Antihypertensive drugs

Objectives

• List major groups of antihypertensive drugs and provide examples
• Describe compensatory responses to each major type of antihypertensive drug
• Summarize major sites of action of sympatholytic drugs in clinical use and provide examples of drugs acting at each site
• Identify four mechanisms of action of vasodilator drugs
• Outline major antihypertensive vasodilator drugs and describe their effects
• Describe the differences between the two types of angiotensin antagonists

Classification of Hypertension

• Normal blood pressure: Systolic <120 and Diastolic <80 mm Hg
• Prehypertension: Systolic 120-139 or Diastolic 80-89 mm Hg
• Hypertension stage 1: Systolic 140-159 or Diastolic 90-99 mm Hg
• Hypertension stage 2: Systolic ≥160 or Diastolic ≥100 mm Hg

Autonomic and Hormonal Control of CV Function

• Baroreceptors monitor blood pressure and initiate compensatory responses
• Sympathetic nervous system (SNS) increases heart rate and contractility and constricts blood vessels to increase blood pressure
• Parasympathetic nervous system (PNS) decreases heart rate to lower blood pressure
• Renal blood flow and pressure influence renin secretion, leading to angiotensin II production and ultimately impacting blood volume
• Hormones like aldosterone regulate sodium and water balance to influence blood volume and pressure

Antihypertensive Drugs: Mechanisms of Increased BP

• Heart (pump-based) hypertension: increased cardiac output, with normal peripheral resistance
• Vascular (peripheral resistance) hypertension: increased peripheral resistance, with normal cardiac output
• Renal/volume hypertension: retention of sodium, water, increased blood volume, and increased cardiac output and peripheral resistance

Sites Controlling Blood Pressure

• Arterioles: resistance to blood flow
• Venules: capacitance vessels
• Heart: pump action for blood output
• Kidneys: regulate blood volume through sodium balance

Na and Smooth Muscle

• Increased sodium concentration inside smooth muscle cells leads to increased calcium concentration
• Sensitivity to stimulatory neurotransmitters and hormones increases, leading to increased vasoconstriction and peripheral resistance
• Decreasing sodium reduces intracellular calcium, relaxing smooth muscle and decreasing peripheral resistance

Non-Drug Approach

• Sodium restriction and diuretic therapy
• Weight loss
• Regular exercise
• Eliminate factors elevating blood pressure (e.g., smoking, excess caffeine, stress) and implement stress-reduction techniques

Baroreceptor Reflex Arc

• Baroreceptors in the carotid sinus detect changes in blood pressure
• Signals are transmitted via the vagus nerve to the brainstem
• The brainstem adjusts the activity of the sympathetic and parasympathetic nervous systems to maintain blood pressure

Stepped Care (Method of Treatment)

• Combine antihypertensive drugs sequentially to reduce drug toxicity and compensatory mechanisms
• Step One: Diuretic, beta-blocker, ACE inhibitor
• Step Two: Other sympatholytics
• Step Three: Vasodilators

Overview of Diuretic Agents

• Diuretics act on various segments of the nephron to increase urine output and reduce extracellular fluid volume
• Types include: acetazolamide, osmotic, loop, thiazide, aldosterone antagonists, and ADH antagonists

Diuretics: Mechanism of Action and Clinical Indications

• Thiazides are preferred for mild to moderate hypertension
• Loop diuretics are used in patients with renal impairment and severe hypertension
• Diuretics decrease blood volume initially, then stabilize to near pre-drug levels within weeks
• Chronic effect reduces peripheral resistance due to decreased Na and Ca

Excessive Diuresis/Adverse Effects

• Hyponatremia, hypotension, hypokalemia (unless potassium-sparing diuretic), hypocalcemia, hypomagnesemia, hypochloremic alkalosis, hyperuricemia, and hyperglycemia

Loop/K-Sparing Diuretics

• Loops indicated in CHF and decreased renal function (creatinine clearance less than 50 ml/min)
• K-sparers are often combined with thiazides/loops to stabilize potassium levels
• Spironolactone is useful in CHF (aldosterone antagonist diuretic)

Compensatory Responses to Vasodilators

• Vasodilator drugs reduce vascular resistance, leading to decreased blood pressure
• Compensatory mechanisms increase renin/angiotensin II and aldosterone, increasing sodium retention and vasoconstriction to elevate blood pressure

Beta-Blockers

• Mechanism of action: reduces cardiac output and renin release
• Clinical indications: hypertension, angina, supraventricular tachycardias
• Adverse effects: bradycardia, fatigue, cold extremities

Labetalol/Carvedilol

• Mechanism of action: alpha-1 and nonselective beta blocker with balanced SNS inhibition
• Clinical indications: hypertensive emergency, pheochromocytoma, moderate to severe hypertension (2nd line)
• Adverse effects: potential for asthma

Selective Alpha-1 Blockers

• Mechanism of action: competitive alpha-1 receptors, balanced vasodilation, decreases peripheral resistance
• Clinical indications: hypertension, useful in CHF
• Adverse effects: dizziness, headache, postural hypotension (particularly with first dose), nasal congestion, male impotence

Alpha-2 Adrenergic Receptors

• Mechanism of action: presynaptic receptors in the periphery/CNS exert negative feedback, inhibiting further norepinephrine release; postsynaptic receptors in CNS inhibit vasomotor/cardiac centers, reducing vasomotor tone, blood pressure, and heart rate

Mechanism of Action of Alpha-2 Receptors

• Agonists bind, activating adenylate cyclase, and producing cyclic AMP
• Effects vary based on location and type of receptors

Clonidine

• Mechanism of action: central alpha-2 agonist, reducing sympathetic outflow to the peripheral nervous system
• Clinical indications: hypertension, severe hypertension
• Adverse effects: sedation, dry mouth, sodium retention, potential for hypertensive crisis

Metabolism of Methyldopa

• Metabolism of L-Dopa (tyrosine) in the body
• Steps include decarboxylation, hydroxylation, and methylation

Methyldopa

• Mechanism of action: converted to alpha-methyl-NE, a central alpha-2 agonist, reducing sympathetic outflow
• Clinical indications: hypertension; generally safe during pregnancy
• Adverse effects: sedation, GI disturbances, hemolytic anemia, liver dysfunction

Hydralazine

• Mechanism of action: exact MOA unknown; may affect intracellular calcium release
• Clinical indications: severe hypertension (requires combination treatment usually with diuretics and beta blockers)
• Adverse effects: vasodilation, edema, headache, reflex tachycardia

Hydralazine (cont.)

• Adverse effects: excessive vasodilation, edema, headache, reflex tachycardia

Calcium Antagonists

• Mechanism of action: blocking voltage-dependent slow calcium channels
• Clinical indications: hypertension (especially dihydropyridines), angina, supraventricular arrhythmias
• Types: verapamil, diltiazem, nifedipine

Verapamil/Diltiazem

• Mechanism of action: block voltage-dependent slow calcium channels in cardiac and smooth muscle, affecting heart rate and AV conduction
• Clinical indications: hypertension, angina, supraventricular arrhythmias
• Adverse effects: constipation, edema

Dihydropyridines: Nifedipine Class

• Mechanism of action: arteriolar dilators, no direct cardiac effects
• Clinical indications: hypertension
• Adverse effects: excessive vasodilation, reflex tachycardia, myocardial ischemia (especially with high doses/rapid onset)

MOA of ACEIs & ARBs

• ACEIs and ARBs decrease peripheral resistance and blood pressure by different mechanisms: inhibiting ACE (ACEIs) or blocking angiotensin-II receptors (ARBs)

ACE Inhibitors

• Mechanism of action: inhibits angiotensin-converting enzyme (ACE), decreases angiotensin II, and increases bradykinin
• Clinical indications: hypertension, heart failure, diabetic nephropathy
• Adverse effects: cough, angioedema, hyperkalemia, renal dysfunction

ACE Inhibitors (Pharmacokinetics)

• Captopril: rapid onset, short duration (t1/2=3h), usu. BID-TID, food decreases bioavalibility, excreted unchanged in the urine
• Enalapril: once-daily prodrug, with enalaprilat (active metabolite) with a t1/2 = 11h
• Lisinopril: slow onset, once daily (t1/2 = 12h), excreted unchanged

Angiotensin II Inhibitors - Losartan

• Mechanism of action: competitive AT1 blockers, reducing angiotensin II's effect
• Clinical indications: hypertension
• Adverse effects: similar to ACE inhibitors, but lower risk of cough, dizziness, headache, fatigue, elevated liver enzymes

Other Angiotensin Receptor (AT1) Antagonists Blockers

• Valsartan, irbesartan, candesartan, telmisartan, olmesartan, eprosartan

Selecting AHPT Drugs (Patient Population-Based Recommendations)

• Summarizes recommended and not-recommended antihypertensive drugs based on patient populations and comorbidities

Angiotensin-Converting Enzyme Inhibitors

• Mechanism of action: inhibits ACE to prevent angiotensin II formation
• Clinical use: hypertension, heart failure, diabetic nephropathy
• Adverse effects: cough, angioedema, etc.

Clinical Correlated Questions (and Answers)

• A series of patient case studies and questions that assess understanding of antihypertensive drugs