Blood pressure regulation and drug targets
Blood pressure (BP) regulation is carried out by several interconnected systems. The baroreflex starts from vascular baroreceptors, impulses travel via afferent fibers (as part of the vagus nerve) to the nucleus of the solitary tract, and from there to an inhibitory interneuron that suppresses the vasomotor center. Sympathetic influences are subsequently mediated through autonomic ganglia and adrenergic receptors of the heart, blood vessels, and kidneys.
In parallel, the renin-angiotensin-aldosterone system (RAAS) operates: renin is released by the juxtaglomerular apparatus of the kidneys, angiotensin I is converted into angiotensin II by ACE, which causes vasoconstriction via AT₁ receptors and stimulates aldosterone release. In hypertension, baroreceptors adapt and fail to signal adequately, making pharmacological intervention necessary.
Centrally acting neurotropic agents
Clonidine is an α₂- and I₁ (imidazoline) receptor agonist in the vasomotor center. It mimics the baroreflex by enhancing inhibitory influences on sympathetic tone, leading to a decrease in total peripheral resistance, myocardial contractility (via β₁), and heart rate (via M₂-vagal effects).
- Clinical use: termination of hypertensive crisis (administered slowly, otherwise peripheral α₂ activation and paradoxical vascular spasm may occur), glaucoma (reduction of aqueous humor production), and withdrawal syndrome.
- Side effects: sedation, orthostatic collapse, pronounced withdrawal syndrome with hypertensive crisis, peripheral edema (due to RAAS activation and reduced renal blood flow).
Similar drugs: moxonidine (selective I₁-receptor agonist, better tolerated), methyldopa (converted into α-methylnoradrenaline and stimulates α₂), guanfacine.
Ganglionic blockers and sympatholytics
Ganglionic blockers (pentamine, hexamethonium, hygronium) interrupt transmission in all autonomic ganglia, reducing vascular tone, renin secretion, and cardiac output. Due to their lack of selectivity, they are used primarily for controlled hypotension rather than for the treatment of essential hypertension.
Sympatholytics (reserpine, guanethidine) deplete catecholamine stores in nerve terminals. Reserpine is characterized by pronounced side effects: drug-induced parkinsonism, depression, sedation.
Adrenoceptor blockers:
- Selective β₁ blockers: atenolol, betaxolol, bisoprolol, nebivolol, metoprolol, talinolol.
- Non-selective β₁/β₂ blockers: propranolol, nadolol.
- α/β-blockers (effectively β₁,₂ + α₁): carvedilol, labetalol.
- α₁-blockers: doxazosin is effective for hypertension (acting on α₁A and α₁B), whereas tamsulosin (predominantly α₁A) practically does not lower blood pressure in BPH.
Agents affecting the RAAS
Sites of action: suppression of renin secretion (by β-blockers), ACE blockade, and AT₁ receptor blockade.
- ACE inhibitors ("-prils"): captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril, trandolapril. They reduce the formation of angiotensin II and decrease the breakdown of bradykinin. Characteristic side effects are dry cough (accumulation of bradykinin) and angioedema.
- Vasopeptidase inhibitors: omapatrilat inhibits ACE and the degradation of vasodilating peptides; its use is limited due to the high risk of angioedema.
- AT₁ receptor blockers (sartans): losartan, irbesartan, valsartan, eprosartan. They do not cause cough and are better tolerated than ACE inhibitors.
Myotropic vasodilators and diuretics
Myotropic agents act directly on vascular smooth muscle cells:
- Dihydropyridine calcium channel blockers: nifedipine, amlodipine, felodipine, nitrendipine, isradipine, lacidipine — resulting in relaxation of the vascular wall.
- Potassium channel activators: K⁺ efflux from the cell causes membrane hyperpolarization and myocyte relaxation.
- Sodium nitroprusside: an NO donor, dilates arteries and veins to an equal extent; used for controlled hypotension and management of crises. Nitroglycerin predominantly dilates veins and is not used for routine hypertension therapy.
- Hydralazine: a direct vasodilator with a not fully elucidated mechanism.
- Experimental classes: vasopressin receptor antagonists, endothelin antagonists, atrial natriuretic peptide analogues.
Among diuretics for arterial hypertension, indapamide has become the mainstay in clinical practice, possessing vasodilating properties in addition to its diuretic effect.
Key points
- Clonidine activates central α₂ and I₁ receptors, mimicking the baroreflex; it is administered slowly due to the risk of peripheral vasoconstriction.
- The triad of significant adverse effects of clonidine: sedation, orthostatic hypotension, and withdrawal syndrome with hypertensive crisis.
- Reserpine, as a sympatholytic, causes parkinsonism, depression, and sedation.
- ACE inhibitors (-prils) typically provoke a dry cough and can cause angioedema.
- Sartans (losartan, etc.) block AT₁ receptors and are free from bradykinin-mediated adverse effects.
- Sodium nitroprusside dilates arteries and veins equally, whereas nitroglycerin dilates veins predominantly.
- Ganglionic blockers are used for controlled hypotension rather than long-term hypertension therapy.
- Indapamide is the preferred diuretic for essential hypertension.