Professor and head of clinical pharmacology department
Mansura university

• A) Non-Drug Therapy
• It includes decrease sodium intake, weight reduction in obese, stop smoking, coffee and alcohol drinking; exercise program and control diabetes hyperlipideamia.
mellitus and

•
• Hypertension is a persistent elevation of blood pressure above 140/90 mm. Hg.
•
• Classification of Hypertension
• According to etiology: essential and secondary
(e.g. thyrotoxicosis).
• According to type: systolic, diastolic and mixed
(more dangerous).
• According to degree:

B) Drug Therapy (Antihypertensives)
• There are many groups of drugs available for treatment of hypertension
• Commonly used drugs
• A ngiotensin converting enzyme inhibitors.
• B eta-blockers.
• C alcium channel blockers.
• D iuretics.

1. Direct vasodilators e.g. hydralazine.
2. Centrally acting agents interfering with adrenergic function e.g. alphametyldopa, clonidine and guanfacine
3. Alpha adrenergic blockers e.g. prazocin.
4. Concurrent alpha and beta blockers e.g. labetalol, carvedilol.
5. Adrenergic neurone blockers e.g. reserpine and alpha methyldopa.
6. Serotonine antagonists e.g. ketanserine.
7. Ganglion blockers e.g. trimetaphan.
8. Potassium channel openers e.g. cromakalim, pinacidil.
9. Imidazoline receptors agonist e.g. moxonidine and rilminidine.

• N.B.
• Avoid agents that increase blood pressure as Sympathomimetics.
Steroids.
NSAIDs.
Carbenoxolone, oral contraceptives, cyclosporine, recombinant human erythropoietin, and products that contain large quantities of sodium.
Such as effervescent solutions.

Mechanisms of Diuretics as an Antihypertensive
• Direct vasodilator effect.
• Decreased vascular receptor sensitivity to vasopressin agents
• Increase synthesize of the vasodilator PGs.
• Diminished cardiac output due to decrease blood volume by the diuretic action.

Indications of Diuretics in Hypertension
• Initial therapy in most hypertensive patients.
• Hypertensive crises.
• Chronic renal failure.
• With other antihypertensive
: Primary hyperaldosteronism

• Indications of beta-blockers in hypertension:
• Hypertensive patient with stable angina, supraventricular or ventricular arrhythmias.
•
• younger age group, hyperkinetic circulation, alcohol withdrawal,labile hypertension and thyrotoxicosis
• Hyperrenenimic hypertension.
• As a part of combined therapy.
• N.B. Beta-blocker of choice in treatment of hypertension should be cardioselective

1 blocker and with a long duration of action e.g. atenolol.

Classification:
• C.C.B.with cardiac effects diltiazem.
e.g. verapamil and
• C.C.B.with vascular effects isradipine.
e.g. nifedipine,
• C.C.B.with tissue protection nifedipine.
e.g. flunarizine,

• Absorption is complete after oral administration.
• It has first pass hepatic metabolism.
• Peak effects of verapamil occur within 15 minutes of its intravenous administration.
• They are bound to plasma proteins.

• Smooth muscle
• They cause relaxation of vascular smooth muscle, bronchiolar, gastrointestinal, and uterine smooth muscle.

• Verapamil and diltiazem reduce cardiac contractility
• They cause brdychycardia more selectively than do the dihydropyridine.
• Dihydropyridines less depressant on the heart than verapamil or diltiazem.

• They decrease platelet aggregability.
• Verapamil inhibits insulin release.
• They are effective in limiting the spread of seizure activity.

• A) C.C.B.with cardiac effects are used in treatment of:
•
• 1-Ischemic heart disease: all types of angina and myocardial infarction.
• Mechanisms of action in Ischemic heart diseases
• Decrease arterial blood pressure, contractility and heart rate so they decrease myocardial oxygen demand.
• Decrease Coronary vascular resistance so increases blood flow to the myocardium.
• Dilatation of epicardial coronary arteries
• Decrease Ca ++ load, which improve myocardial relaxation and decrease myocardial cell necrosis.

• 2-Cardiac arrhythmias e.g. paroxysmal supraventricular tachycardia.
• 3-Hypertrophic obstructive cardiomyopathy: because they produce:
• Reducing contractile force during systole. Enhance relaxation during diastole resulting in improving coronary flow.
• 4-Arterial hypertension: due to vasodilatation of the blood vessels.

C.C.B.with vascular effects
1. Arterial hypertension: due to vasodilatation of the blood vessels.
2. Cerebral vasospasm (nimodipine).
3. Peripheral vascular disease.
4. Chronic renal failure to minimize ischemia
5. Re-perfusion injury in the myocardium.
6. Migraine.

• Verapamil or diltiazem aggravate congestive heart failure.
• Verapamil or diltiazem can cause A.V. block in certain situation.
• Verapamil can cause hepatotoxicity with prologed use.
• Verapamil decrease insulin realease.
• Nifedipine can cause hypotension, flushing, nasal congestion, tinitus .
• Ankle edema (with nifedipine or verapamil ).

• Verapamil with digitalis or with betablockers may cause A-V block.
(nifedipine would be the drug of choice if B-blockers are to be used with CCBs).
• CCBs and direct vasodilators may cause profound hypotension.

• Verapamil should be used with great caution in the presence of heart failure, unstable AV block, sick sinus syndrome, low blood pressure states.
• Nifedipine is contraindicated in idiopathic hypertrophic subaortic stenosis, and unstable angina.

•
•
•

• RENIN
• It is a proteolytic enzyme secreted by the kidney into the blood stream.

• Renin converts Angiotensinogen to Angiotensin I.
• Angiotensin I converted to Angiotensin II by Angiotensin converting enzyme (ACE) and non-ACE enzymes (Cathepsin,
Chymase).
• ACE inhibitors only block the ACE pathway leaving the other pathway working to produce Angiotensin II. This may explain failure of these drugs to control some cases of hypertensive patients and necessitates addition of diuretics to ACE inhibitors in these cases or use of Angiotensin II receptors blockers.

Actions of Angiotensins
• Angiotensin I (precursor of angiotensin II): It has no pharmacological action.
• Angiotensin II : It acts on two receptors; AT
1 and AT
2
• Its action on AT
1 receptor produces the following:
• CVS:
• Arteriolar constriction
• It produces positive inotropic and chronotropic effects .
• Endocrine:
• Increase secretion and synthesis of aldosterone.
• Facilitate catecholamine synthesis and release.
• Increase pituitary vasopressin and ACTH.

Renal :
• V.C of renal efferent arterioles, increases proximal tubular Na + reabsorption
C.N.S
• Increase H2O intake and vasopressin secretion.
• Stimulate central sympathetic discharge.

Its action on
2 the followings:
produce
•
•
•

Inhibitors of Renin Angiotensin System:
• Inhibition of renin release : by beta-blockers, clonidine, alpha methyl dopa and prostaglandin inhibitors e.g. indomethacin.
• Rennin activity inhibitors e.g
. enalakrine
• Angiotensin converting enzyme inhibitors (ACEIs):
• ACEIs with Sulph-hydryl containing ACEIs: e.g. Captopril
• ACEIs without sulph-hydryl group: e.g .
Enalapril
• ACEIs inhibitors which contain phosphinate group e.g. Fosinopril .
• It is metabolised and excreted into both the urine and bile.
• Angiotensin II receptor blockers e.g. Losartan, Valsartan.

1.
Inhibition of peptidyl dipeptidase enzyme that converts angiotensin I to angiotensin
II.
2.
Prevent inactivation of kinins lead to increase the concentration of bradykinins which is a potent vasodilator.

• Captopril is rapidly absorbed from GIT. It is distributed to most tissues except the CNS.
The primary route of excretion is the kidney;
50% is eliminated as unchanged drug.
• Enalapril it is inactive. It undergoes hepatic hydrolysis to form enalaprilat. It is more slowly absorbed and the active metabolite has a long half-life and duration of action. Thus, enalapril is given usually once daily.
• Lisinopril it is not a prodrug it is not metabolized by the liver it is given once daily.

• They decrease peripheral resistance.
• Don’t cause tachycardia inspite of hypotension due to: modification parasympathetic activity.
• They increase renal blood flow; Cerebral and coronary blood flow
• In congestive heart failure, ACEIs increase the cardiac output, and decrease the heart rate.
• They decrease the left ventricular mass and wall thickness and prevent ventricular enlargement after myocardial infraction.

• Hypertension.
• Heart failure.
• Postinfarction ventricular remodeling.
• Possible new uses: Insulin resistance –
Arteriosclerosis.

• First dose hypotension.
• Cough and bronchospasm.
• Angiedema.
• Proteinuria in patients with compromised renal function.
• Neutropenia.
• Skin rashes.
• Hyperkalaemia.
• Temporary loss of taste.
• Headache, dizziness and fatigue.

Contraindications
• Hypotension:
• Hyperkalaemia.
• Severe anaemia.
• Bilateral renal artery stenosis or stenosis in a solitary kidney.
• Immune problems, in particular due to collagen vascular, autoimmune disease or with immunosuppressive drugs.
• Patients’ known to have neutropenia or thrombocytopenia.
• Pregnancy and breast-feeding because ACE inhibitors can cause fetal pulmonary hypoplasia, fetal growth retardation and fetal death.

• Initial dose should be low.
• Diuretic use with caution.
• Measurement of blood urea and creatinine before and one week after treatment then every 3 months.
• Electrolyte assay specially potassium.

• ANGIOTENSIN II RECEPTOR BLOCKERS
• Losartan , valsartan ,candesartan are examples of
A.R.B.S
• They have no effect on bradykinin metabolism.
• The adverse effects are similar to those described for ACE inhibitors but are less common with angiotensin receptor blockers than with ACE inhibitors.

• Classifications
•
•
e.g.
nifedipine, hydralazine, minoxidil.
•
•
e.g. nitrates.
•
e.g. sodium nitroprusside, prazocin, ACEIs

.
General Consideration as Regard Arteriolar V.D
• They preserve renal and cerebral blood flow.
• They almost completely devoid of CNS side effect.
• They don't cause orthostatic hypotension or sexual dysfunction.
• Best indicated in hypertensive heart failure and renal hypertension.

• It directly relaxes small arteries and arterioles.
• It is absorbed from GIT, acetylated in the liver.
Uses
• Combination therapy for hypertension.
• Primary pulmonary hypertension.
Adverse effects
• Systemic Lupus-like syndrome.
• Nasal congestion, flushing, lacrimation, drug fever, skin rash.
• Headache, palpitation, tachycardia, anginal pain, anorexia, nausea, dizziness.

• It is arteriolar vasodilator.
• It is absorbed from GIT. metabolized by the liver.
• Uses
• Severe hypertension in combination therapy.
• Hypertensive in patients with renal disease.
• Used locally in case of baldness.
• Adverse effects
• Palpitation, tachycardia, anginal pain, headache.
• Fluid retention and edema.
• Hypertrichosis: so should not used in female .
• Pericardial effusion.

• It has a direct vasodilator action on the arterioles.
• The drug is 90% bound to plasma albumin.
• Uses
• Hypertensive emergencies e.g. hypertensive encephalopathy, and toxaemia of pregnancy.
• Dosage : it is given by I.V. injection. Start with small dose 50-75 mg rapidly. The dose can be repeated after 10-15 minutes intervals.
• Adverse effects
• Tachycardia which can precipitate angina.
• Hyperglycaemia due to inhibition of insulin release.
• Sodium and water retention.
• Hyperuricemia.
• Others: nausea, vomiting, constipation.

• It has a vasodilator effect on the smooth muscle of the venoarteriolar beds.
• It is rapidly metabolized in red cells to cyanide, which is then metabolized to thiocyanate prior to renal excretion.
• Uses
• Hypertensive encephalopathy
• Refractory cases of congestive heart failure

• Dosages : It is given by IV infusion in 5% dextrose. The initial dose is 0.5
 g/kg/minute and may be increased up to 10
 g/kg/min as necessary to control blood pressure.
• Adverse effects
• Nausea, vomiting, sweating, restlessness headache, palpitation and substernal pain and may be increased up to 10
 g/kg/minute as necessary to control blood pressure.
• Prolonged therapy may lead to accumulation of cyanide
(metabolic acidosis, arrhythmias, death) or thiocyanate
(delirium and psychosis).
• Precautions
• Infusion must not stop abruptly to avoid rebound hypertension.
• In liver disease, cyanide doesn’t convert to thiocyanate and hence more toxic.
• Higher rates of infusion may result in toxicity.

CENTRALLY ACTING ANTIHYPERTENSIVES

 It is an agonist to central postsynaptic

2 adrenoceptors suppressing sympathetic outflow and reduces blood pressure.
 It decreases synthesis of NE.
 It acts on peripheral presynaptic

2 adrenoceptors inhibiting
N.E release.
 It reduces plasma renin activity.
 Reduction of cardiac output due to decrease heart rate.

• Dose
: 0.2-1.2 mg/day orally.
• Therapeutic uses
• Moderate and severe hypertension 0.1 - 0.2 mg twice/day
• Prophylaxis in migraine 0.025 mg twice /day.
• In opiate withdrawal to reduce signs of sympathetic overactivity.
• Sedation and reduction of anxiety in preanaesthetic medication
• Adverse effects
• Dry mouth and sedation.
• Salt and water retention
• Withdrawal syndrome leads to hypertensive crisis.

• It stimulates central alph 2 receptors.
• It in hibits renin release.
• It can be used in cases of hypersion with pregnancy .
• Has a mechanism of action similar to clonidine.
• Hypotensive effect is associated with a fall in peripheral resistance, HR and COP.
• Most common side effects are dry mouth, somnolence, dizziness and asthenia.

 Prazocin and trimazocin
 Indoramine
 Selective blocker to postsynaptic

1receptors.
 First dose phenomenon does not occur.
 It causes sedation, lethargy, drowsiness and dizziness.
 Contraindicated in renal failure and depressive states.
 Dose 25 mg twice /day.

CONCURRENT ALPHA AND BETA ADRENOCEPTOR BLOCKERS
 LABETALOL
 It blocks both alpha (selective

1 blocker) and betareceptors (non-selective

-blocker).
 It reduces plasma renin activity.
 It has a rapid onset of action as an antihypertensive.
 It is used for emergency control of severe hypertension with pheochromo-cytoma, and hypertensive response during abrupt clonidine withdrawal.

• It blocks  and
 receptors.
• It has dircet V.D. effect.
• It has anti oxidant effect.
• It can be used in treatment of heart failure.

 It is a selective antagonist of 5-HT2 receptors.
 It also blocks alpha adrenoceptors.
 It lowers the BP without postural hypotension or reflex tachycardia and the effect is greater on the diastolic blood pressure.
 It does not affect glomerular filteration rate or renal blood flow
 Side effects:
Dizziness, fatigue and polyuria.
 Potential uses
 Orally: hypertension and peripheral vascular diseases.
 I.V.: asthmatic attack, thrombophlebitis, and pulmonary emboli.
 Effective dose
: 20 mg 2-3 times/day

Dopamine (D1) receptor agonist e.g. Fenoldopam
• Pharmacokinetics :
• Given by continuous intravenous administration.
• Metabolized in the liver by conjugation (t 1/2 10 minutes).
• Pharmacological Effects:
• ++ Dl receptors in peripheral arteries leading to arteriodilatation & natriuresis.
• Therapeutic uses:
• Treatment of hypertensive emergency.
• Treatment of post-operative hypertension.
• Adverse effects:
• Reflex tachycardia, headache & flushing.
• ↑ IOP (avoided in patient with glaucoma).

• These include hypertensive encephalopathy, cerebral stroke, acute left ventricular failure, aortic dissection, epistaxis, and severe renal failure.
• Patient should be hospitalised .
• Reduction of blood pressure should be in hours and not in minutes.
• Sublingual nifedipine or captopril may be effective in reducing blood pressure.
• Parenteral therapy:
• Diuretics (frusemide, Bumetanide) I.V.
• Reserpine 1-2 mg I.M (never I.V.)
• Diazoxid 300 mg I.V. very rapidly
• Sodium nitroprusside infusion 2-5
 g/kg/min. according to blood pressure
• Hydralazine 20 mg I.V. slowly diluted.
• Beta blocker (Propranolol) 1-2 mg I.V. slowly diluted.
• Methyl dopa I.V. diluted
• Nifedipine I.V., diluted.
• Nitroglycerin I.V. 1-10
 g/kg/min.