Sympatholytic drugs for hypertension

• Sympatholytics are used to treat hypertension (HT) and pulmonary hypertension.

Beta-Adrenoceptor Blocking Agents

• Beta-blockers primarily lower blood pressure by decreasing cardiac output.
• These agents can also reduce sympathetic outflow from the central nervous system (CNS).
• Further, they can inhibit renin release from the kidneys, reducing angiotensin II and aldosterone secretion.
• Propranolol is the prototype beta-blocker, acting on both beta1 and beta2 receptors.
• Selective beta1 receptor blockers include metoprolol and atenolol, two of the most commonly prescribed beta-blockers.
• Nebivolol selectively blocks beta1 receptors and increases nitric oxide production, leading to vasodilation.
• Selective beta-blockers can be administered cautiously to hypertensive patients also with asthma.
• Nonselective beta-blockers are contraindicated in patients with asthma because they can cause beta2-mediated bronchodilation.
• Beta-blockers should be used cautiously in those with acute heart failure or peripheral vascular disease.
• Beta-adrenoceptor blockers decrease blood pressure through numerous mechanisms of action:
  • Decreased activation of β1 adrenoceptors on the heart
  • Reduced cardiac output
  • Reduced peripheral resistance
  • Decreased renin release
  • Reduced angiotensin II production
  • Decreased aldosterone production
  • Reduced sodium and water retention
  • Decreased blood volume

Therapeutic Uses for Beta-Blockers

• Primary therapeutic benefits are seen in hypertensive patients with concomitant heart disease.
• They may be helpful with supraventricular tachyarrhythmia (atrial fibrillation), previous myocardial infarction, stable ischemic heart disease, and chronic heart failure.
• Beta-blockers should be avoided in patients with asthma, second- or third-degree heart block, and severe peripheral vascular disease.

Pharmacokinetics of Beta-Blockers

• Beta-blockers are orally active for treating hypertension.
• Propranolol undergoes extensive and variable first-pass metabolism.
• Oral beta-blockers may take several weeks to achieve full effect.
• Intravenous formulations are available for esmolol, metoprolol, and propranolol.

Beta-Blocker Adverse Effects

• Hypotension
• Bradycardia
• Fatigue
• Insomnia and nightmares
• Sexual dysfunction

Beta-Blocker Drug Interactions

• Noncardioselective beta-blockers can disrupt lipid metabolism.
• They may decrease high-density lipoprotein cholesterol and increase triglycerides.

Beta-Blocker Withdrawal

• Abrupt withdrawal can lead to severe hypertension, angina, myocardial infarction, and sudden death, especially in patients with ischemic heart disease.
• It is recommended to taper these drugs over a few weeks, particularly in hypertensive patients with ischemic heart disease.

Alpha-Adrenoceptor Blocking Agents

• Alpha-adrenergic blockers such as prazosin, doxazosin, and terazosin are used in hypertension treatment.
• These agents competitively block alpha1-adrenoceptors.
• These agents decrease peripheral vascular resistance.
• They also lower arterial blood pressure by relaxing arterial and venous smooth muscle.
• These drugs cause minimal changes in cardiac output, renal blood flow, and glomerular filtration rate.
• Reflex tachycardia and postural hypotension can occur at treatment onset or with dose increases, requiring slow titration in divided doses.
• Due to less favorable outcome data and side effects, alpha-blockers are not recommended as initial hypertension treatment, except in refractory cases.

Alpha/Beta-Adrenoceptor Blocking Agents

• Labetalol and carvedilol block alpha1, beta1, and beta2 receptors.
• Carvedilol treats both heart failure and hypertension.
• Carvedilol has been shown to reduce morbidity and mortality in heart failure patients.
• Labetalol manages gestational hypertension and hypertensive emergencies.

Centrally Acting Adrenergic Drugs: Clonidine

• Clonidine acts centrally as an alpha2 agonist, inhibiting sympathetic vasomotor centers.
• Clonidine decreases sympathetic outflow to the periphery.
• This leads to reduced total peripheral resistance and decreased blood pressure.
• Clonidine primarily treats hypertension that has not responded adequately to two or more drugs.
• Clonidine does not reduce renal blood flow or glomerular filtration and is, therefore, useful for hypertension complicated by renal disease.
• Clonidine is well-absorbed after oral administration, excreted by the kidney, and available as a transdermal patch.
• Adverse effects of clonidine include sedation, dry mouth, and constipation.
• Rebound hypertension may occur following abrupt clonidine withdrawal.

Centrally Acting Adrenergic Drugs: Methyldopa

• Methyldopa is an alpha2 agonist converted to methylnorepinephrine, diminishing adrenergic outflow from the CNS.
• Sedation and drowsiness are common side effects of methyldopa.
• Methyldopa's use is limited due to adverse effects and the need for multiple daily doses.
• Methyldopa is mainly used for managing hypertension in pregnancy due to its safety record.

Pulmonary Hypertension (PH)

• Pulmonary hypertension is an extremely serious disease characterized by progressive remodeling of the pulmonary vascular tree.
• Remodeling leads to stiffening and narrowing.
• PH causes an unavoidable rise in pulmonary arterial pressure.
• It can lead to right heart failure and death if untreated.
• Following birth, pulmonary vascular resistance becomes much lower than systemic vascular resistance.
• Normal systolic pulmonary artery pressure in adults is approximately 20 mmHg.
• Pulmonary hypertension may rarely be idiopathic, but is more commonly associated with other diseases.
• Vasoconstriction or structural narrowing of pulmonary resistance arteries increases pulmonary arterial pressure, even if cardiac output is normal.
• Endothelial dysfunction is implicated in pulmonary hypertension aetiology.

Pulmonary Hypertension Treatment: Prostacyclin (PGI2) Analogs

• Epoprostenol (pharmaceutical prostacyclin), iloprost, and treprostinil (synthetic analogs) are potent pulmonary vasodilators for pulmonary arterial hypertension.
• These mimic prostacyclin effects in endothelial cells.
• They significantly reduce pulmonary arterial resistance.
• They increase cardiac index and oxygen delivery.
• These agents have short half-lives.
• Epoprostenol and treprostinil are administered as a continuous intravenous infusion.
• Treprostinil is also administered orally, via inhalation, or subcutaneously.
• Iloprost requires frequent dosing when inhaled due to its short half-life.
• Dizziness, headache, flushing, and fainting are common adverse effects.
• Bronchospasm and cough can occur after iloprost inhalation.

Pulmonary Hypertension Treatment: Phosphodiesterase-5 Inhibitors

• Sildenafil and tadalafil inhibit PDE-5 for pulmonary hypertension treatment.
• These drugs inhibit phosphodiesterase (PDE) type 5, the enzyme responsible for cGMP breakdown, in lungs and erectile tissue.
• They increase cGMP, which increases vasodilation.
• They are very effective for the treatment of erectile dysfunction in men.
• The effect of the drugs appear after 30 min of oral administration and lasts 4-5 hours.
• Side effects can include blue discoloration of vision, headache, and optic neuropathy.
• These agents are contraindicated in patients taking nitrates due to increased cGMP, which leads to severe vasodilation, hypotension, and reflex tachycardia leading to aggravation of angina and development of arrhythmia.
• Combining PDE-5 inhibitors with nitrates is dangerous.

Pulmonary Hypertension Treatment: Endothelin Receptor Antagonists

• Endothelin is a vasoconstricting peptide produced by the endothelium.
• Endothelins act on 2 subtypes of receptors: ETA and ETB.
• Most of the effects are mediated through ETA receptors present in vascular smooth muscle and other tissues.
• ETA activation leads to potent vasoconstriction, vascular smooth muscle proliferation, cardiac hypertrophy, and blood pressure elevation.
• Increased endothelin production is implicated in various CVS diseases, including primary pulmonary hypertension, cardiac hypertrophy, heart failure, atherosclerosis, and coronary artery disease.
• Bosentan is an orally active nonselective blocker of both ETA and ETB receptors.
• Ambrisentan is a selective ETA blocker.
• Both bosentan and ambrisentan treat pulmonary hypertension.
• Side effects include increased liver enzymes which can cause liver damage.
• Patients must have monthly liver function tests when taking these drugs.

Pulmonary Hypertension Treatment: Soluble Guanylate Cyclase Stimulators

• Pulmonary hypertension pathophysiology includes endothelial dysfunction, resulting in insufficient stimulation of the NO-sGC-cGMP pathway.
• Endogenous NO levels are reduced in patients with pulmonary arterial hypertension (PAH).
• Riociguat has a dual mode of action. It acts in synergy with endogenous nitric oxide.
• It directly stimulates soluble guanylate cyclase independently of nitric oxide availability.
• This inhibits the entrance of Ca2+ into the cell. This means the cell cannot contract, resulting in vasodilation

Riociguat Properties and Side Effects

• Riociguat is rapidly absorbed, displays almost complete bioavailability (94.3%), and can be taken with or without food, as crushed or whole tablets.
• The half-life of riociguat is approximately 12 h in patients and approximately 7 h in healthy individuals.
• Riociguat and its metabolites are excreted via both renal and biliary routes.
• Dose adjustment should be performed with particular care in patients with moderate hepatic impairment or mild to severe renal impairment.
• Riociguat has a low risk of clinically relevant drug interactions due to its clearance by multiple cytochrome P450 (CYP) enzymes and its lack of effect on major CYP isoforms and transporter proteins at therapeutic levels.
• Overall, riociguat has been well tolerated.
• The most common adverse effects are headache, dizziness, dyspepsia, peripheral oedema, nasopharyngitis, nausea, vomiting, diarrhoea and hypotension.