Pharmacokinetics Notes - KCP 1 Response to Xenobiotics PDF

Pharmacokinetics - Pharmacology Major Drug Permeation and Disposition Processes and Factors Affecting Them: - Drug permeation and disposition processes include absorption, distribution, metabolism, and excretion. - Factors affecting drug permeation and disposition include: - Physic...

Pharmacokinetics - Pharmacology Major Drug Permeation and Disposition Processes and Factors Affecting Them: - Drug permeation and disposition processes include absorption, distribution, metabolism, and excretion. - Factors affecting drug permeation and disposition include: - Physicochemical properties of the drug (e.g., molecular weight, lipophilicity, charge) - Blood flow to target tissues - Protein binding - Membrane barriers - Presence of efflux transporters First Pass Metabolism and Bioavailability and Factors Affecting Them: - First pass metabolism refers to the metabolism of a drug before it reaches the systemic circulation. - Bioavailability is the fraction of the drug that reaches systemic circulation unchanged after administration. - Factors affecting first pass metabolism and bioavailability include: - Hepatic metabolism and enzyme activity - Gut wall metabolism - Intestinal and hepatic blood flow - Drug formulation and route of administration - Interactions with food or other drugs Effect of Plasma Protein Binding on Drug Distribution, Redistribution, and Enterohepatic Circulation: - Plasma protein binding affects the distribution of drugs in the body. - Bound drugs have limited distribution, while unbound (free) drugs are available for tissue uptake and action. - Protein binding also influences a drug\'s ability to redistribute within the body and undergo enterohepatic circulation. - Enterohepatic circulation refers to the recycling of drugs between the liver and the intestine via bile. Two Main Phases of Biotransformation and Their Clinical Significance: - Biotransformation involves the enzymatic modification of drugs into metabolites. - Phase I biotransformation involves oxidation, reduction, or hydrolysis reactions. - Phase II biotransformation involves conjugation reactions, where metabolites are attached to endogenous compounds. - The clinical significance of biotransformation includes: - Inactivation or activation of drugs - Formation of active or toxic metabolites - Drug-drug interactions - Variability in drug response Processes Involved in Excretion of Drugs and Their Clinical Significance: - Excretion refers to the elimination of drugs and their metabolites from the body. - Major excretion routes include renal (urine), biliary (feces), and pulmonary (breath) excretion. - Clinical significance of drug excretion: - Determines the duration of drug action - Influences dosing intervals and therapeutic drug monitoring and toxicity 1. Definition of Pharmacokinetic Parameters using One and Two-Compartment Models: - Bioavailability: The fraction of a drug that reaches systemic circulation unchanged after administration. It represents the extent of drug absorption. - Volume of Distribution (Vd): The theoretical volume that would be necessary to contain the total amount of drug in the body at the same concentration as in the plasma. It describes the apparent distribution of a drug in the body. - Clearance (Cl): The rate at which a drug is eliminated from the body, usually expressed as the volume of plasma cleared of the drug per unit of time. - Elimination Half-life (t1/2): The time required for the concentration of a drug in the body to decrease by half during the elimination phase. It represents the rate at which a drug is removed from the body. 2. Correlation between Vd, t1/2, and Cl and Factors Influencing Them: - Volume of Distribution (Vd): Vd is directly related to the extent of drug distribution within the body. Factors influencing Vd include tissue binding, lipid solubility, plasma protein binding, and drug distribution barriers. - Elimination Half-life (t1/2): t1/2 is inversely related to the rate of drug elimination. Factors influencing t1/2 include drug metabolism and clearance mechanisms. - Clearance (Cl): Cl is directly related to the rate of drug elimination from the body. Factors influencing Cl include hepatic and renal function, enzymatic activity, and drug-drug interactions. 3. First and Zero Order Kinetics and Their Clinical Significance: - First-order kinetics: Drug elimination occurs at a constant fraction (percentage) of the drug concentration per unit of time. Most drugs follow first-order kinetics, where elimination is proportional to drug concentration. The elimination half-life remains constant in first-order kinetics. - Zero-order kinetics: Drug elimination occurs at a constant amount (fixed rate) regardless of drug concentration. This occurs when drug elimination mechanisms are saturated or overwhelmed. In zero-order kinetics, the elimination half-life increases with increasing drug concentration. It is clinically significant when high drug concentrations lead to accumulation and potential toxicity. 4. - Bioequivalence: Bioequivalence refers to the similarity in bioavailability of two formulations of the same drug. Two formulations are considered bioequivalent if they show comparable rate and extent of absorption. - Clinical significance of bioequivalence: Bioequivalence is important for generic drugs, as it ensures that generic formulations produce similar drug concentrations in the body compared to the reference (innovator) drug. This allows for substitution between the generic and reference drug without compromising therapeutic efficacy or safety. Bioequivalence studies are conducted to support generic drug approvals and provide confidence in their clinical use. ### Applied Pharmacodynamics Pharmacodynamics: How drugs exert their effects on the body. It involves understanding the mechanisms underlying drug actions. Receptor: Proteins that bind to specific molecules called ligands located on the surface or within cells. The binding of ligands to receptors triggers cellular responses. Endogenous Ligand: Naturally occurring substances in the body that bind to receptors and produce biological responses (hormones, neurotransmitters, and cytokines) Drug-Receptor Interactions: Occurs when drugs bind to receptors. This binding can activate or inhibit the receptor\'s function leading to changes in cellular signaling pathways and physiological responses. Agonist: Drugs that bind to receptors and activate them to produce a biological response. Antagonist: Drugs that bind to receptors but do not activate them blocking other molecules from activating the receptor, preventing their effects. Partial Agonist: Binds to receptors and produce a weaker response compared to full agonists. Inverse Agonist: Binds to receptors and induce the opposite effect to agonists decreasing the constitutive activity of the receptor, producing a negative response. Mechanisms of Drug Action: - Receptors: Drugs can bind to receptors and modulate their activity, influencing cellular signaling pathways and physiological responses. - Carriers: Drugs can act as substrates or inhibitors of carrier proteins, affecting the transport of endogenous substances across cell membranes. - Ion Channels: Drugs can modulate the opening or closing of ion channels, regulating the flow of ions across cell membranes and altering electrical signaling. - Enzymes: Drugs can interact with enzymes, either inhibiting or enhancing their activity, leading to modulation of biochemical reactions and cellular processes. Types/Families of Receptors: - G protein-coupled receptors: Cell surface receptors that activate intracellular signaling pathways through interactions with G proteins. - Ligand-gated ion channels: Membrane proteins that open in response to ligand binding, allowing ions to pass through and generating an electrical signal. - Enzyme-linked receptors: Cell surface receptors with built-in enzymatic activity. - Nuclear receptors: Intracellular receptors that bind to DNA and regulate gene expression in response to ligand binding. Receptor Regulation and Functions: - Receptor regulation involves the modulation of receptor expression, trafficking, and sensitivity in response to various factors. - Receptors play crucial roles in cell-to-cell communication, maintaining homeostasis, and controlling physiological processes. - They are targets for therapeutic interventions. Dose-Response Curve and Features of a Normal Dose-Response Curve: - A dose-response curve illustrates the relationship between the dose of a drug and the magnitude of its effect. - A normal dose-response curve typically exhibits the following features: - Threshold: The minimum dose required to elicit a detectable response. - Slope: The steepness of the curve, indicating the sensitivity to changes in dose. - Maximum Effect (Emax): The peak response achieved at high doses. - Variability: Individual differences in response due to factors like genetics, physiology, and disease. Graded Dose-Response Curve: - A graded dose-response curve quantifies the magnitude of response as the drug dose increases. - It shows a continuous and graded increase or decrease in response with increasing dose. - The curve is useful for comparing the effectiveness of different doses of a drug in an individual. Quantal Dose-Response Curve: - A quantal dose-response curve categorizes the response into a binary (yes/no) outcome. - It depicts the proportion of individuals in a population that exhibit a specific response at different doses. - The curve is useful for determining the effective dose (ED50) or lethal dose (LD50) in a population. Affinity, Spare Receptors, ED50, LD50, and TD50: - Affinity: Affinity refers to the strength of binding between a drug and its receptor. It determines the likelihood of drug-receptor interaction. - Spare Receptors: Spare receptors are receptors present in excess of what is needed for maximum response. Even when some receptors are occupied, maximum response can still be achieved. - ED50: The effective dose (ED50) is the dose of a drug that produces a therapeutic effect in 50% of the population or individuals. - LD50: The lethal dose (LD50) is the dose of a drug that causes death in 50% of the population or individuals. - TD50: The toxic dose (TD50) is the dose of a drug that produces a toxic effect in 50% of the population or individuals. Types of Antagonism: - Competitive Antagonism: Competitive antagonists bind to the same receptor site as the agonist, competing for binding. Increasing the concentration of the agonist can overcome the antagonism. - Non-competitive Antagonism: Non-competitive antagonists bind to a different site on the receptor or alter the receptor\'s function, preventing the agonist from producing a response. Interpretation of Dose-Response Curve for Agonist, Partial Agonist, and Antagonist: - Agonist: An agonist produces a dose-dependent increase in response, reaching a maximum effect (Emax) at high doses. - Partial Agonist: A partial agonist produces a dose-dependent increase in response, but the maximum effect achieved is lower (partial) compared to a full agonist. - Antagonist: An antagonist does not produce a response but can block or reduce the response produced by an agonist. Clinical Implication of Administering a Partial Agonist following a Full Agonist: - Administering a partial agonist following a full agonist can result in reduced overall drug efficacy. The partial agonist may compete with the full agonist for receptor binding, leading to diminished activation and a suboptimal therapeutic response. Efficacy and Potency of Drugs: - Efficacy: Efficacy refers to the maximum effect or response that a drug can produce. It indicates the therapeutic benefit. - Potency: Potency refers to the dose or concentration of a drug required to produce a specific effect. It reflects the drug\'s strength or activity. Therapeutic Index and Its Clinical Significance: - Therapeutic Index (TI) is a measure of a drug\'s safety margin. It is the ratio of the lethal dose (LD50) to the effective dose (ED50). - A higher therapeutic index indicates a wider margin of safety, meaning the drug is less likely to cause toxic effects at therapeutic doses. A lower therapeutic index raises concerns about potential toxicity and requires careful dosing and monitoring. ### Clinical pharmacokinetics Plasma Concentration-Time Curve After Oral and IV Dose and Factors Affecting It: - After an oral dose, the plasma concentration-time curve typically shows a gradual increase as the drug is absorbed from the gastrointestinal tract, reaching a peak concentration (Cmax) at a variable time (Tmax). The curve then gradually declines as the drug is metabolized and eliminated. - Factors affecting the plasma concentration-time curve include the rate and extent of absorption, route of administration, dose, and formulation. - Rate of absorption: Faster absorption leads to a steeper rise in plasma concentration and an earlier Tmax. - Extent of absorption: Higher absorption leads to a higher Cmax and a larger area under the curve (AUC), representing the total exposure to the drug. - Route of administration: Different routes may have varying absorption rates and bioavailability, affecting the shape of the curve. - Dose: Higher doses generally result in higher peak concentrations and longer durations of action. - Formulation: Different formulations (e.g., immediate-release, extended-release) can alter the rate and duration of drug release, affecting the shape of the curve. Plasma Concentration-Time Curve After Repeated Dose and Steady State Concentration: - After repeated oral or IV infusion doses, the plasma concentration-time curve reaches a steady state. This is when the rate of drug administration equals the rate of elimination. - Initially, the plasma concentration rises with each dose until it reaches a steady state, typically after 4-5 half-lives. - At steady state, the plasma concentration fluctuates within a narrow range around a steady-state concentration (Css), reflecting a balance between drug input and elimination. Effect of Dose and Half-life on Steady State Concentration: - Higher doses result in higher steady-state concentrations, as more drug is being administered. - Longer half-lives allow for a longer time to reach steady state and result in higher steady-state concentrations. Conversely, shorter half-lives reach steady state more quickly and have lower steady-state concentrations. Importance, Use, and Methods for Calculating Loading and Maintenance Dose: - Loading dose: A loading dose is used to rapidly achieve a desired therapeutic concentration of a drug. It is calculated based on the desired steady-state concentration (Css), volume of distribution (Vd), and bioavailability. - Maintenance dose: The maintenance dose is used to maintain a desired steady-state concentration over time. It is calculated based on the desired steady-state concentration (Css), clearance (Cl), and dosing interval. - Loading and maintenance doses are important in situations where immediate therapeutic effects are needed and to maintain effective drug concentrations over time. - Calculation methods include: - Loading dose = Vd × Css / F (F is bioavailability) - Maintenance dose = Css × Cl × τ (τ is dosing interval) ### Drug toxicity and ADR  Drug Toxicity: Drug toxicity refers to the harmful effects caused by the administration of a drug or medication. It occurs when the concentration or duration of exposure to a drug exceeds the body\'s tolerance or leads to adverse effects. Factors Influencing Drug Toxicity: 1. Dose: Higher doses of a drug can increase the likelihood of toxicity. 2. Duration of Exposure: Prolonged exposure to a drug can increase the risk of toxicity. 3. Individual Variability: Factors such as age, genetics, underlying health conditions, and concurrent medication use can influence an individual\'s susceptibility to drug toxicity. 4. Metabolism and Elimination: Impaired drug metabolism and elimination can result in drug accumulation and increased toxicity. 5. Route of Administration: Different routes of administration can affect drug absorption, distribution, metabolism, and elimination, potentially impacting drug toxicity. Tests Used to Determine General Toxicity and Specific Toxicity: 1. General Toxicity: General toxicity tests assess the overall toxic effects of a drug on various organs or systems in animal models, such as acute toxicity tests or subchronic toxicity tests. 2. Specific Toxicity: Specific toxicity tests focus on evaluating the toxicity of a drug to specific organs or systems, such as cardiac toxicity, hepatic toxicity, nephrotoxicity, or neurotoxicity. Adverse Drug Reactions (ADR): - Adverse Drug Reactions (ADRs) are unintended and harmful effects that occur as a result of drug therapy. - They can be classified into different types: - Type A (Augmented): Predictable, dose-dependent reactions related to the known pharmacological actions of the drug. - Type B (Bizarre): Unpredictable reactions that are not related to the known pharmacological actions of the drug. - Type C (Chronic): Reactions occurring after prolonged drug use. - Type D (Delayed): Reactions occurring after a significant time period from drug exposure. - Type E (End-of-treatment): Reactions occurring upon discontinuation of a drug. - Type F (Failure): Lack of therapeutic response or ineffectiveness of a drug. Risk Factors for Development of ADRs: - Individual factors: Age, genetics, underlying health conditions, and impaired organ function. - Polypharmacy: Concurrent use of multiple medications increases the risk of drug interactions and adverse effects. - Drug-related factors: Drug properties, dosing regimen, and route of administration can influence the occurrence of ADRs. Pharmacodynamics and Pharmacokinetic Basis of Drug Interactions: - Pharmacodynamics: Drug interactions affecting pharmacodynamics involve alterations in the drug\'s effects on the body, such as receptor interactions, enzyme inhibition, or modulation of signaling pathways. - Pharmacokinetics: Drug interactions affecting pharmacokinetics involve alterations in the drug\'s absorption, distribution, metabolism, or elimination, resulting in changes in its concentration and duration of action. Pregnancy Risk Categories of Drugs: - Pregnancy risk categories classify drugs based on their potential risks to the fetus during pregnancy: - Category A: Adequate and well-controlled studies in pregnant women have not shown any risk to the fetus. - Category B: Animal studies have not demonstrated fetal risk, but there are no well-controlled studies in pregnant women. - Category C: Animal studies have shown adverse effects on the fetus, but there are no well-controlled studies in pregnant women, or studies in pregnant women are lacking. - Category D: Positive evidence of fetal risk exists, but potential benefits may outweigh the risks in certain situations. - Category X: Studies in animals or humans have demonstrated fetal abnormalities or risks, and the risks outweigh any potential benefits. These drugs should not ### Autonomic nervous system Divisions of the Nervous System: - The nervous system is divided into two main divisions: the central nervous system (CNS) and the peripheral nervous system (PNS). - The PNS further divides into the somatic nervous system (SNS) and the autonomic nervous system (ANS). Parasympathetic and Sympathetic Outflows: - The parasympathetic and sympathetic divisions are two branches of the ANS. - Parasympathetic Outflow: - Spinal Cord Division of Origin: Craniosacral; originates from the brainstem (cranial nerves) and the sacral region (S2-S4) of the spinal cord. - Length of Preganglionic and Postganglionic Neurons: Long preganglionic neurons and short postganglionic neurons. - Neurotransmitter: Acetylcholine (ACh) is released by both preganglionic and postganglionic neurons. - Receptors at the Ganglionic and Target Organ Synapse: Ganglionic synapse uses nicotinic receptors, and target organs have muscarinic receptors. - Sympathetic Outflow: - Spinal Cord Division of Origin: Thoracolumbar; originates from the thoracic (T1-T12) and lumbar (L1-L3) regions of the spinal cord. - Length of Preganglionic and Postganglionic Neurons: Short preganglionic neurons and long postganglionic neurons. - Neurotransmitter: ACh is released by preganglionic neurons, while norepinephrine (NE) is released by postganglionic neurons (exception: sweat glands use ACh). - Receptors at the Ganglionic and Target Organ Synapse: Ganglionic synapse uses nicotinic receptors, and target organs have adrenergic receptors (alpha and beta receptors). Major Control Centers of the ANS in the Central Nervous System: - Hypothalamus: Plays a crucial role in regulating and integrating autonomic functions. - Brainstem: Contains nuclei involved in autonomic regulation, including the medulla, pons, and midbrain. Examples of Sympathetic and Parasympathetic Involvement: - Sympathetic Involvement: Fight-or-flight response, stress response, increased heart rate, dilation of the pupils, bronchodilation, increased BP, decreased gastrointestinal motility. - Parasympathetic Involvement: Rest-and-digest response, relaxation, decreased heart rate, constriction of the pupils, increased gastrointestinal motility, bladder contraction. Effects of Abnormal ANS Activity or Lack of Activity: - Abnormal ANS activity can result in various disorders, such as: - Autonomic neuropathy: Dysfunction of the autonomic nerves leading to impaired regulation of bodily functions. - Orthostatic hypotension: A drop in BP upon standing, resulting in dizziness or fainting. - Excessive sweating: Hyperhidrosis or anhidrosis (lack of sweating) due to dysregulation of sweat glands. - Urinary and bowel dysfunction: Problems with bladder control, constipation, or diarrhea due to disrupted ANS control. - Cardiovascular disorders: Irregular heart rate, BP abnormalities, or abnormal cardiovascular responses. ### Direct acting cholinergic drugs and anticholinesterases Classification of Drugs Acting on the Parasympathetic Nervous System: Direct Acting Cholinomimetics: - Choline esters: Acetylcholine, Methacholine - Alkaloids: Pilocarpine Indirect Acting Cholinomimetics: - Reversible: Edrophonium, Physostigmine, Neostigmine - Irreversible: Organophosphorous compounds (e.g., parathion, malathion) Mechanism of Action, Pharmacological Effects, and Therapeutic Uses of Direct Acting Cholinergic Drugs and Anticholinesterases: Direct Acting Cholinergic Drugs: - Mechanism of Action: Directly activate muscarinic receptors. - Pharmacological Effects: - Miosis (pupillary constriction) - Bronchoconstriction - Increased glandular secretions - Decreased heart rate - Increased gastrointestinal motility - Therapeutic Uses: - Acetylcholine and Methacholine: Primarily used in research and diagnostic procedures. - Pilocarpine: Used in ophthalmology for miosis induction and to increase salivary gland secretions in conditions like Sjogren\'s syndrome. Anticholinesterases: - Mechanism of Action: Inhibit the enzyme acetylcholinesterase (AChE), leading to increased acetylcholine levels and enhanced cholinergic transmission. - Pharmacological Effects: - Prolonged stimulation of muscarinic and nicotinic receptors in the parasympathetic nervous system. - Therapeutic Uses: - Edrophonium: Used for the diagnosis of myasthenia gravis. - Physostigmine and Neostigmine: Used to treat myasthenia gravis, postoperative urinary retention, and to reverse the effects of certain muscle relaxants. Common Adverse Effects and Contraindications of Direct Acting Cholinergic Drugs and Anticholinesterases: - Adverse Effects: - Excessive salivation - Sweating - Bronchoconstriction - Bradycardia (slow heart rate) - Gastrointestinal disturbances (e.g., nausea, vomiting, diarrhea) - Contraindications: - Asthma or chronic obstructive pulmonary disease (COPD) - Bradycardia or heart block - Peptic ulcer disease - Urinary tract obstruction Pharmacological Basis of Symptoms and Treatment of Organophosphorus and Mushroom Poisoning: - Organophosphorus Poisoning: - Mechanism: Organophosphorus compounds irreversibly inhibit acetylcholinesterase, leading to accumulation of acetylcholine and overstimulation of cholinergic receptors. - Symptoms: Excessive salivation, sweating, miosis, bronchoconstriction, bradycardia, gastrointestinal distress, muscle twitching, seizures. - Treatment: Administration of anticholinergic drugs (e.g., atropine) to block excess cholinergic stimulation and use of cholinesterase reactivators (e.g., pralidoxime) to reverse the inhibition of acetylcholinesterase. - Mushroom Poisoning (e.g., Amanita muscaria): - Mechanism: Contain muscarinic agonists (e.g., muscarine) that activate cholinergic receptors. - Symptoms: Profuse sweating, salivation, tearing, gastrointestinal disturbances, bradycardia, miosis. - Treatment: Supportive care, administration of atropine to counteract excessive cholinergic effects. ### Cholinergic antagonists Classification of Cholinergic Antagonists: Muscarinic Antagonists: - Atropine: Increases heart rate, dilate pupils, reduce secretions, and treat bradycardia. Atropine is also used as an antidote for certain poisonings and to prevent or treat organophosphate pesticide exposure. - Scopolamine: Used to prevent motion sickness and nausea, particularly in situations such as travel or surgery. Scopolamine can also cause sedation and has some amnesic properties, which are utilized in certain medical procedures. - Ipratropium: Ipratropium is a muscarinic antagonist primarily used as an inhaler to relieve bronchospasm in conditions like asthma and COPD. It helps relax the smooth muscles in the airways, allowing easier breathing. Unlike some other muscarinic antagonists, ipratropium has minimal systemic absorption, reducing the likelihood of systemic side effects. - Pirenzepine: Pirenzepine is a selective muscarinic antagonist primarily used in the treatment of peptic ulcers. It selectively blocks the M1 receptors in the stomach, reducing gastric acid secretion. Pirenzepine is not commonly used in many countries, as alternative medications such as proton pump inhibitors are more frequently prescribed. Ganglion Blocking Agents: 1. Hexamethonium: blocks transmission of nerve impulses at the ganglia. It has limited therapeutic uses, such as treating hypertension, but is not commonly used due to safer alternatives. Adverse effects include postural hypotension, dry mouth, blurred vision, urinary retention, and constipation. Mechanism of Action, Pharmacological Effects, and Therapeutic Uses of Muscarinic Antagonists: Mechanism of Action: - Muscarinic antagonists competitively block muscarinic receptors, preventing the binding of acetylcholine and inhibiting the actions of the parasympathetic nervous system. Pharmacological Effects: - Dilation of pupils (mydriasis), Decreased glandular secretions (dry mouth), Decreased gastrointestinal motility, Relaxation of bronchial smooth muscles, Increased heart rate (tachycardia), Decreased urinary bladder contraction Common Adverse Effects and Contraindications of Muscarinic Antagonists: Adverse Effects: Dry mouth, Blurred vision, Urinary retention, Constipation, Increased heart rate, Central nervous system effects (e.g., sedation, confusion, hallucinations) Contraindications: - Glaucoma: Muscarinic antagonists can increase intraocular pressure. - Urinary retention: These drugs can exacerbate urinary retention in individuals with prostatic hypertrophy. - Bowel obstruction: Muscarinic antagonists can worsen symptoms of intestinal obstruction. ### Neuromuscular blocking agents Neuromuscular Blockers: - Non-depolarizing Neuromuscular Blockers (e.g., d-Tubocurarine): competitively antagonize acetylcholine at the neuromuscular junction, preventing muscle contraction. - Depolarizing Neuromuscular Blockers (e.g., Succinylcholine): act as agonists at the neuromuscular junction, initially causing depolarization and muscle fasciculation, followed by prolonged depolarization and flaccid paralysis. Spasmolytics: - Centrally acting spasmolytics (e.g., Diazepam, Baclofen, Tizanidine): act on the CNS to reduce skeletal muscle tone and relieve muscle spasms. - Directly acting spasmolytics (e.g., Dantrolene): interfere with calcium release from the sarcoplasmic reticulum, preventing excitation-contraction coupling in skeletal muscle. Mechanisms of action: - Neuromuscular blockers block or mimic acetylcholine at the neuromuscular junction. - Non-depolarizing agents competitively antagonize acetylcholine. - Depolarizing agents initially cause depolarization and subsequent desensitization of nicotinic receptors. Pharmacokinetic features: - Non-depolarizing agents have limited lipid solubility and difficulty crossing membranes. - Depolarizing agents like Succinylcholine undergo rapid hydrolysis by plasma cholinesterase. Therapeutic uses: - Neuromuscular blockers: facilitate endotracheal intubation, achieve muscle relaxation during surgery, reduce fractures or orthopaedic manipulations. - Spasmolytics: relieve acute muscle spasms, treat spastic conditions associated with diseases like multiple sclerosis or cerebral palsy, provide muscle relaxation during electroconvulsive therapy. Adverse effects of neuromuscular blockers: - Common effects: respiratory paralysis, hypotension, bronchospasm. - Depolarizing agents (Succinylcholine) can also cause hyperkalaemia, malignant hyperthermia, masseter muscle rigidity, and prolonged apnoea in genetically predisposed individuals. Drug-drug interactions: - Neuromuscular blockers may interact with general anaesthetics and aminoglycosides, leading to potentiation or synergistic effects. ### Adrenergic agonists 1. Direct-acting adrenergic agonists: - Selective: - Alpha 1 agonist: Phenylephrine - Mechanism of action: Phenylephrine selectively stimulates alpha 1 adrenergic receptors, leading to vasoconstriction of blood vessels and increased peripheral resistance. - Therapeutic uses: Phenylephrine is used as a nasal decongestant, to raise BP in cases of hypotension, and as a mydriatic agent (to dilate the pupil) during ophthalmic procedures. - Alpha 2 agonist: Clonidine - Mechanism of action: Clonidine primarily acts as an alpha 2 adrenergic agonist in the central nervous system, leading to decreased sympathetic outflow and reduced peripheral vascular resistance. - Therapeutic uses: Clonidine is used to treat hypertension, attention deficit hyperactivity disorder (ADHD), and opioid withdrawal symptoms. - Beta 1 agonist: Dobutamine - Mechanism of action: Dobutamine selectively stimulates beta 1 adrenergic receptors, resulting in increased myocardial contractility and CO. - Therapeutic uses: Dobutamine is used in cases of heart failure and cardiac decompensation to increase CO. - Beta 2 agonist: Salbutamol (Albuterol) - Mechanism of action: Salbutamol selectively stimulates beta 2 adrenergic receptors, leading to bronchodilation and relaxation of smooth muscle in the airways. - Therapeutic uses: Salbutamol is commonly used in the treatment of asthma, chronic obstructive pulmonary disease (COPD), and bronchospasm. Non-selective: - Alpha 1, Alpha 2, Beta 1, Beta 2 agonist: Adrenaline (Epinephrine) - Mechanism of action: Adrenaline acts on all adrenergic receptor subtypes, resulting in vasoconstriction, bronchodilation, increased heart rate, and increased contractility. - Therapeutic uses: Adrenaline is used in emergencies such as anaphylaxis, cardiac arrest, and severe asthma attacks. - Alpha 1, Alpha 2, Beta 1 agonist: Noradrenaline (Norepinephrine) - Mechanism of action: Noradrenaline stimulates alpha 1, alpha 2, and beta 1 adrenergic receptors, leading to vasoconstriction and increased BP - Therapeutic uses: Noradrenaline is used in cases of severe hypotension and shock. - Beta 1, Beta 2 agonist: Isoprenaline (Isoproterenol) - Mechanism of action: Isoprenaline stimulates beta 1 and beta 2 adrenergic receptors, resulting in increased heart rate, increased contractility, and bronchodilation. - Therapeutic uses: Isoprenaline is primarily used in the treatment of bradycardia and heart block. - D1, Beta 1, Alpha 1 agonist: Dopamine - Mechanism of action: Dopamine acts on dopamine, beta 1, and alpha 1 adrenergic receptors, leading to increased CO and renal vasodilation. - Therapeutic uses: Dopamine is used in cases of acute heart failure, shock, and renal perfusion impairment. 2. Mechanism of action and pharmacological effects of adrenergic agonists: - Adrenergic agonists bind to and activate adrenergic receptors, which are G-protein coupled receptors located on the cell surface. - Direct-acting agonists directly interact with the receptors, while indirect-acting agonists modulate the release, reuptake, or metabolism of endogenous catecholamines. - Activation of alpha 1 receptors results in vasoconstriction, increased peripheral resistance, and mydriasis. - Activation of alpha 2 receptors decreases sympathetic outflow, resulting in reduced peripheral vascular resistance and decreased BP. - Activation of beta 1 receptors increases heart rate, myocardial contractility, and CO. - Activation of beta 2 receptors leads to bronchodilation, vasodilation in skeletal muscles, and uterine relaxation. - Activation of dopamine receptors has various effects depending on the subtype, including renal vasodilation and increased CO. 3. Rationale of therapeutic uses and contraindications of adrenergic agonists: - Adrenergic agonists are used therapeutically based on their specific receptor actions and pharmacological effects. - They are employed to treat conditions such as hypotension, shock, bronchospasm, asthma, bradycardia, and nasal congestion. - Contraindications include hypertension, hyperthyroidism, cardiac arrhythmias, and certain types of glaucoma. 4. Common and major adverse effects of adrenergic agonists: - Common adverse effects include increased heart rate, increased BP, headache, tremor, anxiety, palpitations, and gastrointestinal disturbances. - Major adverse effects may include cardiac arrhythmias, myocardial ischemia, pulmonary edema, hypertensive crisis, and rebound hypotension. ### Adrenergic antagonists Adrenergic receptor antagonists: - Alpha blockers: - Selective reversible (α1) antagonist: Prazosin - Mechanism of action: Prazosin selectively blocks alpha 1 adrenergic receptors, resulting in vasodilation, decreased peripheral resistance, and relaxation of smooth muscle in the bladder neck and prostate. - Therapeutic uses: Prazosin is used primarily to treat hypertension, benign prostatic hyperplasia (BPH), and urinary symptoms associated with BPH. - ii\. Nonselective irreversible antagonist: Phenoxybenzamine - Mechanism of action: Phenoxybenzamine irreversibly blocks both alpha 1 and alpha 2 adrenergic receptors, leading to vasodilation and decreased peripheral resistance. - Therapeutic uses: Phenoxybenzamine is used in the management of pheochromocytoma (adrenal gland tumor) and as an adjunct in the treatment of certain conditions involving excessive sympathetic activity. - Nonselective reversible antagonist: Phentolamine - Mechanism of action: Phentolamine competitively blocks both alpha 1 and alpha 2 adrenergic receptors, resulting in vasodilation and decreased peripheral resistance. - Therapeutic uses: Phentolamine is used in the diagnosis and treatment of conditions such as pheochromocytoma, hypertensive emergencies, and erectile dysfunction. - Beta blockers: - Nonselective beta blocker: Propranolol - Mechanism of action: Propranolol competitively blocks both beta 1 and beta 2 adrenergic receptors, leading to decreased heart rate, reduced myocardial contractility, and bronchoconstriction. - Therapeutic uses: Propranolol is used to treat hypertension, angina, arrhythmias, migraine, essential tremor, and certain anxiety disorders. - Cardioselective beta blocker: Metoprolol - Mechanism of action: Metoprolol selectively blocks beta 1 adrenergic receptors, primarily affecting the heart, resulting in decreased heart rate and reduced myocardial contractility. - Therapeutic uses: Metoprolol is commonly used in the management of hypertension, angina, and heart failure. - Partial agonist: Pindolol - Mechanism of action: Pindolol acts as a partial agonist at beta adrenergic receptors, producing a less pronounced blockade of receptor activity compared to full antagonists. - Therapeutic uses: Pindolol is used in the management of hypertension and angina. - Beta and alpha blocker: Labetalol - Mechanism of action: Labetalol blocks both beta adrenergic receptors and alpha 1 adrenergic receptors, leading to decreased heart rate, reduced peripheral resistance, and vasodilation. - Therapeutic uses: Labetalol is used to treat hypertension, especially in hypertensive emergencies and preeclampsia. Mechanism of action and pharmacological effects of adrenergic blocking agents: - Adrenergic blocking agents competitively bind to adrenergic receptors, preventing the binding of endogenous catecholamines. - Alpha blockers block alpha adrenergic receptors, resulting in vasodilation, decreased peripheral resistance, and smooth muscle relaxation. - Beta blockers block beta adrenergic receptors, leading to decreased heart rate, reduced myocardial contractility, and, in the case of nonselective blockers, bronchoconstriction. Rationale of therapeutic uses and adverse effects of adrenergic blocking agents: - Adrenergic blocking agents are used therapeutically to treat conditions such as hypertension, angina, arrhythmias, migraines, anxiety disorders, and certain benign prostatic hyperplasia symptoms. - Adverse effects may include hypotension, bradycardia, bronchoconstriction, fatigue, dizziness, sexual dysfunction, and in the case of nonselective blockers, worsening of asthma symptoms. Common and major adverse effects of adrenergic blocking agents: - Common adverse effects include orthostatic hypotension, dizziness, fatigue, bradycardia, cold extremities, and gastrointestinal disturbances. - Major adverse effects may include heart block, exacerbation of bronchospasm, exacerbation of heart failure, and masking of hypoglycaemic symptoms in diabetic patients. ### Autocoid Pharmacology Physiological effects of autacoids on the human body: - Autacoids are locally acting substances that are synthesized and released within the body, exerting a wide range of physiological effects. - Examples of autacoids include prostaglandins, histamine, serotonin, and leukotrienes. - Prostaglandins play a role in inflammation, pain, and fever regulation, gastric acid secretion, blood clotting, and smooth muscle contraction and relaxation. - Histamine is involved in allergic reactions, immune responses, gastric acid secretion, and regulation of neurotransmission in the central nervous system. - Serotonin (5-HT) is implicated in various physiological functions, including mood regulation, sleep-wake cycles, appetite, and gastrointestinal motility. - Leukotrienes are potent mediators of inflammation, especially in conditions such as asthma, where they cause bronchoconstriction, increased mucus secretion, and airway inflammation. Pharmacological basis and therapeutic uses of specific agents: - Prostaglandin analogues (e.g., Misoprostol): They mimic the actions of endogenous prostaglandins and are used therapeutically for gastric ulcer prevention, induction of labor, and medical abortion. - Antihistamines (e.g., Diphenhydramine): They block histamine receptors and are used to relieve symptoms of allergies, such as itching, sneezing, and runny nose. - Serotonin agonists (e.g., Sumatriptan): They activate serotonin receptors and are used in the treatment of migraines and cluster headaches. - Serotonin antagonists (e.g., Ondansetron): They block serotonin receptors and are effective in preventing nausea and vomiting associated with chemotherapy or postoperative conditions. - Leukotriene antagonists (e.g., Montelukast): They inhibit the effects of leukotrienes and are used in the management of asthma and allergic rhinitis. Differentiation of first-generation and second-generation antihistamines: - First-generation antihistamines (e.g., Diphenhydramine): They readily cross the blood-brain barrier, resulting in sedation and drowsiness as common adverse effects. - Second-generation antihistamines (e.g., Loratadine, Cetirizine): They are designed to have reduced penetration into the central nervous system, leading to decreased sedation compared to first-generation antihistamines. Pharmacological basis for adverse effects of specific agents: - Prostaglandin analogues: Adverse effects may include gastrointestinal disturbances (e.g., diarrhea, abdominal pain), uterine contractions, and potential risks of bleeding or miscarriage. - Antihistamines: Adverse effects can vary but commonly include sedation, drowsiness, dry mouth, blurred vision, urinary retention, and constipation. - Serotonin agonists and antagonists: Adverse effects may include headache, dizziness, gastrointestinal disturbances, flushing, and in rare cases, serotonin syndrome characterized by agitation, confusion, rapid heart rate, and increased body temperature. - Leukotriene antagonists: Adverse effects are generally mild but may include headache, gastrointestinal disturbances, and, rarely, psychiatric symptoms such as mood changes or suicidal ideation.