2. Arterial Blood Pressure
• Force or tension of blood pressing against the artery walls is known as
Blood pressure
• BP is brought about by Contraction of the left ventricle, systemic
vascular resistance, elasticity of the arterial walls as well as blood
volume
• i.e. blood pressure is simply a product of cardiac output and
systemic vascular resistance
• There are a couple of major systems involved in blood pressure
regulation.
3. ANTI-HYPERTENSIVE AGENTS
ALPHA1 ADRENERGIC RECEPTOR BLOCKERS
BETAADRENERGIC RECEPTOR BLOCKERS (Selective and
Non-selective)
CENTRALLY ACTING ADRENERGIC DRUGS
CALCIUM CHANNEL BLOCKERS (Dihydropyridines and Non-
Dihydropyridines)
DIURETICS (Loop Diuretics, Thiazide Diuretics and Potassium-
sparing Diuretics)
AGENTS ACTING ON RENIN-ANGIOTENSIN-ALDOSTERONE
SYSTEM
OTHERS
4. Alpha-1 blockers e.g. Doxazosin and Prazosin
Beta Blockers
a) Selective Beta blockers: Atenolol and Metoprolol
a) Non-Selective Beta- blockers such as Labetalol and Carvedilol
5. Centrally acting adrenergic drugs which work by
blocking sympathetic activity within the brain e.g.
Clonidine and Methyldopa
6. Calcium Channel Blockers
These are divided into two main sub-classes
Dihydropyridines and Non-Dihydropyridines
Dihydropyridines selectively inhibit L-type Calcium
channels in the vascular smooth muscle
Non-Dihydropyridines which are non-selective
7. Diuretics
There are 3 major classes of diuretics that are used in the treatment of
hypertension.
Loop Diuretics
Thiazide Diuretics
Potassium-Sparing Diuretics
9. RAAS Agents
Agents that work on Renin-Angiotensin-Aldosterone System include
• Renin
• Angiotensin Converting Enzyme Inhibitors
• Angiotensin II Receptors Type I or AT1 Receptors Inhibitors
10. RAAS Agents Contd
Agents that work on Renin-Angiotensin-Aldosterone System include
• Renin
• Angiotensin Converting Enzyme Inhibitors
• Angiotensin II Receptors Type I or AT, Receptors Inhibitors
11. Other Anti-Hypertensive Agents
Other anti-hypertensive agents, that do not fall into any of the classes
discussed above
o Bosentan
oFenoldopam
oSodium nitroprusside and Nitroglycerin
12. Other Anti-Hypertensive Agents Contd
Other anti-hypertensive agents, that do not fall into any of the classes
discussed above
o Bosentan
oFenoldopam
oSodium nitroprusside and Nitroglycerin
13. Other Anti-Hypertensive Agents Contd
Other anti-hypertensive agents, that do not fall into any of the classes
discussed above
o Bosentan
oFenoldopam
oSodium Nitroprusside and Nitroglycerin
14. Direct Acting Smooth Muscle Relaxant
Drugs e.g. Hydralazine and Minoxidil
Hydralazine, direct-acting smooth muscle relaxant.
Hydralazine mechanism of action not entirely determined
yet.
Minoxidil stimulates smooth muscle ATP-activated
potassium channels opening for membrane stabilization.
Editor's Notes
Arterial blood pressure is regulated by pressure sensitive neurons called baroreceptors located in the aortic arch and carotid sinuses.
If the blood pressure falls too low, those baroreceptors can send signals to the adrenal medulla, causing release of catecholamines and thus increase in sympathetic activity through activation of α and β receptors. So activation of β1 receptors causes increase in the heart rate and stroke volume and thus increased cardiac output which leads to the increase in blood pressure.
On the other hand, activation of α1 receptors on the smooth muscle causes vasoconstriction and thus increase in vascular resistance which again leads to increase in blood pressure.
Alpha-1 blockers block alpha-1 receptors in the smooth muscle thus causing decrease in systemic vascular resistance and ultimately decrease in blood pressure e.g. Doxazosin and Prazosin.
Selective Beta blockers: Atenolol and Metoprolol which selectively block beta-1 receptors on the heart thus causing decrease in cardiac output and thereby decrease in blood pressure.
Non Selective Beta-blockers such as Labetalol and Carvedilol that can additionally block alpha-1 receptors and thus simultaneously decrease vascular resistance. Furthermore, beta blockers can inhibit beta-1 receptors present in the kidney and thus suppress release of renin, formation of angiotensin II and secretion of aldosterone. So these effects result in decrease in systemic vascular resistance and again fall in blood pressure.
This works by blocking sympathetic activity within the brain e.g. Clonidine and Methyldopa.
Clonidine selectively stimulates presynaptic alpha-2 receptors thus providing a negative feedback to reduce catecholamine production and release which leads to decrease in systemic vascular resistance and cardiac output and ultimately decreased blood pressure.
Methyldopa on the other hand also lowers blood pressure through the same mechanism. However, unlike clonidine it is not active on itself, so first it must be converted to its active metabolite called methyl norepinephrine to produce its effect.
Dihydropyridines inhibit L-type calcium channels in the vascular smooth muscle. Under normal conditions when calcium enters the smooth muscle cell, it causes it to contract which leads to increased vascular resistance and thus increase in blood pressure. So when dihydropyridine drug blocks the entry of calcium into the vascular smooth muscle cell, the contraction is inhibited which leads to decreased resistance to blood flow and thus lowering of blood pressure. Examples of drugs that belong to this group are Amlodipine, Felodipine, Nicardipine and Nifedipine. Side effects of Dihydropyridines are related to systemic vasodilation i.e. dizziness, headache, flushing and peripheral oedema, swelling of gums, also known as gingival hyperplasia.
Non-dihydropyridines: They are non-selective inhibitors of L-type calcium channels. In other words, they are not only capable of blocking calcium channels on vascular smooth muscle but also calcium channels on cardiac cells such as those of SA node and AV node which leads to reduced myocardial contractility, slower heart rate and slower conduction. That is why these agents exhibit significant anti-arrhythmic properties. Though decreased heart contractions will typically result in decreased cardiac output, non-dihydropyridines do not significantly decrease cardiac output most likely because of the reflex tachycardia that occurs as a result of vasodilation e.g. of drugs belonging to this class of drugs are Diltiazem and Verapamil.
Side effects of these agents include excessive bradycardia and cardiac conduction abnormalities.
Also, verapamil which happens to be the least selective calcium channel blocker can exert significant inhibition of calcium channels in the smooth muscle that lines the gastro-intestinal tract which can lead to constipation.
Loop Diuretics: Furosemide works by reducing reabsorption of sodium chloride in the kidney leading to significant diuresis.
With less volume in the vascular space less blood returns to the heart so cardiac output reduces. This in turn leads to decrease in blood pressure, particularly, in the patients with volume-based hypertension and Chronic Kidney Disease(CKD).
Thiazide Diuretics: Hydrochlorothiazide, which also reduces reabsorption of sodium chloride in the kidneys, but to a much smaller degree than loop diuretics. This leads to initial decrease in the intravascular volume, decrease in cardiac output and ultimately lower blood pressure. However, the long term effects on blood volume are minimal and sustained anti-hypertensive effects are thought to be produced by thiazide-induced vasodilation.
Potassium-Sparing Diuretics such as Triamterene and Spironoloratone which increase diuresis by either interfering with the sodium-potassium exchange in the kidneys or by blocking the actions of aldosterone.
Potassium-sparing diuretics are often used in combination with loop and thiazide diuretics to reduce loss of potassium, that occur with the use of these drugs.
Agents that work on Renin-Angiotensin-Aldosterone System (RAAS). There are three pharmacological targets that can be used to reduce the activity of AngiotensinII, which is ultimately responsible for causing blood pressure to increase.
Renin: The enzyme responsible for the conversion of Angiotensinogen to precursor of Angiotensin II that is Angiotensin I, so renin is the target of renin inhibitors i.e. Alliskiren.
Angiotensin Converting Enzyme Inhibitors: These are the agents which inhibit the conversion of Angiotensin I to Angiotensin II. The enzyme (ACE) just like the inhibition of renin, inhibition of ACE also leads to decreased production of Angiotensin II. However, what makes ACE inhibitor different is that in addition to lowering Angiotensin II levels, they can also elevate bradykinin levels. Bradykinin is a peptide that cause blood vessels to dilate by stimulating the release of nitric oxide and prostacyclin. However, normally ACE inactivates bradykinin, so its inhibition leads to bradykinin-induced vasodilation, e.g Benazipril,Catopril, Enalapril, Lisinopril, Quinapril and Ramipril.
Angiotensin II Receptors Type I or AT, Receptors Inhibitors; Binding of Angiotensin II to these receptors is actually responsible for most of the effects of Angiotensin II, including vasoconstriction and stimulation of aldosterone release.
These receptors are the targets of Angiotensin II receptor blockers or ARB i.e Cadensartan, Irbesartan, Losartan, Olmesartan and Valsartan.
In summary, the agents that work on RAAS either block the production of Angiotensin II or block its actions on the AT Receptors. These in turn leads to decreased systemic vascular resistance but without significant changes in cardiac output.
Additionally, these agents reduce the effects of Angiotensin II on renal hemodynamics.
Specially, Angiotensin II constricts the efferent arteriole, thereby, generating back pressure in the glomerulus which can lead to injury. So by reducing the activity of Angiotensin II, these agents also renal-blood flow and thereby reduce the risk of renal injury.
Side Effects: Because the agents suppress aldosterone release, their use can contribute to development of hyperkalemia. Furthermore, ACE inhibitors in particular, may cause dry cough or in rare cases, Angioedema, which can be life threatening.
This is thought to be due to increased levels of bradykinin and substance P.
Bosentan: It is a competitive antagonist of a potent vasoconstrictor called Endothelin I which acts on Endothelin A and Endothelin B receptors located on pulmonary vascular cells. By blocking the action of Endothelin I on these receptors, Bosentan leads to vasodilation which decreases pulmonary vascular resistance; for that reason Bosentan is often a drug of choice for treatment of pulmonary hypertension.
Fenoldopam: It is a selective dopamine I receptor agonist, the dopamine I receptors are located on the smooth muscle cells in the peripheral vasculature as well as the renal coronary cerebral and mesenteric arteries. By stimulating dopamine-I receptor.
Fenoldopam produces generalized arterial vasodilation which leads to decreased peripheral resistance and thus lower blood pressure. Additionally, Fenoldopam inhibits tubular sodium reabsorption, which results in natriuresis and diuresis. Due to its rapid onset of action, and short duration of action, Fenoldopam is used in the Hospitals for short term management of severe hypertension.
Sodium Nitroprusside and Nitroglycerin: They serve as a source of nitric oxide (NO) a potent peripheral vasodilator.
Minoxidil, works by stimulating opening of ATP-activated potassium channels, in the smooth muscle leading to memebrane stabilization. This makes vasoconstriction less likely.
While these agents significantly decrease peripheral resistance, they also produce significant compensatory reflex tachycardia and renin release, therefore these drugs are typically administered in combination with a diuretic and a beta-blocker.
N.B: Topical application of minoxidil promotes hair growth, hence it is used in the treatment of baldness.