TREATMENT OF HYPERTENSION

Profs. Abdulqader Alhaider; Azza El-Medany Department of Pharmacology College of Medicine

OBJECTIVES At the end of lectures, the students should : Identify factors that control blood pressure Identify the pharmacologic classes of drugs used in treatment of hypertension Know examples of each class.

OBJECTIVES ( continue) Describe the mechanism of action, therapeutic uses & common adverse effects of each class of drugs including : Adrenoceptor blocking drugs ( β & α blocking drugs ) Diuretics Calcium channel blocking drugs Vasodilators

OBJECTIVES ( cont.) Converting enzyme inhibitors Angiotensin receptor blockers. Describe the advantages of ARBs over ACEI

FACTORS IN BLOOD PRESSURE CONTROL

Hypertension Blood pressure is determined by : 1- Blood volume 2- Cardiac output ( rate & contractility ) 3- Peripheral resistance

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Hypertension Is a major risk factor for cerebrovascular disease, heart failure, renal insufficiency and myocardial infarction. It is often asymptomatic until organ damages reaches a critical point.

Antihypertensive therapy Initially consists of lifestyle changes, such as weight reduction, smoking cessation, reduction of salt, saturated fat,, excessive alcohol intake, and increased exercise before drug therapy. Is initiated.

Indications for Drug Therapy  Sustained blood pressure elevations > 140/ 90 mmHg.  when minimally elevated blood pressure is associated with other cardiovascular risk factors (smoking, diabetes, obesity, hyperlipidemia, genetic predisposition).  When end organs are affected by hypertension (heart, kidney, brain).

Drug Management of Hypertension  Diuretics  Cardio inhibitory drugs  Beta- blockers  Calcium –channel blockers  Centrally acting sympatholytic Vasodilators (a1-antagosits; Hydralazine) Drugs acting on renin-angiotensin aldosterone system

B. Potassium-sparing diuretics Amiloride as well as spironolactone reduce potassium loss in the urine. Spironolactone has the additional benefit of diminishing the cardiac remodeling that occurs in heart failure.

Cardio inhibitory Drugs

β- Adrenoceptor –Blocking Agents β- adrenoceptor blocking agents can be used in mild to moderate hypertension. In severe cases used in combination with other drugs. Nadolol (non cardio selective) Bisoprolol, Atenolol, metoprolol ( cardio selective) Labetalol, carvidalol ( α – and β adrenergic blockers )

Beta-Adrenoceptor –Blocking Agents They lower blood pressure by : Decreasing cardiac output. Decreasing renin release (very important effect and more related to the clinical response)

α 1 -adrenoceptor blockers Prazocin, Terazocin Added to β- blockers for treatment of hypertension of pheochromocytoma

CALCIUM CHANNEL BLOCKERS

Classification  Dihydropyridine group (Nifedipine, Nicardipine, Amlodipine (Amlor R ) is more selective as vasodilator than a cardiac depressant. This group is used for treatment of hypertension  Verapamil is more effective as cardiac depressant, therefore it is not used as antihypertensive agent.  Diltiazem.Used mainly for angina

❏ Mechanism of Action: (Arterial) Block the influx of calcium through L-type calcium channels resulting in: 1- Peripheral vasodilatation (at arteries) 2- Decrease cardiac contractility & heart rate?? Both effects lower blood pressure

Pharmacokinetics: ❏ given orally and intravenous injection ❏ well absorbed from G.I.T ❏ verapamil and nifedipine are highly bound to plasma protiens ( more than 90%) while diltiazem is less ( 70-80%)

(Cont’d): ❏ onset of action --- within 1-3 min --- after i.v. 30 min – 2 h --- after oral dose ❏ verapamil & diltiazem have active metabolites, nifedipine does not ❏ sustained-release preparations can permit once-daily dosing

Clinical uses Treatment of chronic hypertension with oral preparation Nifedipine used for Raynoids phenomena Nicardipine can be given by I.V. route & used in hypertensive emergency

ADVERSE EFFECTS VerapamilDiltiazemNifedipine Headache, Flushing, Hypotension Peripheral edema (ankle edema) Cardiac depression, A-V block, bradycardia Reflex Tachycardia Constipation

Centrally acting sympatholytic drugs e.g. Clonidine direct α 2 -agonist Reduce sympathetic outflow to the heart thereby decreasing cardiac output (by decreasing heart rate & contractility ). Reduced sympathetic output to the vasculature, decreases sympathetic vascular tone, which causes vasodilation & reduced systemic vascular resistance, which decreases arterial pressure.

α methyl dopa indirect α 2 agonist is converted to methyl norepinephrine centrally to diminish the adrenergic outflow from the C.N.S. This lead to reduced total peripheral resistance, and a decreased blood pressure. Safely used in hypertensive pregnant women

Side effects of centrally acting sympatholyics Depression Dry mouth, nasal mucosa Bradycardia Impotence Postural hypotension Fluid retention & edema with chronic use Sudden withdrawal of clonidine can lead to rebound hypertension

VASODILATORS

Compensatory Response to Vasodilators

Vasodilators Na nitropruside DiazoxideMinoxidilHydralazin e Arterio & venodilator Arteriodilator Site of action Release of nitric oxide ( NO) Opening of potassium channels Opening of potassium channels in smooth muscle membranes by minoxidil sulfate ( active metabolite ) DirectMechanism of action Intravenous infusion Rapid intravenous Oral Route of admin.

Na nitropruside DiazoxideMinoxidilHydralazine Continue Vasodilators 1.Hpertensive emergency 1.Hypertensive emergency ( in the past ) 1.severe hypertension 1.Moderate - severe hypertension. CHF Therapeutic uses 2.Treatment of hypoglycemia due to insulinoma 2.correction of baldness 2.Hypertensive pregnant woman

Na nitroprusideDiazoxideMinoxidilHydralazineContinue Vasodilators Severe hypotension Hypotension, reflex tachycardia, palpitation, angina, salt and water retention ( edema) Adverse effects 1.Methemoglobin during infusion 2. Cyanide toxicity 3. Thiocyanate toxicity Inhibit insulin release from β cells of the pancreas causing hyperglycemia Contraindicated in diabetic Hypertrichosis. Contraindicated in females lupus erythematosus like syndrome Specific adverse effects

Give reason : β-blockers & diuretics are added to vasodilators for treatment of hypertension?

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Endothelium, brain & Other Proteolytic Enzymes Chymase Endoperoxidase A vasoconstrictor peptide Synthesis Precursor is Angiotensinogen ; a plasma  -globulin synthesized in the liver. Secreted by renal juxtaglomerular apparatus AT 1 AT 2  Renal SN activation  Renal Blood flow by  2 agonists & PG I 2  Renal Blood flow by  2 agonists & PG I 2  Blood Pressure

angiotensin- converting enzyme Angiotensin I (inactive) Angiotensin II (active vasoconstrictor) Bradykinin (active vasodilator) Inactive metabolites ACE inhibitors Mechanism of action of Angiotensin-converting enzyme inhibitors (ACEI) angiotensin- converting enzyme Angiotensin I (inactive) Angiotensin II (active vasoconstrictor) Bradykinin (active vasodilator) Inactive metabolites

Mechanism of action: Converting enzyme inhibitors lower blood pressure by reducing angiotensin II, and also by increasing vasodilator peptides such as bradykinin. reduction of sympathetic activity (use is not associated with reflex tachycardia despite causing arterioral and venous dilatation) Reduce the arteriolar and left ventricular remodelling that are believed to be important in the pathogenesis of human essential hypertension and post-infarction state Dilatation of arteriol  reduction of peripheral vascular resistance (afterload ) Increase of Na + and decrease of K + excretion in kidney by inhibition Aldosterone secretion

Pharmacokinetics Captopril, Lisonopril; Enalapril and Ramipril. All are rapidly absorbed from GIT after oral administration. Food reduce their bioavailability. Enalapril, ramipril are prodrugs, converted to the active metabolite in the liver Have a long half-life & given once daily except Captopril Enalaprilat is the active metabolite of enalapril given by i.v. route in hypertensive emergency.

Phrmacokinetics Captopril is not a prodrug Has a short half-life & given twice /day All ACEI are distributed to all tissues except CNS.

Clinical uses  Treatment of hypertension  Treatment of heart failure  Diabetic nephropathy. How do they work?

ADVERSE EFFECTS:  Acute renal failure, especially in patients with bilateral renal artery stenosis  Hyperkalemia How?

(Cont ’ d):  Persistent cough  Angioneurotic edema (swelling in the nose, throat,tongue, larynx)

(Cont ’ d): ( cough & edema due to bradykinin)  severe hypotension in hypovolemic patients (due to diuretics, salt restriction or gastrointestinal fluid loss)

(Cont ’ d):  Taste loss  Skin rash, fever ( taste loss. is due to a sulfhydryl group in the molecule of captopril ).

Contraindications During the second and third trimesters of pregnancy due to the risk of : fetal hypotension, anuria, renal failure & malformations. Bilateral renal artery stenosis or stenosis of a renal artery with solitary kidney. How?

Drug interactions With potassium-sparing diuretics (e.g: Spirinolactone) NSAIDs impair their hypotensive effects by blocking bradykinin-mediated vasodilatation.

BLOCKERS OF AT 1 RECEPTOR losartan, valosartan, irbesartan - competitively inhibit angiotensin II at its AT 1 receptor site  most of the effects of angiotensin II - including vasoconstriction and aldosterone release - are mediated by the AT 1 receptor  they influence RAS more effective because of selective blockade (angiotensin II synthesis in tissue is not completely dependent only on renin release, but could be promote by serin- protease -

angiotensinogen angiotensin I angiotensin II renin ACE nonrenin proteases cathepsin t-PA chymase CAGE

Continue They have no effect on bradykinin system causing neither: cough, wheezing nor angioedema

Losartan, valsartan, irbesartan

Adverse effects As ACEI except cough,wheezing, and angioedema. Same contraindications as ACEI.

Drug Combination for Hypertension Hydrochlorothiazide (12.5 mg+ Valsartan (60 or 80 mg) (Co-Diovan R ) Hydrochlorothiazide (12.5 mg + Losartan (50 or 100 mg) Hydrochlorothiazide (12.5 mg + Lisinopril (10 or 20 mg)

Drugs for treatment of hypertensive crisis Labetalol Hydralazine (in pregnancy) Sodium nitroprusside (2 nd line) General characters of good drug for Crisis: Fast & short acting Given by IV

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