Download Antihypertensive Drugs

Antihypertensive Drugs
Dr. Sasan Zaeri
PharmD, PhD
(Department of Pharmacology)
Introduction
Hypertension
≥ 140 mmHg
≥ 90 mmHg
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Systolic Blood
Pressure (SBP)
Diastolic Blood
Pressure (DBP)
Types of
Hypertension
Essential
Secondary
A disorder of unknown origin affecting the
Blood Pressure regulating mechanisms
Secondary to other disease processes
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Environmental
Factors
Stress
Na+ Intake
Obesity
Smoking
Treatment – Why?
 To prevent target organ damage:





Eye (retinopathy)
Brain (stroke)
Kidney (chronic renal disease)
Heart (coronary artery disease, CHF)
Peripheral arteries (atherosclerosis)
 Even asymptomatic hypertension needs to be
treated
Normal Blood Pressure Regulation
 Blood Pressure = Cardiac output (CO)
X Resistance to passage of blood
through precapillary arterioles (PVR)
 CO is maintained by Heart (3) and
postcapillary venules (2)
 PVR is maintained by arterioles (1)
 Kidney (4) controls BP by affecting
volume of intravascular fluid in long
term
 Baroreflex and renin-angiotensinaldosterone system regulate the
above 4 sites
 Local agents like Nitric oxide cause
vasodilation and decreases BP
 All antihypertensives act via
interfering with normal mechanisms
Baroreceptor Reflex Pathway
Antihypertensive Drugs

Diuretics


Thiazides, loop diuretics, K-sparing diuretics
Sympathoplegic drugs


ß-adrenergic blockers, α -adrenergic blockers, Centrally acting
drugs
Direct vasodilators


Calcium channel blockers, Minoxidil, Hydralazine, Sodium
nitroprusside
Angiotensin antagonists

Angiotensin-converting Enzyme (ACE) inhibitors, Angiotensin
receptor 1(AT1) blockers
Diuretics
 Mechanism of antihypertensive action:
 Initially: diuresis – depletion of Na+ and body fluid
volume – decrease in cardiac output
 Subsequently after 4 - 6 weeks, reduction in total
peripheral resistance (TPR)



Thiazides: Hydrochlorothiazide
Loop diuretics: Furosemide
K+ sparing diuretics: Spironolactone, triamterene and
amiloride
Diuretics
Diuretics
 Thiazide diuretic is the first-choice drug in mild
hypertension
 Thiazide diuretic can be used with a potassium
sparing diuretic

Example: Triamterene-H
 Loop diuretics are used only in complicated cases
 CRF, CHF marked fluid retention cases
Thiazide diuretics
 Adverse Effects (mostly seen in higher doses):

Hypokalaemia

Hyperglycemia: precipitation of diabetes

Hyperlipidemia: rise in total LDL level – risk of stroke

Hyperurecaemia: inhibition of uric acid excretion

Hypercalcemia
 Thiazide diuretics reduce mortality and morbidity in
patients with BP
Beta-adrenergic blockers
 Mechanism of action:


Reduction in CO
Decrease in renin release from kidney (beta-1 mediated)
 Non-selective: Propranolol (others: nadolol, timolol, pindolol,
labetolol)
 Cardioselective: Metoprolol (others: atenolol, esmolol,
betaxolol)
 Advantages:
 Prevention of sudden cardiac death in post MI patients
 Prevention of CHF progression
Beta-adrenergic blockers
 Advantages of cardio-selective over non-selective:
 In asthma
 In diabetes mellitus
 In peripheral vascular disease
 Current status in treatment of BP:
 First line along with diuretics and ACEIs
 Preferred in angina pectoris
 Preferred in Post MI patients – useful in preventing
progression to CHF and mortality
Αlpha-adrenergic blockers
 Mechanism of action:
 Vasodilatation by blocking of alpha adrenergic
receptors in smooth muscles: Reduction in PVR,
reduction in CO by reduction in venomotor tone
 Specific alpha-1 blockers: prazosin, terazosin and
doxazosine
 Non selective alpha blockers (phenoxybenzamine,
phentolamine) are not used in chronic essential
hypertension

Only used in pheochromocytoma
Αlpha-adrenergic blockers
 Adverse effects:


Prazosin causes postural hypotension
 First-dose effect
Fluid retention in monotherapy
 Advantages:



Improvement of carbohydrate metabolism (diabetics)
Improvement of lipid profile (↓ LDL, ↑ HDL)
Treatment of benign prostatic hyperplasia (BPH)
 Current status in treatment of PB:

Not used as first line agent, used in addition with other
conventional drugs which are failing – diuretic or beta
blocker
Centrally-Acting Drugs
 Mechanism of action:
 Inhibition of adrenergic discharge in brain by agonizing
alpha-2 receptors: fall in PVR and CO
 Methyldopa
 Various adverse effects – cognitive impairement, postural
hypotension, hemolytic anemia
 Not used therapeutically now except in Hypertension during
pregnancy
 Clonidine
 Not frequently used now because of tolerance and
withdrawal hypertension
Calcium Channel Blockers Classification
Calcium Channel Blockers (CCBs)
 Mechanism of action:
 Blockade of L-type voltage-gated calcium channels in heart and
vessels: vascular smooth muscle relaxation (↓ PVR), negative
chronotropic and ionotropic effects in heart (↓CO)
 DHPs (amlodipine and nifedipine) have highest smooth muscle
relaxation followed by diltiazem and verapamil
Calcium Channel Blockers
 Advantages:

Can be given to patients with




Asthma with BP
Angina with/without BP
Peripheral vascular disease
Prophylaxis of migraine
 Immediate acting Nifedipine is not encouraged
anymore
 Not first line of antihypertensive unless indicated
Vasodilators - Hydralazine
 Mechanism of action:
Hydralazine molecules combine with receptors in the
endothelium of arterioles and causes Nitric oxide release –
relaxation of vascular smooth muscle – fall in PVR
 Adverse effects:
 Reflex tachycardia
 Salt and water retention
 Drug-induced lupus erythematosus

 Uses:


Moderate hypertension when 1st line fails – with betablockers and diuretics
Hypertension in pregnancy
Vasodilators-Sodium Nitroprusside
 Mechanism of action:
 Rapidly produces nitric oxide to relax both resistance and
capacitance vessels (↓PVR and CO)
 Uses: Hypertensive Emergencies
 (slow infusion)
Vasodilators – Minoxidil
 Mechanism of action:
 Hyperpolarization of smooth muscles by opening potassium
channels and thereby relaxation of vascular smooth muscles

mainly 2 major uses – antihypertensive and alopecia
 Rarely indicated in hypertension
 Only in life threatening chronic hypertensions e.g. in chronic renal
failure
 More often in alopecia to promote hair growth
Angiotensin Converting Enzyme (ACE)
Inhibitors
What is Renin – Angiotensin
System (RAS)?
RAS
 Renin is produced by juxtaglomerular cells of kidney
 Renin is secreted in response to:
 Decrease in arterial blood pressure
 Decrease in Na+ in tubular fluid
 Increased sympathetic nervous activity
 Renin acts on a plasma protein, Angiotensinogen, and cleaves it
to produce Angiotensin-I
 Angiotensin-I is rapidly converted to Angiotensin-II by ACE
(present in luminal surface of vascular endothelium)
 Angiotensin-II stimulates Aldosterone secretion from Adrenal
Cortex
RAS
Increased
Blood Vol.
Rise in BP
Vasoconstriction
Na+ & water
retention
Kidney
(Adrenal cortex)
RAS – Actions of Angiotensin-II
1.
Powerful vasoconstrictor particularly arteriolar
2.
It increases myocardial force of contraction (CA++
influx promotion)
3.
Mitogenic effect – cell proliferation
4.
Aldosterone secretion stimulation – retention of
Na++ and water in body
5.
Vasoconstriction of renal arterioles – rise in IGP –
glomerular damage
Angiotensin-II
 What are the chronic ill effects?
 Volume overload and increased PVR

Hypertension – long standing will cause ventricular
hypertrophy

Cardiac hypertrophy and remodeling

Renal damage
Risk of increased CVS related morbidity and mortality

 ACE inhibitors reverse actions of Ang II
ACE Inhibitors
 Captopril, Enalapril, Ramipril, Fosinopril
etc.
ACEIs – Antihypertensive action
 RAS is overactive in 80% of hypertensive
cases and contributes to the maintenance of
vascular tone and volume overload

RAS inhibition by ACEIs causes Lower PVR
and volume overload hence lower BP
ACEIs – Adverse effects
 Cough – persistent cough in 20% cases induced by inhibition of
bradykinin breakdown in lungs
 Hyperkalemia (routine check of K+ level)
 Acute renal failure (bilateral renal artery stenosis)
 Angioedema: swelling of lips, mouth, nose etc.
 Foetopathic: hypoplasia of organs, growth retardation etc
 Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia
Place of ACE inhibitors in HTN
 Drug of choice in:

HTN with diabetes (nephroprotective)

HTN with chronic renal disease

HTN with CHF

HTN with MI

Minimal worsening of quality of life – general
wellbeing, sleep and work performance etc.
ACE inhibitors – other uses
 Congestive Heart Failure (CHF)
 Myocardial Infarction (MI)
 Diabetic Nephropathy
Angiotensin Receptor Blockers
(ARBs)
Angiotensin Receptors: Most of the physiological actions of
angiotensin are mediated via AT1 receptor
 ARBs block the actions of A-II: vasoconstriction, aldosterone
release
 No inhibition of ACE, therefore no accumulation of bradykinin
 Cough is rare with ARBs
 Indications of ARBs are similar to those of ACEIs.
 Examples: Losartan, candesartan, valsartan and telmisartan