TREATMENT OF HYPERTENSION. Profs. Abdulqader Alhaider; Azza El-Medany Department of Pharmacology...
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TREATMENT OF HYPERTENSION
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Profs. Abdulqader Alhaider; Azza El-Medany
Department of PharmacologyCollege of Medicine
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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.
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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
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OBJECTIVES ( cont.)
• Converting enzyme inhibitors • Angiotensin receptor blockers.• Describe the advantages of ARBs over ACEI
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FACTORS IN BLOOD PRESSURE CONTROL
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Hypertension
Blood pressure is determined by :
1- Blood volume
2- Cardiac output ( rate & contractility )
3- Peripheral resistance
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i
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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.
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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 .
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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).
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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
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B. Potassium-sparing diureticsAmiloride 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.
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Cardio inhibitory Drugs
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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 )
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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)
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α1-adrenoceptor blockers
• Prazocin , Terazocin
• Added to β- blockers for treatment of hypertension of pheochromocytoma
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CALCIUM CHANNEL BLOCKERSCALCIUM CHANNEL BLOCKERS
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• Classification Dihydropyridine group (Nifedipine,
Nicardipine , Amlodipine (AmlorR) 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
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❏ 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
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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%)
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(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
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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
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ADVERSE EFFECTSVerapamil Diltiazem Nifedipine
Headache , Flushing , Hypotension
Headache, Flushing, Hypotension
Headache , Flushing, Hypotension
Peripheral edema (ankle edema)
Peripheral edema (ankle edema)
Peripheral edema (ankle edema)
Cardiac depression, A-V block , bradycardia
Cardiac depression , A-V block , bradycardia
Reflex Tachycardia
Constipation
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Centrally acting sympatholytic drugs e.g. Clonidine direct
α2-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.
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α methyl dopaindirect
• 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
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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
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VASODILATORSVASODILATORS
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Compensatory Response to Vasodilators
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VasodilatorsHydralazi
neMinoxidil Diazoxid
eNa
nitropruside
Site of action
Arteriodilator Arteriodilator Arteriodilator Arterio & venodilator
Mechanism of action
Direct Opening of potassium channels in smooth muscle membranes by minoxidil sulfate ( active metabolite )
Opening of potassium channels
Release of nitric oxide ( NO)
Route of admin.
Oral Oral Rapid intravenous
Intravenous infusion
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ContinueVasodilators
Hydralazine Minoxidil Diazoxide Na nitropruside
Therapeutic uses
1.Moderate -severe hypertension.CHF
1.severe hypertension
1.Hypertensive emergency( in the past )
1.Hpertensive emergency
2.Hypertensive pregnant woman
2.correction of baldness
2.Treatment of hypoglycemia due to insulinoma
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ContinueVasodilators
Hydralazine Minoxidil Diazoxide Na nitropruside
Adverse effects
Hypotension, reflex tachycardia, palpitation, angina, salt and water retention ( edema)
Severe hypotension
Specific adverse effects
lupus erythematosus like syndrome
Hypertrichosis.
Contraindicated in females
Inhibit insulin release from β cells of the pancreas causing hyperglycemia
Contraindicated in diabetic
1.Methemoglobinduring infusion2. Cyanide toxicity3. Thiocyanate toxicity
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Give reason : β-blockers & diuretics are added to
vasodilators for treatment of hypertension?
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te
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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
AT1
AT2
Renal SN activation Renal SN activation Renal Blood flow by2 agonists & PGI2Renal Blood flow by2 agonists & PGI2Blood Pressure
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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
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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
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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.
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Phrmacokinetics
• Captopril is not a prodrug • Has a short half-life & given twice /day
• All ACEI are distributed to all tissues except CNS.
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Clinical uses Treatment of hypertension
Treatment of heart failure
Diabetic nephropathy . How do they work?
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ADVERSE EFFECTS:
Acute renal failure, especially in patients
with bilateral renal artery stenosis
Hyperkalemia How?
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(Cont’d):
Persistent cough
Angioneurotic edema (swelling in the nose , throat,tongue, larynx)
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(Cont’d):
( cough & edema due to bradykinin)
severe hypotension in hypovolemic patients (due to diuretics, salt restriction or gastrointestinal fluid loss)
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(Cont’d):
Taste loss
Skin rash, fever
( taste loss. is due to a sulfhydryl group in the molecule of captopril ).
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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?
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Drug interactions
• With potassium-sparing diuretics (e.g: Spirinolactone)
• NSAIDs impair their hypotensive effects by blocking bradykinin-mediated
vasodilatation.
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BLOCKERS OF AT1 RECEPTORlosartan, valosartan, irbesartan
- competitively inhibit angiotensin II at its AT1 receptor site
most of the effects of angiotensin II - including vasoconstriction and aldosterone release - are mediated by the AT1 receptorthey 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 -
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angiotensinogen
angiotensin I
angiotensin II
renin
ACE
nonrenin proteasescathepsin
t-PAchymaseCAGE
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Continue
They have no effect on bradykinin system
causing neither: cough, wheezing nor
angioedema
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Losartan, valsartan , irbesartan
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Adverse effects• As ACEI except cough,wheezing, and
angioedema.
• Same contraindications as ACEI.
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Drug Combination for Hypertension
• Hydrochlorothiazide (12.5 mg+ Valsartan • (60 or 80 mg) (Co-DiovanR)• Hydrochlorothiazide (12.5 mg + Losartan (50 or 100 mg)• Hydrochlorothiazide (12.5 mg + Lisinopril
(10 or 20 mg)
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Drugs for treatment of hypertensive crisis
• Labetalol• Hydralazine (in pregnancy)
• Sodium nitroprusside (2nd line)General characters of good drug for Crisis:• Fast & short acting• Given by IV
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