyme in GI. Mucosa & Liver.
Dietary Tyramine reaches circulation Taken up
by nerve terminals
Octopamine (Replaces nor adrenaline in Storage
Granules)
(Ineffective N.T)
No Effect on α1 Receptors
Sympathoplegia
B.P
They are not used Anti M.P Now.
