Anaesthetics PDF

ANAESTHETICS Dr. Richard Delali Agbeko Djochie (PhD, MSc., B. Pharm. MPSGH) Lecturer, Department of Pharmacotherapeutics & Pharmacy Practice, SoPPS, UCC Objectives By the end of this lecture, students should be able to: 1. Understand the classification of anesth...

ANAESTHETICS Dr. Richard Delali Agbeko Djochie (PhD, MSc., B. Pharm. MPSGH) Lecturer, Department of Pharmacotherapeutics & Pharmacy Practice, SoPPS, UCC Objectives By the end of this lecture, students should be able to: 1. Understand the classification of anesthetics and their mechanisms of action. 2. Explain the pharmacokinetics and pharmacodynamics of anesthetics. 3. Identify the clinical uses, contraindications, adverse effects, and drug interactions of different anesthetics. 4. Discuss their application in clinical scenarios. Intro Definition Anaesthesia refers to a reversible state of unconsciousness, analgesia, amnesia, and muscle relaxation used during surgical and diagnostic procedures. Types of Anaesthesia 1. General Anaesthesia: Induces unconsciousness and total body anesthesia. 2. Local Anaesthesia: Blocks sensation in a specific area without affecting consciousness. 3. Regional Anaesthesia: Blocks sensation to a larger area by targeting specific nerve pathways (e.g., spinal or epidural). Pathophysiology of Pain and Consciousness Pain signals travel via peripheral nerves to the central nervous system (CNS). Consciousness arises from interactions between the cortex and subcortical structures. Anesthetics modulate synaptic transmission and neuronal activity in these pathways. Classification of Anesthetics Anesthetics can be broadly classified into two categories: 1. General Anesthetics: Induce a reversible loss of consciousness and sensation throughout the body. a. Inhalational Anaesthetics - Administered via inhalation (e.g., Nitrous Oxide, Isoflurane, Sevoflurane) or b. Intravenous Anaesthetics – administered through the IV route (e.g., Propofol, Ketamine, Thiopentone, Etomidate). NB: Balanced anaesthesia is when intravenous and inhalational anaesthetics are combined 2. Local Anesthetics: Block sensory nerve conduction in a specific area without affecting consciousness. Common examples include a. Ester-linked (e.g., Procaine, Tetracaine). b. Amide-linked (e.g., Lidocaine, Bupivacaine, Ropivacaine). General Anaesthesia Aim of General Anaesthesia Pain relief Induce Sleep Muscle relaxation General anesthesia is a state characterized by Unconsciousness, Analgesia (absence of pain), Amnesia (loss of memory of procedure) Skeletal muscle relaxation, and Loss of reflexes. No single drug can achieve all of these actions GAs Modern anesthesiology often employs a balanced anesthesia approach, utilizing a combination of intravenous and inhaled drugs. The combination is tailored to achieve the desired depth of anesthesia for the specific procedure and patient. An ideal anesthetic drug is one that induces a rapid and smooth loss of consciousness, is quickly reversible upon discontinuation, and possesses a wide margin of safety. GAs The potency of inhaled anesthetics is commonly determined by the minimum alveolar concentration (MAC). The minimum alveolar concentration represents the concentration of an inhaled anesthetic in the alveoli of the lungs at which 50% of individuals do not respond to a noxious stimulus, such as surgical incision, and remain immobile. The lower the MAC, the more potent the inhaled anesthetic is considered. A lower MAC indicates that a lower concentration of the anesthetic is required to achieve the desired anaesthetic effect. For example, halothane has a MAC of approximately 0.75%, while nitrous oxide has a much higher MAC, indicating it is less potent. Factors Influencing MAC: Age, temperature, and the presence of other drugs. MAC tends to decrease with increasing age and may be lower in hypothermic conditions. GAs For intravenous anesthetics, potency can be assessed using the ED50, which is the dose required to achieve a specific effect in 50% of subjects. This can include endpoints such as loss of consciousness, loss of righting reflex, or prevention of movement in response to noxious stimuli. Intravenous Anaesthetics Propofol Mechanism of Action (MOA): Potentiates the inhibitory effect of GABA at GABA-A receptors, enhancing chloride ion influx and hyperpolarizing neuronal membranes, leading to sedation and hypnosis. Indications: Induction and maintenance of anesthesia. Sedation during diagnostic or minor surgical procedures. ICU sedation for mechanically ventilated patients. Contraindications: Hypersensitivity to propofol or its components (e.g., soybean oil or egg lecithin). Disorders of fat metabolism. Pharmacokinetics: Onset: Rapid (30–60 seconds). Duration: Short (3–10 minutes due to redistribution). Metabolism: Hepatic metabolism to inactive metabolites. Excretion: Renal. Propofol - 2 Drug Interactions: Potentiation of CNS depression with opioids, benzodiazepines, or alcohol. Increased hypotensive effects with antihypertensives. Adverse Effects: Hypotension and bradycardia. Respiratory depression. Pain at the injection site. Propofol infusion syndrome (rare but severe). Clinical Advantages: Smooth induction and recovery. Minimal postoperative nausea and vomiting. Antiemetic properties. Ketamine Mechanism of Action (MOA): NMDA receptor antagonist, inhibiting excitatory glutamate signaling. This produces dissociative anesthesia, analgesia, and amnesia. Indications: Emergency surgeries requiring hemodynamic stability. Analgesia for severe pain. Pediatric anesthesia. Sedation during short, painful procedures. Contraindications: Severe hypertension or cardiovascular disease. Intracranial hypertension. Psychiatric disorders (e.g., schizophrenia), psychiatric disorders may exacerbate symptoms. Pharmacokinetics: Onset: Rapid (30–60 seconds). Duration: 5–10 minutes (IV); longer for IM. Metabolism: Hepatic (CYP450 enzymes); active metabolite (norketamine). Excretion: Renal. Ketamine - 2 Drug Interactions: Increased risk of hypertension with sympathomimetics. Potentiates CNS depression with benzodiazepines or opioids. Adverse Effects: Emergence reactions (e.g., vivid dreams, hallucinations). Hypertension and tachycardia. Increased intracranial and intraocular pressure. Clinical Advantages: Preserved airway reflexes and spontaneous respiration. Potent analgesic effects. Minimal cardiovascular depression. Etomidate Mechanism of Action (MOA): Potentiates GABA-A receptor activity, causing sedation and hypnosis without significant analgesia. Indications: Induction of anesthesia, especially in hemodynamically unstable patients. Contraindications: Known hypersensitivity. Chronic adrenal insufficiency due to transient adrenal suppression. Pharmacokinetics: Onset: Rapid (10–20 seconds). Duration: 4–8 minutes. Metabolism: Hepatic and plasma esterases. Excretion: Renal and biliary. Etomidate - 2 Drug Interactions: Enhanced respiratory depression with opioids or benzodiazepines. Suppresses cortisol synthesis when used with corticosteroid inhibitors. Adverse Effects: Adrenal suppression. Myoclonus during induction. Nausea and vomiting. Clinical Advantages: Minimal cardiovascular and respiratory effects. Thiopental Mechanism of Action (MOA): A barbiturate that enhances GABA-A receptor activity, prolonging chloride channel opening and causing CNS depression. Indications: Induction of anesthesia. Rapid control of seizures. Reduced intracranial pressure in neurosurgery. Contraindications: Severe cardiovascular or respiratory depression. Porphyria. Hypersensitivity to barbiturates. Pharmacokinetics: Onset: Ultra-rapid (10–20 seconds). Duration: Short (5–10 minutes due to redistribution). Metabolism: Hepatic; active metabolites. Excretion: Renal. Thiopental Drug Interactions: Potentiates respiratory and CNS depression with opioids or sedatives. Enhanced effects with CYP450 inhibitors. Adverse Effects: Respiratory depression and apnea. Hypotension and myocardial depression. Laryngospasm (during induction). Pain at injection site or tissue necrosis if extravasated. Clinical Advantages: Ultra-rapid onset. Effective in reducing cerebral metabolic rate and intracranial pressure. Inhalational Anesthetics Isoflurane Mechanism of Action (MOA): Potentiates GABA and glycine receptor activity while reducing excitatory NMDA receptor activity. Indications: Maintenance of general anesthesia. Contraindications: Malignant hyperthermia susceptibility. Severe hepatic dysfunction. Pharmacokinetics: Onset: Moderate (blood-gas partition coefficient = 1.4). Metabolism: Minimal (0.2% hepatic). Elimination: Primarily exhaled unchanged. Isoflurane - 2 Drug Interactions: Increased hypotension with beta-blockers. Enhanced respiratory depression with opioids. Adverse Effects: Respiratory depression. Postoperative shivering. Malignant hyperthermia (rare). Clinical Advantages: Stable cardiac profile. Sevoflurane Mechanism of Action (MOA): Enhances GABA-A receptor activity, depressing CNS excitability. Indications: Induction and maintenance of anesthesia. Contraindications: Malignant hyperthermia susceptibility. Severe renal impairment (potential fluoride toxicity). Pharmacokinetics: Onset: Rapid (blood-gas partition coefficient = 0.69). Metabolism: 5% hepatic. Elimination: Primarily via exhalation. Sevoflurane - 2 Drug Interactions: Increased sedation with CNS depressants. Adverse Effects: Nephrotoxicity (due to compound A production). Nausea and vomiting. Clinical Advantages: Non-irritating to the airway. Rapid induction and emergence. Halothane Mechanism of Action (MOA): Potentiates GABA-A receptor activity, enhancing chloride ion influx and neuronal inhibition. It also reduces excitatory neurotransmitter release by acting on NMDA receptors. Indications: Maintenance of general anesthesia. Used in pediatric anesthesia (due to non-irritating properties). Contraindications: Malignant hyperthermia susceptibility. Severe hepatic dysfunction or prior halothane hepatitis. Cardiovascular instability. Pharmacokinetics: Onset: Moderate (blood-gas partition coefficient = 2.4). Metabolism: 20% metabolized in the liver. Elimination: Primarily exhaled; metabolites are hepatotoxic. Halothane - 2 Drug Interactions: Potentiates hypotension with beta-blockers. Increases arrhythmogenic effects with catecholamines. Augmented CNS depression with opioids or sedatives. Adverse Effects: Halothane hepatitis (idiosyncratic hepatotoxicity). Cardiac arrhythmias (sensitizes the heart to catecholamines). Malignant hyperthermia. Postoperative nausea and vomiting. Clinical Advantages: Smooth induction and maintenance. Non-irritating to the airway, suitable for pediatric patients. Nitrous Oxide Mechanism of Action (MOA): Antagonizes NMDA receptors, inhibiting excitatory neurotransmission, while modulating GABA-A receptors to enhance inhibitory effects. Indications: Maintenance of general anesthesia (in combination with other agents). Analgesia in minor procedures (e.g., dental or obstetric procedures). Used as a carrier gas for volatile anesthetics. Contraindications: Pneumothorax, bowel obstruction, or other air-trapping conditions (due to expansion of air spaces). Vitamin B12 deficiency (may inhibit methionine synthase). Severe cardiovascular or respiratory compromise. Pharmacokinetics: Onset: Rapid (low blood-gas partition coefficient = 0.47). Elimination: Almost entirely exhaled unchanged. Nitrous Oxide - 2 Drug Interactions: Increases the potency of other inhalational anesthetics. Augments CNS depression when combined with sedatives or opioids. Adverse Effects: Diffusion hypoxia (during recovery if not supplemented with oxygen). Nausea and vomiting. Long-term use can lead to megaloblastic anemia or neuropathy (due to methionine synthase inhibition). Clinical Advantages: Excellent analgesic properties. Rapid onset and recovery. Minimal cardiovascular and respiratory effects. Local Anaesthetics Local Anaesthetics These are drugs used to induce a reversible loss of sensation in a limited region of the body without necessarily resulting in a loss of consciousness. They are also used for more invasive procedures, such as regional anesthesia for joint or spinal pain, and for certain eye operations. LAs are generally suitable for minor procedures that do not require general or regional anesthesia, and for procedures that are relatively quick and do not require an overnight hospital stay. They are typically administered via injection or topical application, and their duration of action can range from 30 minutes to 12 hours or more, depending on the specific local anesthetic used and the location of the block. The addition of vasoconstrictors, such as epinephrine, to LAs can help prolong their duration of action by reducing blood flow and systemic absorption of the drug. 29 Desirable Characteristics of LA Rapid onset of action Brief, reversible block of nerve conduction Low degree of systemic toxicity Soluble in water and stable in solution Effective on all parts of the nervous system 30  Lidocaine Mechanism of Action (MOA): Blocks voltage-gated sodium channels, preventing nerve depolarization and impulse propagation. Indications: Local infiltration anesthesia. Nerve blocks. Antiarrhythmic agent. Contraindications: Hypersensitivity to amide-linked agents. Severe hepatic impairment. Pharmacokinetics: Onset: Rapid (2–5 minutes). Duration: 1–2 hours. Metabolism: Hepatic (CYP450 enzymes). Excretion: Renal. Lidocaine - 2 Drug Interactions: Increased toxicity with CYP450 inhibitors. Additive CNS depression with sedatives. Adverse Effects: CNS toxicity (e.g., seizures, dizziness). Cardiovascular depression (at high doses). Clinical Advantages: Versatile; can be used with vasoconstrictors to prolong action. Bupivacaine Mechanism of Action (MOA): Blocks sodium channels, stabilizing neuronal membranes and reducing excitability. Indications: Regional anesthesia (e.g., epidural, spinal). Postoperative pain management. Contraindications: Cardiac arrhythmias or heart block. Pharmacokinetics: Onset: Moderate (10–20 minutes). Duration: Long (3–9 hours). Metabolism: Hepatic. Excretion: Renal. Bupivacaine - 2 Drug Interactions: Increased toxicity with CYP450 inhibitors. Adverse Effects: Cardiotoxicity (e.g., arrhythmias). CNS toxicity at high doses. Clinical Advantages: Long duration of action. Procaine Mechanism of Action (MOA): Blocks sodium channels, preventing nerve impulse propagation. Indications: Local infiltration anesthesia. Contraindications: Hypersensitivity to ester-linked agents. Pharmacokinetics: Onset: Slow. Duration: Short (30–60 minutes). Metabolism: Plasma cholinesterases. Excretion: Renal. Drug Interactions: Antagonism of sulfonamide antibiotics. Adverse Effects: Allergic reactions (due to PABA production). Clinical Advantages: Low systemic toxicity. Bupivacaine Bupivacaine is a long-acting amide-type local anesthetic commonly used for regional anesthesia and analgesia. It is highly effective in providing prolonged pain relief in various clinical settings, including surgical procedures, labor pain management, and chronic pain conditions. Mechanism of Action Bupivacaine blocks sodium ion channels in neuronal cell membranes, thereby inhibiting the initiation and propagation of action potentials. This action prevents the transmission of nerve impulses, leading to localized anesthesia. Bupivacaine - Pharmacokinetics Absorption: The rate and extent of absorption depend on the site of administration, dosage, and use of vasoconstrictors (e.g., epinephrine). Distribution: Bupivacaine is highly protein-bound (95%) in plasma, particularly to alpha-1-acid glycoprotein, contributing to its prolonged action. Metabolism: Metabolized primarily in the liver by cytochrome P450 enzymes, specifically CYP1A2 and CYP3A4. Excretion: Excreted mainly via the kidneys, with less than 10% of the drug eliminated unchanged. The elimination half-life is approximately 2.7 to 3.5 hours in adults. Bupivacaine - Indications Clinical Uses Regional Anesthesia: Epidural, spinal, and peripheral nerve blocks. Infiltration Anesthesia: Localized tissue infiltration during surgical and diagnostic procedures. Pain Management: Postoperative pain control and obstetric analgesia (e.g., labor epidural). Dosing Doses vary based on the type of procedure, site of administration, and patient factors (e.g., age, weight, comorbidities). A common dose for epidural anesthesia is 0.25%–0.5% bupivacaine, with or without epinephrine to prolong the duration of action. Adverse Effects Central Nervous System (CNS): Dizziness, tinnitus, convulsions, and in severe cases, CNS depression. Cardiovascular System: Bupivacaine is more cardiotoxic than other local anesthetics, potentially causing arrhythmias, hypotension, or cardiac arrest, especially at high doses or accidental intravenous injection. Allergic Reactions: Rare but may include rash, itching, or anaphylaxis. Local Toxicity: Neurological damage or prolonged numbness at the injection site in rare cases. Precautions and Contraindications Precautions: Use cautiously in patients with hepatic impairment due to reduced metabolism. Avoid inadvertent intravascular injection to minimize systemic toxicity. Contraindications: Hypersensitivity to bupivacaine or other amide-type anesthetics. Severe cardiovascular or respiratory dysfunction. Advantages and Limitations Advantages: Long duration of action (up to 8 hours with a single dose). Effective for both sensory and motor blockade. Limitations: Increased risk of cardiotoxicity compared to other local anesthetics like lidocaine.