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of Treatment Effective BP (Prevent damage to Blood Vessels) Morbidity, Mortality Assess other CVS Risk Factors Hyperlipidemia Diabetes Management Non-Pharmacological Lifestyle Modification Blood Pressure (BP) Regulation ACE Inhibitor MOA
Aim of Treatment Treat Cause
Hypertensive Drugs Act by interfering the mechanisms Classification by principle site (mechanism on which they act) BP Control in Hypertensive Similar Mechanisms as Normotensive Baroreceptors, Renal Blood Volume Pressure Control Systems set at -Blockers MOA
Central Sympathetic Agents MOA
Anti-Hypertensives Diuretics Chlorothiazide Hydrochlorothiazide (Thiazide Group) Frusemide (Loop Diuretic) MOA Na+, H2O Excretion (via Kidney) Blood Volume, Cardiac Output Thiazide Inhibit NaCl Reabosrption (Distal Convulated Tubule) Loop Diuretics Inhibit NaCl Reabsorption (Ascending Limb of Loop of Henle) Sympathoplegic Agents Drugs Blocking Postsynaptic Adrenoceptors ( , Blockers) Produce Selective Effects Reserpine Rarely Used (Adrenergic Neuron Blocking) MOA Inhibit Function of Sympathetic Nervous System -Adrenergic Blockers Propranolol MOA Binds Receptors (Heart, Kidney) Metoprolol Atenolol Inhibit Catecholamine Effects Carvedilol Cardiac Output ( 1) Labetolol Inhibit Renin Release Kidney ( 1) Angiotensin II, Aldosterone Require Few Weeks to Develop Full Effects Adverse Effects Contraindications Fatigue Obstructive Airway Disease Hypotension (Asthma) (Block Bronchial Bradycardia Smooth Muscle 2 Receptors) Insomnia, Nightmares Severe Peripheral Vascular Lipid, Glucose Metabolism Disease Heart Block Mask Hypoglycemia Erectile Dysfunction Acute Heart Failure ( Libido, Impotence) -Adrenergic Blockers Prazosin MOA Terazosin Competitively Block -1 Adrenerceptors Inhibit Catecholamine Induced Vasoconstriction Peripheral Vascular Resistance (PVR) Relax Arterial, Venous Smooth Muscle Additional Benefit BPH (Benign Prostatic Hypertrophy) (Bind 1 Receptors at Smooth Muscle of Bladder Neck, Prostate) (Cause Relaxation) Adverse Effects st Postural Hypotension (1 Dose Syncope) Initial Reflex Tachycardia st (Suggest small 1 dose, at bedtime) Both , Adrenergic Blocker Property Carvedilol Labetolol (used in Pregnancy) Centrally Acting (Adrenergic Drugs) Clonidine MOA 2Adrenergic Agonists Methyldopa Sympathetic Outflow (from Brain Vasopressor Centers) TPR, BP -Methyldopa Clonidine Safe Used Pregnancy (Widely Used) Adverse Effects Adverse Effects (Generally Mild) Sedation, Drowsiness Mental Depression Mood Changes Dry Mouth Erectile Dysfunction Sleep Disturbances (Nightmares) Block Production (Action) of Angiotensin Angiotensin Converting Enzyme Inhibitors (ACEI) Captopril MOA PVR (Peripheral Vascular Resistance) Enalapril Block ACE Lisinopril Perindopril (ACE convert Ag I Ag II, Vasoconstrictor) Ag II, Aldosterone Ramipril Na, H2O Retention Adverse Effects Dry Cough Hyperkalemia Skin Rash Hypotension Fever Contraindication Pregnancy Bilateral Renal Artery Stenosis Renal Impairment (use with caution) Angiotensin II Receptor Blocker (ARBs) (Angiotensin Receptor Antagonist) Losartan MOA Selectively Blocks Ag II Receptors (eg. Vascular) Valsartan Candesartan Prevent Ag II mediated Vasoconstriction Irbesartan Block Aldosterone Secretion Adverse Effects Dry Cough (Infrequent) Hyperkalemia Skin Rash Hypotension Fever Contraindication Pregnancy Bilateral Renal Artery Stenosis Renal Impairment (use with caution) Vasodilators Calcium Channel Blockers (CCB) Hydralazine, Minoxidil Sodium Nitroprusside (Parenteral) Diazoxide (Emergencies) (Parenteral) MOA Relax Vascular Smooth Muscle ( Resistance) Some acts Predominantly on Arterioles (some also Relax Veins) Hypertensive Usefulness (Limited by Side Effects) Compensatory Tachycardia Na+, H2O Retention (Compensatory Responses - Arterial Resistance, BP) (Mediated by Baroreceptors, Sympathetic Nervous System, RAAS) Compensatory Mechanism Reflex Stimulation of Heart ( Myocardial Contractility, Heart Rate, Oxygen Consumption) Adverse Effects Headache Arrhythmia Precipitate Angina Hydralazine, Minoxidil Hydralazine Parenteral (HT Emergency)
After 6-8 Weeks Cardiac Output return towards Normal Peripheral Vascular Resistance Adverse Effects Frequent Micturition (Initially) Hypokalemia (Except K+-Sparing) (May need K+ Supplements) (due to K+ Loss coupled to Na+ Reabsorption) Serum [Lipid] Impaired Glucose Tolerance Postural Hypotension (Elderly, Volume Depleted) Precipitate Acute Attack - [Uric Acid] (Avoid in Diabetes, Hyperlipidemia, Gout)
Minoxidil Oral (Refractory, Severe HT) Chronic Treatment Hypertrichosis (Body Hair) (Male Pattern Baldness) Act 1° on Arteries, Arterioles (Cause Vasodilation) Due to Sympathetic Reflex Intact, seldom cause Orthostatic Hypotension Sexual Dysfunction Calcium Channel Blockers (CCB) Amlodipine MOA Relax Vascular Smooth Muscle Diltiazem Dilate (mainly Arterioles) Felodipine Nifedipine Verapamil Intracellular Calcium Maintain Smooth Muscle Tone, Myocardial Contraction Ca2+ enter muscle cells (via special Ca2+ channels) CCB Block Inward Ca2+ movement (via Ca2+ channels in Heart, Vascular Smooth Muscle) st Contraindicated 1 Line Agents (Ineffective) Asthmatics Diabetes Angina Peripheral Vascular Disease nd Older Generation CCB 2 Generation CCB (Newer) Verapamil Amlodipine Felodipine Least Selective CCB Nicardipine (Effects Ca2+ Entry for both Cardiac, Vascular Smooth Depressant Effect on Heart Muscle Cells) ( Affinity for Vascular Ca2+ Channels than Heart Ca2+ Depressant Effect on Heart Channels) (-ve Inotropic Effect, HR) Adverse Effects Constipation Flushing Tachycardia Ankle Edema Headache Fatigue (due to BP) Dizziness, Vertigo Hypotension
Which Drug to Use BP (Benefit General Hypertensive Population) Does not matter which drug class is used Therapy should start with Single Drug ( Dose) Individualized Depending on patient groups (specific drug class may be preferred) Presence of Concomitant Disease Diuretic/ Beta Blocker CVS Morbidity, Mortality (Similar benefits with ACEI, CCBs) Single, Combination Drug BP Not Controlled (After 6 Weeks) Dose Change to another Drug Class Add 2nd Drug If Target BP Not Achieved Add Drug (from Another Class) (Synergistic Action) ( Dose can cause Adverse Effects) Monotherapy Polytherapy Compliance Compliance (Can use - Fixed Dose Combination Drug - Compliance) ( -Blocker + Diuretics) ( -Blocker + CCBs) Not Adequate BP Control Synergistic Effect Resistant Hypertension Causes Non Compliance (Commonest Cause in Malaysia) 2° Hypertension White Coat Hypertension Excess Na+ Intake Drug Interactions (NSAID, Sympathomimetics, Stimulant Abuse Amphetamine) Non-Compliance Hypertension (usually Asymptomatic) (Therapy aimed to Prevent Disease Sequelae) (Rather than Relieve Discomfort) (Drug Adverse Effects Influence Patient) Compliance Simplify Dosage Regimen ( Adverse Effects, Dosage Frequency) Educate Patient (Potential Adverse Effects) (Follow up) Sites of Antihypertensive Drug Actions
Sites of Action of Drugs
Principles of Combination Therapy
Mechanisms for Controlling BP Baroreceptors Sympathetic Nervous System Rapid moment to moment regulation of BP BP causes Pressure Sensitive Neurons to send Impulses to CVS Centers (Baroreceptors in Aortic Arch, Carotid Sinus) Compensatory BP (Vasoconstriction, Cardiac Output) Reflex response of Sympathetic ( Parasympathetic) output to Heart, Vasculature Management of Hypertension
RAAS Kidney Alter Blood Volume, Responds to Arterial Pressure (Release Renin) Ag II BP (Potent Vasoconstrictor) Stimulate Aldosterone Secretion (RenalNa+ Reabsorption, Blood Volume, BP) Local release of hormones from Vascular Endothelium
Fixed Dose Combination Available Drugs Atenolol/ Chlorthalidone Perindopril/ Indapamide Losartan/ Hydrochlorothiazide st Not recommended 1 Line However, with Severe HT (where Monotherapy unlikely to control BP) (May be considered 1st Line Urgency to BP) Advantage Disadvantage Compliance Not allowing Titration of Individual (Allow Pills to be taken) Drug Doses Sites of Actions (Diuretics)
Diuretics alone often adequate (Mild
Combination Drugs -Blockers + Diuretics Benefit Proven, Vasodilator can be added for still resistant -Blockers + CCB Cheap, Suitable for Concurrent CHD CCB + ACEI Concurrent Dyslipidemia, Diabetes ACEI + Diuretics Concurrent Heart Failure, DM, Stroke
Hypertensive Emergency Rare, Life Threatening (Need to rapidly BP) Drugs Sodium Nitroprusside IV (Fast Vasodilation Effect) (Relax Arterial, Venous Smooth Muscle) ( TPR, Venous Return) ( Half-Life, mins Continuous Infusion) Diazoxide (Arteriolar Vasodilator) (Toxicity Excess Hypotension) Labetolol (Both , Blocker) (Do not cause Reflex Tachycardia) Esmolol, Nicardipine, Nitrates Non-Pharmacological (Patient Motivation) Weight (for Overweight) Na+ Restriction Alcohol Avoidance (Alcohol Acute BP) Physical Exercise (Regular) Eat Healthily (Fruits, Vegetables) Stop Smoking (Smoking Acute BP) Stress Management
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