Basic pharmacology of antianginal drugs

Discussing the use of antianginal drugs for ischemic heart disease, which is myocardial damage caused by impaired blood flow through coronary arteries.

The coronary circulation in normal conditions involves the division of each coronary artery into two branches: subendocardial and subepicardial. These branches supply corresponding zones of the myocardium, with upper branches connecting to lateral vessels. Collateral vessels serve as backups when blood flow is insufficient, redistributing blood through shunting if one branch experiences inadequate flow due to atherosclerosis.

Coronary blood flow can become insufficient, leading to ischemic heart disease which manifests as acute or chronic. Acute ischemic heart disease includes myocardial infarction and unstable angina, collectively termed acute coronary syndrome. Chronic ischemic heart disease often presents as stable angina or is also known as chest frog (angina pectoris). The term 'anti-anginal' refers to drugs used for stable angina treatment.

Understanding Stable Angina Pectoris Stable angina pectoris, a manifestation of myocardial ischemia, presents as attacks that are more stable depending on the underlying cause. It can be classified into tension angina, vasospastic angina, and microvascular angina. Tension angina occurs during physical exertion or emotional stress and disappears at rest.

Distinguishing Features of Stable Anginas The clear dependence of stable angina attacks on physical exertion or emotional stress is a key differential diagnostic criterion for this form. Vasospastic anginas mainly occur at night or in the early morning with short durations lasting usually from two to five minutes.

Understanding Myocardial Oxygen Demand The mismatch between myocardial oxygen demand and delivery leads to ischemic chest pain. The heart's oxygen demand is mainly determined by two parameters: heart function dependent on the rate and force of contractions, and cardiac workload represented by pre- and post-load. Oxygen delivery to the myocardium depends on coronary vessel tone; higher tone reduces oxygen supply.

Metabolic Regulation in Cardiac Function Regulation of energy consumption in the heart involves cyclic adenosine monophosphate (cAMP) metabolism. Increased cAMP levels enhance cardiac contraction frequency and strength through macroergic phosphate utilization. Inadequate oxygen supply due to mechanical obstruction can lead to adenosine accumulation, dilating coronary vessels but failing during high-demand situations like physical activity or stress.

Balancing Oxygen Delivery to the Myocardium The need and delivery of oxygen to the myocardium are crucial for maintaining a balance between myocardial oxygen demand and supply. Antianginal drugs act to achieve this balance by affecting coronary vessel tone, which influences oxygen delivery. Myocardial oxygen demand depends mainly on heart function (heart rate and contractility) and preload/postload pressures.

Factors Affecting Oxygen Delivery Oxygen delivery to the myocardium is influenced by coronary vessel tone; decreased tone increases delivery. Myocardial oxygen demand primarily relies on heart function (rate/contractility) & preload/postload pressures, affected by venous capacitance vessels' tonus.

Classification of Antianginal Drugs Based on Oxygen Effects Antianginal drugs are classified based on their effects on oxygen delivery to the myocardium and the myocardial oxygen demand. They can be grouped into those that reduce myocardial oxygen demand, increase oxygen delivery to the heart, or combine both mechanisms. Beta-adrenergic blockers like atenolol and metoprolol belong to drugs that decrease myocardial oxygen demand.

Mechanisms of Action in Antianginal Medications Different antianginal medications act through various mechanisms such as increasing cardiac oxygen supply (e.g., dipyridamole) or reflex action (e.g., validol). Organic nitrates like nitroglycerin fall under drugs that enhance heart's oxygen delivery while reducing its need for oxygen. Calcium channel blockers include verapamil and diltiazem in one group and nifedipine and amlodipine in another; they have different actions but share a common goal of affecting calcium channels.

Beta-adrenergic blockers can be classified based on several criteria such as generation, selectivity towards beta-adrenoceptors, lipophilicity, vasodilation properties, and pharmacokinetic characteristics. The classification includes multiple generations: non-selective first-generation blockers like propranolol; cardio-selective second-generation drugs like atenolol and metoprolol; and third-generation blockers with additional vasodilatory effects such as carvedilol.

Impact of Beta-Adrenergic Blockers on Cardiomyocytes Beta-adrenergic blockers have a significant effect on the heart by acting on different types of cardiomyocytes. Atypical cardiomyocytes in the sinus node differ from typical ones in their impulse generation and conduction system effects. These blockers reduce heart rate, contractility strength, and myocardial excitability.

Cellular Effects of Beta-Adrenergic Blockers The mechanism of action at the cellular level involves activation of adrenoceptors leading to calcium concentration increase or hyperpolarization through specific channels. Blocking beta 1 adrenoceptors disrupts cyclic processes affecting calcium channels' function and potential depolarization phases, ultimately reducing intracellular calcium concentrations.

Beta-adrenergic blockers reduce the frequency and force of heart contractions, leading to decreased cardiac workload. This results in a reduced oxygen demand by the myocardium.

Understanding Vasodilatory Mechanisms of Beta-Adrenergic Blockers Beta-adrenergic blockers with additional vasodilatory properties have antianginal effects. The mechanisms of vasodilation involve calcium-dependent smooth muscle tone increase and alpha-1 adreceptor stimulation leading to vessel relaxation. Endothelial nitric oxide is a key factor in relaxing blood vessels by activating cyclic guanosine monophosphate.

Effects of Carvedilol and Nebivolol on Vascular Function Carvedilol acts as an antagonist to alpha-adrenoreceptors, disrupting inositol phosphate signaling for smooth muscle contraction inhibition. Nebivolol selectively blocks beta 1 receptors and may enhance nitric oxide release from endothelium through potential beta 3 receptor stimulation.

Physicochemical Properties of Beta-Blockers Beta-blockers have physicochemical properties that enhance vasodilation in dependent individuals. They can be classified into hydrophilic like atenolol and lipophilic like propranolol, metoprolol, nebivolol, and carvedilol. Amphiphilic beta-blockers exhibit both hydrophilic and lipophilic characteristics.

Hydrophilicity of Beta-Blockers Hydrophilic beta-blockers are incompletely absorbed in the gastrointestinal tract due to their poor penetration through barriers such as the blood-brain barrier. Their bioavailability ranges from 30% to 70%, with atenolols around 50%. These drugs are mainly excreted unchanged by the kidneys.

Lipophilicity of Beta-Blocker Lipophilic beta-blockers are rapidly absorbed in the gastrointestinal tract but have lower bioavailability compared to hydrophilics (10%-40%). The first-pass effect through liver metabolism reduces their bioavailability further. Bisoprolols demonstrate moderate accessibility with a dual elimination pathway via kidneys (50%) and hepatic metabolism.

Beta-blockers are considered a first-line treatment for stable angina, especially effective during sympathetic nervous system activation like physical exertion or emotional stress. They can increase coronary vessel tone but should be avoided in vasospastic angina as they may worsen the condition by redistributing blood flow unfavorably.

Beta-blockers influence coronary circulation by affecting the tone of coronary vessels. Atherosclerotic plaque in the vessels can obstruct blood flow, leading to insufficient perfusion. Adenosine accumulation causes vasodilation, reducing resistance and increasing perfusion; however, beta-blockers do not affect vessel tone in areas with high adenosine levels.

Beta-adrenergic blockers have typical side effects such as bradycardia, reduced force of cardiac contractions, and atrioventricular conduction disturbances. Additionally, they can lead to lowered blood pressure and increased smooth muscle tone in bronchi and peripheral vessels. Lipophilic beta-blockers may induce depression through the blockade of beta-2 adrenoceptors.

Understanding Ivabradine Mechanism of Action Ivabradine acts on the brain's trophic factor, particularly in neurons of the cortex and hippocampus. It blocks HCN channels in the sinus node, reducing heart rate by decreasing automaticity. By inhibiting sodium currents through these channels, it slows down phase four depolarization, leading to decreased heart rate without affecting contractile force.

Clinical Applications and Side Effects Ivabradine selectively reduces heart rate without impacting myocardial contractility or oxygen demand. Its main side effects include visual disturbances like phosphenes observed in around 14% of patients initially taking it. The drug can also cause bradycardia and headaches but is a suitable alternative to beta-blockers for stable angina or heart failure when beta-blockers are contraindicated or ineffective.

Mechanism of Action and Calcium Exchange Ranolazine acts by inhibiting late sodium ion currents in cardiomyocytes, reducing their contractility. The exchange of calcium ions in the cell occurs through a two-mode exchanger: direct mode and reverse mode depending on intracellular calcium concentrations.

Effects on Cardiomyocytes The operation of the three-ring exchanger depends on action potential and concentration gradients of sodium and calcium ions inside/outside the cell. Ranolazine shifts this exchanger to work in reverse during depolarization, leading to increased intracellular calcium levels that enhance myocardial contraction efficiency.

Organic nitrates are rarely developed and can cause side effects like headaches, dizziness, constipation, nausea, vomiting, and weakness. The main representatives include nitroglycerin derived from sorbitol esters and isosorbide mononitrate. They promote the accumulation of cyclic guanosine monophosphate in smooth muscle cells leading to relaxation of blood vessel walls and internal organ muscles.

Mechanism of Vasodilatory Effect of Organic Nitrates Organic nitrates like nitrate act as vasodilators by affecting the smooth muscle cells of blood vessels. The mechanism involves calcium influx, formation of a complex with myosin light chain kinase, and activation of protein kinases leading to smooth muscle relaxation.

Bioactivation and Sensitivity to Organic Nitrates Bioactivation occurs directly in the smooth muscle cells through mitochondrial aldehyde dehydrogenase 2 type under the influence of nitroglycerin. Nitroglycerin releases nitric oxide which further forms S-nitrothiol causing vessel relaxation. Variations in aldehyde dehydrogenase 2 type gene can impact sensitivity to organic nitrates.

Organic nitrates have a complex mechanism of action in providing antianginal effects by primarily dilating veins, reducing venous return and preload. They also decrease the tone of resistance arteries, lowering overall peripheral resistance and post-load on the heart.

Organic nitrates influence coronary blood flow by dilating large coronary vessels and collaterals, enhancing oxygen delivery to the myocardium. They redistribute coronary blood flow in favor of ischemic areas due to their vasodilatory effects on larger vessels without affecting small ones.

Application of Organic Nitrates in Stable Angina Treatment Organic nitrates are used in the treatment of stable angina. Short-acting nitrates like nitroglycerin and isosorbide dinitrate are applied sublingually to relieve episodes of stable angina quickly. Nitroglycerin acts faster within 1-3 minutes, while isosorbide dinitrate takes effect after 3-4 minutes lasting up to 2 hours due to its metabolites formation.

Use of Extended-release Organic Nitrates Extended-release nitrates such as nitroglycerin, isosorbide dinitrate, and sorbitol nitrate are mainly used for preventing episodes of stable angina but considered second-line therapy compared to beta-blockers due to tolerance development and endothelial dysfunction. Prolonged organic nitrates can be administered orally or transdermally for stable vasospastic angina along with additional calcium channel blockers therapy when needed.

Organic nitrates have side effects in acute myocardial infarction, limiting necrosis zone. One common side effect is orthostatic hypotension, which can be prevented by proper administration techniques like sitting while taking them to avoid orthostatic hypotension when taken standing or lying down.

Understanding Tolerance Mechanisms to Organic Nitrates Organic nitrates can be safe based on tolerance mechanisms, involving various vascular and cardiac processes. True tolerance may occur when these mechanisms are not related to changes in myocardial cells or endothelial function but rather the activation of other systems like the renin-angiotensin-aldosterone system.

Mechanisms Behind True Tolerance Development Mechanisms of true tolerance include impaired bioactivation of organic nitrates due to depletion of sulfhydryl groups in enzyme active centers, leading to disrupted regeneration and subsequent bioactivation failure in smooth muscle vessels. Additionally, increased phosphodiesterase activity contributes to cyclic guanosine monophosphate breakdown into an inactive metabolite.

Strategies Against Nitrate Tolerance Oxidative stress from nitrate use accumulates reactive oxygen species in vessel smooth muscles, disrupting mitochondrial function and enzyme activities responsible for organic nitrate bioactivation. Activation of the renin-angiotensin-aldosterone system leads to water retention hindering hemodynamic effects; strategies like intermittent dosing or co-administration with certain agents aim at reducing this risk.

Molsidomine, an inhibitor of angiotensin 2 receptor blockers, is used as a convenient alternative to organic nitrates in cases of contraindications or poor tolerance. It can also be used when there is already tolerance to the effects of organic nitrates. The drug is less likely to cause tolerance issues and is effective for preventing angina attacks.

Calcium channel blockers are classified based on their chemical structure into hydrazine pyridine derivatives. These blockers primarily affect vascular channels more than cardiac channels, with drugs like nifedipine and amlodipine belonging to this category. The distinguishing feature of these medications is that their names end in 'pine,' indicating their action on vascular channels.

Mechanism of Action: Calcium Channels and Muscle Contraction BMKK mechanism of action involves the calcium-dependent contraction of smooth muscles due to calcium accumulation in the cytoplasm, leading to muscle contraction. Slow calcium channel blockers inhibit the entry of calcium into cells, disrupting smooth muscle contraction and causing vasodilation. These blockers also affect other smooth muscle cells in internal organs.

Impact on Blood Vessels: Vasodilation Effects Blockers directly block slow calcium channels, preventing calcium influx into cells and resulting in relaxation of smooth muscles including blood vessels. They impact resistive and coronary vessels by dilating them but do not affect capacitance vessels.

Effects on Cardiomyocytes: Contractions Reduction In atypical cardiomyocytes, slow channel blocker effects are similar to beta-adrenergic blockers but act through direct blockade rather than indirect mechanisms like beta-blockers. The drugs reduce cardiac contractions' strength by inhibiting ion flow through L-type channels specifically affecting typical cardiomyocytes.

BMKK mechanism of action involves inducing reflex tachycardia. Hydra pyridine and calcium channel blocker primarily affect the resistance vessel tone, reducing overall peripheral vascular resistance. This leads to decreased afterload and myocardial oxygen demand.

Optimizing Oxygen Delivery and Blood Pressure Regulation with BMKKs BMKK pharmacokinetics enhance oxygen delivery to the heart. Calcium channel blockers like nifedipine have a short half-life leading to significant drop in blood pressure, sympathetic nervous system activation, and tachycardia. Prolonged-release forms of nifedipine or other long-acting calcium channel blockers are preferred for angina therapy.

Metabolism Modulation for Calcium Channel Blockers Calcium channel blocker metabolism involves hepatic enzymes affecting drug efficacy. Inducers of hepatic enzymes accelerate their metabolism while inhibitors like verapamil potentiate their effects by inhibiting microsomal liver enzymes and P-glycoprotein.

The use of calcium channel blockers like verapamil in IBS treatment can be effective for tension angina and vasospastic angina due to their anti-hypertensive and antiarrhythmic effects. They are also beneficial for arterial hypertension and supraventricular tachycardia, belonging to the antiarrhythmic class.

Side Effects of BMKK and Beta-Blockers BMKK side effects combine with beta-blockers. Calcium channel blockers have distinct side effects, making them recognizable. These effects include headaches, dizziness, heart palpitations, and increased risk of myocardial ischemia.

Categorization of Side Effects The side effects are categorized into groups based on duration of action: short-acting hydra pyridines exhibit rapid absorption leading to quick concentration peaks in the blood plasma but also sharp drops in blood pressure shortly after administration. Long-acting hydra pyridines show smoother absorption patterns allowing gradual peak concentrations and elimination from the body without drastic fluctuations.

Nicorandil acts as a dual mechanism antianginal agent by activating potassium channels in cardiac myocytes, leading to membrane depolarization and calcium channel closure. This results in smooth muscle relaxation and decreased calcium influx into the cells. It also exhibits nitrate-like effects through cyclic GMP-dependent protein kinase activation, promoting intracellular calcium sequestration.

Dipyridamole affects adenosine levels by inhibiting a metabolic enzyme, leading to coronary vessel dilation. It is primarily used for diagnosing ischemic heart disease through a pharmacological stress test. The drug induces coronary steal phenomenon where healthy vessels dilate further but already dilated vessels in the ischemic area reach their limit.