Antihypertensive Agents 2024-2025 PDF

Antihypertensive Agents 1 Prof. Amina SALLAM 2024-2025 1  Learning Objectives 1. Classify the antihypertensive agents based on their mechanism of action. 2. Illustrate the BP lowering me...

Antihypertensive Agents 1 Prof. Amina SALLAM 2024-2025 1  Learning Objectives 1. Classify the antihypertensive agents based on their mechanism of action. 2. Illustrate the BP lowering mechanism of various drugs. 3. Compare and contrast between all drug classes regarding their actions, clinical use, adverse effects and medical concerns. 4. Highlight the appropriate use of drugs during emergency. 5. Indicate the appropriate treatment of HTN during pregnancy. 6. Select the appropriate medication regimen for a given condition. 2  Sympathetic Depressants Alpha2-selective agonists Adrenergic Neuron Blockers (reserpine & guanethidine) Receptors Blockers - Alpha1-receptors antagonists - Beta-receptors antagonists 3  III- 2. Beta Blockers Non-selective: propranolol, nadolol, timolol, pindolol Cardio-selective: atenolol, acebutolol, metoprolol Members with ISA: pindolol & oxprenolol 4 Beta Blockers Classification 5  Beta Blockers Classification Carvedilol and labetalol also cause α1 blockade. The partial agonist β2 activity not necessarily to be at the same type of receptors blocked. β3 6 7  Beta Blockers Actions Suppress all the cardiac properties, with consequent  in cardiac work. BP is reduced by additional mechanisms: ⎯ Decreasing renin release (β1 in kidney) ⎯ Blocking presynaptic β receptors →  NA release Some members possess membrane stabilizing activity What is the effect of beta blockers on the TPR 8  Blockers Acute Effect 9   Blockers Use In HTN o Overall, although the acute effects of these drugs may include a rise in peripheral resistance, chronic drug administration leads to a fall in peripheral resistance in patients with HTN. o Often used combined with either a diuretic or a vasodilator. o Less effective in the elderly and in individuals of African origin. o Having the ability to reduce the HR, they are mainly of value in HTN associated with other CV conditions. 10   Blockers Other Actions Bronchi: bronchospasm in asthmatic patients. Liver: block the β2-mediated glycogenolysis and gluconeogenesis. Members with no ISA reduce the β3-mediated lipolysis thus they can increase plasma TGs. Eye: reduce IOP by reduction of aqueous humour synthesis. CNS: anxiolytic effect (some members). 11   Blockers CV Use o Very valuable in the treatment of angina and chronic heart failure and following MI. o Slow AV conduction, therefore useful in preventing ventricular arrythmias. o Used to protect heart in conditions such as thyrotoxicosis and pheochromocytoma. 12   Blockers Non-CV Use o To reduce the frequency and intensity of migraine headaches. o Timolol (eyedrops) is locally used in glaucoma (2). o The manifestations of anxiety (chest pain, fatigue, and insomnia) may respond dramatically to low dose of propranolol. o Contribute to symptomatic treatment of alcohol withdrawal in some patients. 13  Nebivolol The most highly selective β1-adrenergic receptor blocker. Has the additional quality of eliciting vasodilation due to an action of the drug on endothelial NO production. Nebivolol does not adversely affect lipid profile. Better results on insulin sensitivity and oxidative stress for an equivalent reduction of BP and HR (as compared to metoprolol in patients with metabolic syndrome). 14  Labetalol Available as a mixture of two isomers; one is a potent nonselective β blocker and the other isomer is a potent α1 blocker. It has a 3:1 ratio of β:α antagonism. Available in IV and oral forms. Hypotension induced by labetalol is not associated with tachycardia (compare with only α blockers). Due to its both β and α blocking activity, it is favourable in HTN due to hypertensive emergency and pheochromocytoma. 15  Carvedilol Antagonizes the actions of catecholamines more potently at β receptors than at α1 receptors. It also attenuates oxygen free radical-initiated lipid peroxidation and inhibits mitogenesis of VSMCs independently of adrenoceptor blockade. These effects may contribute to the clinical benefits of the drug in chronic heart failure. 16  Esmolol An ultra-short-acting β1-selective antagonist (~10 minutes). Given by continuous infusion. The therapeutic actions of the drug are terminated rapidly when its infusion is discontinued. Esmolol is safer than longer-acting agents for use in asthmatic patients who require β-adrenoceptor antagonism. For control of supraventricular arrhythmias, and perioperative HTN. 17  Sotalol A non-selective β-receptor blocker that has marked antiarrhythmic effects, thus used ONLY in cases of arrythmia. (discussed later) 18  Beta Blockers ADRs Bradycardia, slowing of conduction, precipitation of HF in susceptible individuals. Bronchospasm in susceptible individuals (Why??). Cold extremities, fatigue, and exercise intolerance (why??) Increased risk of hypoglycemic coma (with which drug??) Increased LDL/HDL ratio and TGs → (who??) Impotence and decreased libido. 19  Beta Blockers Concerns Sudden withdrawal of therapy is a box warning (why??) Recovery from hypoglycaemia is a significant concern. Caution in patients with peripheral vascular disease (who??) A life-threatening adverse cardiac effect of a β antagonist may be overcome directly with glucagon (why preferred over isoprenaline??) ― Glucagon is the gold standard to treat beta blocker toxicities being able to directly increase cardiac inotropy via adenyl cyclase activation. 20  Please Note Responses to β blockers are highly variable among individuals: ― In one study, 30−60% of people with HTN failed to achieve adequate BP control. Some of this variability is caused by genetic variation affecting either how the drug blocks β-receptors or how the drug is processed and broken down in the human body. Resting bradycardia and a reduction in the HR during exercise are indicators of the drug β-blocking effect, and changes in these parameters may be used as guides for regulating dosage. 21 Comparison 22 Comparison 23 Comparison 24  Comparison Beta Blockers Revised 2016 25 Renin-Angiotensin-Aldosterone System 26 27  RAAS Local systems in various tissues and organs are capable of generating AngII. – These include the adrenal gland, brain, heart, kidney, vasculature, gonads, pancreas, prostate, retina, and liver. 28 Drugs Affecting RAAS 29  ACE Inhibitors The most commonly-indicated medications in the treatment of CV and renal diseases, including HTN, HF, acute coronary syndrome, nephrotic syndrome, and diabetes. ACE inhibitors differ in their chemical structure, potency, bioavailability, plasma half-life, route of elimination, as well as their distribution and affinity for tissue-bound ACE. 30  ACE Inhibitors Members The non-prodrug lisinopril and The only agents that do not have to be activated in the the SH-containing member captopril body to be effective Perindopril, enalapril, benazepril, quinapril, ramipril, trandolapril, zofenopril and fosinopril: prodrugs available for oral use …..at Enalaprilat is the only member that’s available as oral and IV. Most reach peak serum levels within 1 hour. Since most of the activation occurs in the liver, a non-prodrug form is preferable in patients with underlying liver issues. 31  ACE Inhibitors Actions Inhibit the potent Ang II and conserve the potent bradykinin. ― Dilatation of both arterioles and venules   TPR and  CO. ― Decrease aldosterone release   blood volume   CO. Reduce systolic and diastolic BP in both hypertensive and normotensive subjects. ― Inhibit cardiac and vascular RAAS   CV remodeling. Extremely useful in the treatment of heart failure and after MI. 32  Role In Associated Diseases Have a useful role in CKD because they diminish proteinuria by reduction of renal vascular resistance. This effect is particularly valuable in diabetes, and these drugs are now recommended for diabetic patients even in the absence of HTN. There is evidence of decreasing onset of frank diabetes in individuals with HTN. 33  Why Beneficial In Diabetes Ang II has been implicated in insulin resistance by inhibiting insulin receptor dependent PI3K signaling cascade. By acting on AT1 receptors, Ang II decreases insulin-induced NO production and at the same time activates NADPH oxidase leading to enhanced production of other ROS and enhancing inflammation. It is not surprising that HTN is a common characteristic of insulin-resistant diabetes, with observed increase in tissue Ang II seen coupled with the inhibition of NO. It has been shown that in diabetic patients, therapeutic inhibition of the RAAS increased NO activity in renal endothelium, having a positive influence on renal function, and possibly CV function as well. 34  ACE Inhibitors ADRs Hypotension: Initial (first) dose phenomenon. Persistent cough and wheezing. Angioedema: the most significant ADR that can affect the tongue leading to airway obstruction. Slight hyperkalemia. Loss of the sense of taste. 35  ACE Inhibitors Concern 1 Blood dyscrasias: Combination with immunosuppressants such as azathioprine has been associated with anemia. The interaction appears to be due to the erythropoietin-lowering effect of ACE inhibitors increasing the risk of anemia. Reported cases of neutropenia when captopril is combined with procainamide or with allopurinol increasing the risk of infections. 36 Ang II Receptors 37 Renal Effects Efferent arterioles predominantly express the AT1 Ang receptor. AT2 AT1 Afferent arterioles predominantly express the AT2 Ang receptor. 38  ACE Inhibitors Concern 2 Decline in renal function The effect on kidneys is reversible and depends on the status of the renal function at the start of therapy. ACE inhibitors should not be withheld but dosages should be carefully titrated, with monitoring of renal function and serum potassium levels. Consider significant hyperkalemia with concomitant use of potassium sparing diuretics. 39  ACE Inhibitors CIs o Patients with pre-existing bilateral renal artery stenosis, ESRD, or nephrosclerosis. N.B. Patients with acute volume loss due to vomiting or diarrhea may be particularly susceptible to demonstrate kidney impairment. o Pregnancy and lactation (X). o Patients with hereditary or idiopathic angioedema. o NSAIDs attenuate their antihypertensive effect (why?) 40  Ang II Receptors Blockers Losartan and valsartan were the first marketed ARBs. Azilsartan, candesartan, irbesartan, olmesartan, telmisartan and eprosartan. Selectively bind to and inhibit the Ang II AT1 receptors in VSMCs, adrenal cortex, kidney and heart abolishing the effects of Ang II on these tissues: Blood vessels: Vasodilatation   TPR. They also  Ang II- mediated VSMCs hypertrophy   vascular remodeling. Adrenal cortex:  aldosterone secretion   blood volume. Heart:  Ang II-mediated myocardial hypertrophy   cardiac remodeling. 41  ARBs Indications Indicated to treat HTN, congestive heart failure, and diabetic nephropathy. Valsartan is approved for pediatric HTN in patients > 6 years. They are often used as an ACE inhibitor therapy replacement for patients who cannot tolerate the cough or angioedema of ACE inhibitors. 42  ARBs vs ACE Inhibitors More selective blockers of Ang II effects than ACE inhibitors. Do not affect the bradykinin. More hypotensive symptoms than ACE inhibitors, hyperkalemia, and renal insufficiency. Less cough and angioedema (why ??). Contraindications are the same as ACE inhibitors. 43  ARBs vs ACE Inhibitors In diabetic patients, ACE inhibitors are more nephroprotective and safer than ARBs ?? Benefits similar to ACE inhibitors in patients with HF and CKD. Combination of both is not recommended (recent recommendation). As a conclusion, they are alternative to ACE inhibitors in case not tolerated. 44  RAAS Inhibitors Advantages Special benefit in case of HTN with high plasma renin activity. Either as monotherapy or in multiple drug regimen. Suitable for HTN associated with diabetes, asthma, angina, or HF. Prescribed to both young and elderly. Highly tolerated: — No edema or significant electrolyte imbalance. — Rare postural hypotension. 45  RAAS Inhibitors Monitoring Renal function and electrolytes need to be checked regularly due to the effects of the drugs on the RAAS. For patients with increasing potassium, drop in GFR, or increasing creatinine, the drug needs to be adjusted accordingly or discontinued. For patients who are on diuretics, correct volume depletion before starting these agents. Pay attention to the K+ supplementation with diuretics. 46