Chapter 11 - Antihypertensive Agents

• Diagnosis of Hypertension


  • Repeated, reproducible measurement of elevated blood pressure
  • End-organ Damage: damage in kidney, heart, brain resulting in diminished perfusion of the organs
  • Risk Factors: smoking, metabolic syndrome (obesity, dyslipidemia and diabetes), end organ damage and family history
  • Epidemiologic Evidences: genetic factor (gene variation), psychological stress, environmental and dietary factors
• Primary Hypertension


  No specific cause; idiopathic
• Idiopathic Treatment


  Reduction of blood volume, sympathetic effects, vascular smooth muscle tension and angiotensin effects
• Secondary Hypertension


  Specific diagnosable abnormality
• Surgical Treatment for Secondary Hypertension


  • Renal artery constriction
  • Coarctation of aorta
  • Pheochromocytoma
  • Cushing's disease
  • Aldosteronism
• Hydraulic Equation


  BP = CO x PVR
• Anatomic Sites for Blood Pressure Regulation

  • Arterioles
  • Postcapillary Venules (Capacitance Vessels)
  • Heart
  • Kidney
• Baroreflex


  • Primary autonomic mechanism for blood pressure homeostasis
  • Responsible for rapid, moment-to-moment adjustment in blood pressure
  • ↑ Reflex (Sympathetic Outflow) = ↑ PVR and ↑CO; thus ↑BP
• Classification of Hypertension

  • Normal: < 120 / 80 mmHg
  • Elevated: 120 – 129 / 80 mmHg
  • Stage 1 Hypertension: ≥ 130 - 139 / 80 - 89 mmHg
  • Stage 2 Hypertension: 140 – 159 / 90 – 99 mmHg
  • Hypertension Crisis: ≥ 180 / 120 mmHg
• Diuretics


  • MOA: depletion of Sodium and blood volume and cardiac output
  • Lowers BP by 10 – 15 mmHg
  • Single Therapy: for Mild or Moderate Essential Hypertension
  • Combination Therapy: Sympathoplegic and Vasodilators (decrease sodium retention)
  • Toxicity: ↓ Potassium (except potassium sparing); ↓ Magnesium; Impair Glucose Tolerance; ↑ Serum Lipid Concentration; ↑ Uric Acid Concentration
  • Hypokalemia is dangerous for patients taking Digitalis, chronic arrhythmias, acute myocardial infarction and left ventricular dysfunction
• Thiazide Diuretics


  • MOA: Block Na/Cl Transporter (distal convoluted tubule)
  • Mild to moderate hypertension and normal renal and cardiac function
  • Half-life: Chlorthalidone > Hydrochlorothiazide
• Loop Diuretics


  • MOA: Block Na/K/2Cl Transporter (Loop of Henle)
  • Severe hypertension
  • Multiple Drugs with Sodium Retaining Properties
  • Renal Insufficiency; Glomerular Filtration Rate is < 30 – 40 mL/min
  • Cardiac Failure and Cirrhosis
• Potassium Sparing Diuretics


  • MOA: Block Aldosterone Receptor (collecting tubule)
  • Avoid Potassium Depletion and Increase Natriuresis
  • Favorable Effect on Patients with Heart Failure
• Sympathetic Nervous System Altering Drugs


  • Moderate to Severe Hypertension
  • In combination with Diuretics
• Centrally Acting Drugs


  • MOA: α2 adrenoceptor agonist
  • Reduce sympathetic outflow; reduce norepinephrine release
• Methyldopa


  • Enters BBB through Aromatic Amino Acid Transporter
  • Hypertension in Pregnancy
  • Reduces PVR with HR and CO
  • Reduce Renal Vascular Resistance
  • Toxicity: Sedation; Mental Lassitude; Impaired Mental Concentration; Nightmares; Depression; Vertigo; Extrapyramidal Signs; Lactation; Positive Coombs Test; Hemolytic Anemia; Hepatitis and Drug Fever
• Clonidine


  • Reduction of Cardiac Output (↓ HR; ↓PVR and Relaxation of Capacitance Vessels)
  • Toxicity: Dry Mouth; Sedation
  • Contraindications: Mental Depression
  • Withdrawal: Life Threatening Hypertensive Crisis; Nervousness; Tachycardia; Headache and Sweating
  • Treatment for Induced Hypertensive Crisis: α- or β-adrenoceptor blocking agents
• Adrenergic Neuron Blocking Agents


  • MOA: prevents normal physiologic release of norepinephrine from postganglionic sympathetic neurons
  • Causes inhibition of ejaculation and hypotension
• Guanethidine


  • Reduces cardiac sympathetic effects
  • MOA: inhibits release of Norepinephrine from Sympathetic Nerve Ending; Replaces Norepinephrine
  • Toxicity: Sympathoplegia – Postural Hypotension; Diarrhea and Impaired Sexual Function
  • Drug Interactions: Sympathomimetic Drugs – Hypertension; Tricyclic Antidepressants – Attenuated and Severe Hypertension
• Reserpine


  • MOA: blocks VMAT and ↓ Norepinephrine, Serotonin, and Dopamine
  • Decrease CO and PVR
  • Toxicity: Sedation; Lassitude; Nightmares and Depression; Parkinsonism-like effects; Diarrhea, Cramps and Increase Gastric Acid Secretion
• β-Adrenoceptor Blocking Drugs


  • MOA: block β1 receptors
  • Prevent sympathetic cardiac stimulation
  • Reduce renin secretion
  • Lowers BP in Mild to Moderate Hypertension; Prevents Reflex Tachycardia
  • Reduce Mortality after Myocardial Infarction and Heart Failure
• Propranolol


  • MOA: non-selective β-blocker
  • Decrease CO
  • Inhibits Renin Release
  • Toxicity: Bradycardia; Cardiac Conduction Disease; Asthma; Peripheral Vascular Insufficiency
  • Withdrawal: Nervousness; Tachycardia; Angina and increased BP
• Metoprolol


  • MOA: β1 Selective Blocker
  • Cardioselective and Favorable for patients with Asthma, Diabetes or Peripheral Vascular Disease
  • Effective in Mortality Reduction in Patients with Heart Failure and useful in Hypertension and Heart Failure
• Atenolol


  β1 Selective Blocker less effective than Metoprolol in preventing hypertension complications
• Pindolol, Acebutolol and Penbutolol


  • Decrease vascular resistance
  • Beneficial for Patients with Bradyarrhythmia or Peripheral Vascular Disease
• Labetalol


  Treatment for Hypertension of Pheochromocytoma and Hypertensive Crisis
• Carvedilol


  • Blocks α1 receptors
  • Reduces mortality in Patients with Heart Failure and useful in Hypertension and Heart Failure
• Nebivolol


  • MOA: Increase endothelial release of NO via induction of endothelial nitric oxide synthase
  • With vasodilating properties
• Esmolol


  • Management of Intraoperative and Postoperative Hypertension
  • Treatment associated with Tachycardia and Hypertensive Emergencies and Aggravation of Severe Heart Failure
• α-Adrenoceptor Blocking Drugs


  • MOA: blocks α receptors
  • Dilates Resistance and Capacitance Vessels
  • Combination Therapy: β antagonist and diuretic
  • Treatment for Men with Concurrent Hypertension and Benign Prostatic Hyperplasia
• Prazosin, Terazosin and Doxazosin


  • MOA: selective blocking of α1 receptors in arterioles and venules
  • Produce less tachycardia
  • Allows norepinephrine to exert unopposed negative feedback
  • Toxicity: Dizziness; Palpitations; Headache; Lassitude
• Phentolamine and Phenoxybenzamine


  Diagnosis and Treatment of Pheochromocytoma and Situations Associated with Exaggerated Release of Catecholamines
• Vasodilators


  • Relax smooth muscles of the Arterioles, decreasing Systemic Vascular Resistance
  • Decreased arterial resistance, mean atrial blood pressure elicit compensatory responses
  • Compensatory Responses are mediated by Baroreceptors, Sympathetic Nervous Systems, Renin, Angiotensin and Aldosterone
• Hydralazine


  • Oral Vasodilator
  • MOA: release of nitric oxide from drugs or endothelium
  • Dilates Arterioles
  • Combination Therapy: (with Nitrates) Effective in Heart Failure
  • Adverse Effects: Headache; Nausea; Anorexia; Palpitations; Sweating and Flus
• Doxazosin


  • Selective blocking of α1 receptors in arterioles and venules
  • Produce less tachycardia
  • Allows norepinephrine to exert unopposed negative feedback
• Vasodilators


  • Relax smooth muscles of the Arterioles, decreasing Systemic Vascular Resistance
  • Decreased arterial resistance, mean atrial blood pressure elicit compensatory responses
  • Compensatory Responses are mediated by Baroreceptors, Sympathetic Nervous Systems, Renin, Angiotensin and Aldosterone
• Nitric Oxide


  Release of nitric oxide from drugs or endothelium
• Hydralazine


  • Oral Vasodilator
  • Dilates Arterioles
  • Combination Therapy: (with Nitrates) Effective in Heart Failure
• Sodium Nitroprusside


  • Parenteral Vasodilator
  • Dilates Arterial and Venous Vessels
  • Nitroprusside → Nitric Oxide and Cyanide → Thiocyanate
  • Hypertensive Emergencies and Severe Heart Failure
  • Administered by Infusion Pump
  • Cyanide Toxicity: Metabolic Acidosis, Arrhythmia, Excessive Hypotension and Death

  Antidote

  Sodium Thiosulfate and Hydroxocobalamin
• Minoxidil


  • Oral Vasodilator
  • Hyperpolarization due to Opening of Potassium Channels
  • Dilates Arterioles
  • Combination Therapy: β blocker and Loop Diuretic (due to sympathetic stimulation and sodium and fluid retention)

  Topical Minoxidil (Rogaine)

  Hair Growth Stimulant