Intravenous Anaesthetic Agents PDF

# Intravenous Anaesthetic Agents ## Intravenous Anaesthetic Agents - Thiopentone, Methohexitone - Ketamine, Propofol, Etomidate and Benzodiazepines Dr Eugenia Lamptey Anaesthesia, UGMS January 2022 ## Definition of IVA - A drug or combination of drugs which will induce anaesthesia safely and reve...

# Intravenous Anaesthetic Agents ## Intravenous Anaesthetic Agents - Thiopentone, Methohexitone - Ketamine, Propofol, Etomidate and Benzodiazepines Dr Eugenia Lamptey Anaesthesia, UGMS January 2022 ## Definition of IVA - A drug or combination of drugs which will induce anaesthesia safely and reversibly when injected in sufficient quantities and could also be given intermittently, or by infusion, to maintain anaesthesia. - Such a drug should cause loss of consciousness in one arm-brain circulation time when given in adequate and appropriate doses. - One arm-brain circulation is the time taken for IVA in the arm, through the heart, up to the brain (usually 30 - 60 secs). ## Intravenous Anaesthetic Agents - As general Anaesthetic agents, they produce reversible: - Hypnosis - Amnesia - Analgesia - Immobility - Inhibition of nociceptive reflexes - Reduction of some autonomic reflexes, e.g. gag, vasoconstriction, tachycardia ## The Ideal IVA Agent - Long shelf life and resistant to microbial contamination - Water soluble - easily dissolvable - Stable solution (no preservatives added) - No pain on injection - Safe after inadvertent arterial injection - Non irritant to perivenous tissues if you accidentally inject outside vein - No toxic effect on other tissues ## Ideal IVA - Small volumes needed i.e. potent - Rapid onset - Rapid recovery. Non-cumulative (no active metabolites, no hangover) - No excitatory effects (e.g. cough, hiccup, involuntary movement) - No respiratory depression - No cardiovascular depression - No interaction with NMBA - No hypersensitivity - No histamine release - No postoperative nausea and vomiting - No emergence phenomena (e.g. delirium, nightmares) ## Ideal IVA Agent - No effect on cerebral blood flow - No endocrinologic effect - No stimulation of porphyria - Independent of liver and kidneys for metabolism and excretion - Inexpensive ## IVA ### Advantages - Rapid and smooth induction - Little equipment required - Easy admin of drugs ### Disadvantages - Difficult retrieval of drugs once administered - Less control of duration and depth of anaesthesia ## IVA pharmacological principles - All intravenous anaesthetic agents are administered in aqueous solution; as oil or emulsion. - Only free (unionized) unbound drug crosses the BBB. Drugs bound to protein are unavailable for uptake by any organ. - Only unionized molecules at pH 7.4, cross BBB to produce the anaesthetic effect. - The ionized fraction in blood binds to sites that bind to proteins. Lipid solubility determines how fast/much it crosses the BBB. ## Ideal IVA - Therefore, most are alkaline salt solutions or water miscible emulsions. - IVA bypass absorption because they are delivered directly into the bloodstream. ## IVA Types - There are 2 main groups: - Rapidly acting (primary induction agents) - Slower acting - Phencyclidines - ketamine - Benzodiazepines - Large dose opioids – fentanyl ## IVA Types ### Rapidly acting - Barbiturates - *Thiopentone*: Comes in various cones. So read - Methohexitone - Imidazoles - Etomidate - Phenols - Propofol ### Slow acting - Phencyclidines - Ketamine - Benzodiazepines - Diazepam - Midazolam - Opioids (in large doses) - Fentanyl - Alfentanil - Sufentanil ## Pharmacokinetics of IV Agents - After IV injection, anaesthesia is produced by the IVA crossing into the brain. - The anaesthetic effect would be controlled by: - Blood flow to the brain - Protein binding (toxicity increases in hypoproteinemia as more unbound reach the brain) - ECF pH and pKa of drug (determine:-unionized fraction) - The relative solubility of drug in lipid and water - Speed, dose and concentration of injection - Cardiorespiratory side effects increase with speed of injection, dose and concentration of agent. Less is more, slow, don’t overdose. ## Pharmacokinetics of IVA - After an intravenous injection, the drug is absorbed faster, and the body becomes saturated. - Highly perfused organs, including the brain, liver, heart, muscle (vessel-rich group, VRG) take up proportionately large amounts of drug compared to less perfused organs e.g., fatty tissue (vessel-poor group, VPG). - Medications move down concentration gradients to the blood = Patient wakes up [Redistribution]. This causes lower blood plasma concentration. - After the highly perfused organs are saturated during initial distribution, the greater mass of the less perfused organs continue to take up drug from the bloodstream. - As plasma concentration falls, some drug leaves the highly perfused organs, along a concentration gradient into plasma, to maintain equilibrium. - This redistribution from the vessel-rich group is responsible for termination of the effect of many IV Anaesthetic drugs. - The termination of the action of the drug when the patient wakes up, is not because of the IVA being metabolized or eliminated, but because of redistribution. ## Pharm of IVA - In anxious patients, a large percentage of the initial dose will enter muscle, because the vessels in this state are dilated. - A large dose of IVA is needed to saturate the muscle before the overflow enters the brain to cause the desired effect. - The patient will therefore require a large amount of IVA to sleep. This may cause an overdose. - This underscores the importance of giving anxiolytics as premedication. ## Pharm IVA - Most drugs are hepatically metabolized and renally excreted. - Chronic alcoholism induces hepatic enzymes and thus increases metabolism of all IVA agents. - Renal disease will slow down excretion of drug. - Co-morbid conditions - seriously ill drugs > dosing factors - Age: extremes of ages require less. ## Barbiturates (derivatives of barbituric acid) - Substitution affects potency and metabolism - C5 substitution with alkyl or aryl groups is essential for hypnotic activity. - C5 phenolic group gives anticonvulsant activity - phenobarbitone - C2 oxygen = oxybarbiturate - C2 sulphur = thiobarbiturate ## Barbiturates - Barbiturates act by: - Depressing the RAS in the brainstem. - Depressing the nerve synapses (not the axons) - Suppression of excitatory neurotransmitters - Increasing the transmission of inhibitory neurotransmitters. ## Thiopentone - Most common IVA in Ghana - Sulphur analogue of pentobarbitone presented as: - Water soluble pale yellow powder. - Garlic smell. - 6% of Na2CO3 to prevent precipitation of free acid by CO2 in air, to prevent crystal formation. - It has bacteriostatic properties, is alkaline, and has a long shelf life. ## Thiopentone - Presented in different types of vials. - Solution is bacteriostatic and alkaline. - pH of 2.5% solution = 10.5. - Protein binding – 70-80%. This reduces glomerular filtration of drug. - Perivenous accident → blisters/inflammation ## Routes of administration and dosage - IV: 4-6mg/kg for induction. - Rectal: 22mg/kg (unpredictable absorption, rarely used). - Induction dose depends on weight, age, physical status. ## Pharmacokinetics - Redistribution - Metabolism in the liver by oxidation and desulphuration. - Metabolism follows zero order kinetics. Accumulates in the body therefore not suitable for continuous infusion. It does not depend on anything - you can’t control. - So, it's not used for sedation in an ICU. - Metabolites, such as Pentobarbitone, are active and excreted in the urine and bile. - Therefore, in renal and hepatic dysfunction the dose should be reduced. ## Pharmacodynamics - thiopentone ### CNS - Sedative - Hypnotic - Potent anticonvulsant at hypnotic doses ### CVS - Anti-analgesic (at subanaesthetic level) i.e., when used as sole anaesthetic, patients have severe pain when waking up. - You shouldn’t use it alone. - Cerebral blood flow (CBF) decreased - Cerebral Metabolic Oxygen consumption (CMRO2) decreased. This is protective because it decreases O2 demand in the brain. - Intra-cranial pressure (ICP) decreased - Intra-ocular pressure (IOP) decreased ### CVS - Myocardial contractility is depressed - Blood pressure decreased in the presence of hypovolaemia, b-blockers, vasodilators, and in cardiac disease. - Cardiac output (CO) decreased - Systemic vascular resistance (SVR) decreased → peripheral vasodilation - Reflex tachycardia may follow initial bradycardia, this may increase the myocardial oxygen demand. ### RESP - Induction - deep breath, apnoea then ↑ respiratory rate & ↑ tidal volume (Vt) - Respiratory depression proportional to dose and speed of injection - Increased irritability of respiratory mucosa (Caution in Asthmatics) - Bronchospasm - Laryngeal spasm - Reduces sensitivity of resp. Centre to ↑CO2,↓O2. This may lead to hypercapnoea and hypoxaemia. ### Renal + Uterine - Renal blood flow decreased in proportion to the drop in blood pressure. - Glomerular filtration rate (GFR) decreased - Anti-diuretic hormone (ADH) decreased - Urine output decreased - Crosses placenta readily. So, deliver baby after 6 minutes of induction. ### Hepatic - Induction of liver enzymes - Liver blood flow decreased ### Local effects: Accidental injection into surrounding tissues - Thrombophlebitis, pain, thrombosis. There is slight pain on injection. - Extravasation may cause blistering - Intra-arterial injection causes severe pain and vasospasm. It can form crystals in arteries → end arteries → blocks blood flow → gangrene ## Uses of Thiopentone - Induction of anaesthesia - Sedation (bolus, not as infusion) - Status epilepticus. - Severe head injury (for cerebral protection {↓ICP, ↓CMRO2}) ## Contraindications - You cannot intubate. Use inhalation agents. - Airway obstruction (avoiding “can't ventilate, can't intubate”) - Previous hypersensitivity reaction a barbiturate. - Acute intermittent porphyria - No IV access ## Precautions and relative contraindications - Severe CVS dx - fixed CO states, may lead to severe hypotension. - Heavy sedation and alcohol intake. - Severe hepatic dx (reduced protein binding); depends, all enzymes are deranged, metabolism - Chronic renal failure (reduced protein binding). - Neuromuscular dx e.g. myasthenia gravis; respiratory depression may be exaggerated, severe muscle weakness. - Poorly controlled asthma (may get worse). ## Precautions (relative CI) - Metabolic rate states e.g. hypothyroidism, they are very sensitive to thiopentone. - Extremes of age - ↓ dosage - Day care anaesthesia - may lead to slow recovery - Obstetrics - give enough to anaesthetise mother but not depress baby ## Complications - Extravascular injection → tissue necrosis - Intra-arterial injection → intense pain, blanching of arm, loss of radial pulse, cyanosis, delayed loss of consciousness. - Treatment - Leave needle there. - Alert surgeon. - Flush with saline and/or LA, papaverine, heparin. - Stellate ganglion/brachial plexus block. - Keep limb warm. - Alpha blockers to vaso dilate arm - Anaphylaxis - rare, usually fatal. - Methohexitone: excitatory effects (that’s the main side effect). ## Ketamine - Available in 50mg/ml, 100mg/ml and 10mg/ml vials. - The vials contain sterile water/NaCl. - The preparations include 10mg/ml, 50mg/ml, 100mg/ml concentrations in 10ml, 2ml, 1ml vials with benzethonium chloride as a preservative. ## Ketamine - Phencyclidine derivative introduced in 1965. - Soluble in water. - The pH is 3.5 - 5.5. - The pKa is 7.5. - Slow onset (difficult to know when sleep occurs) - Smooth induction of anaesthesia. - Produces dissociative anaesthesia - patients gaze into the distance, with hypertonus, involuntary muscle movements, jaw rigidity and nystagmus occurring (i.e., there is intense analgesia with superficial sedation). - It is a potent analgesic. - It stimulates the CVS → increased blood pressure, pulse. - Large dose: depresses CVS and respiration ## Ketamine ### Doses - IV: 2mg/kg. - Oral: 10mg/kg takes 60-90min. - TIVA: 2-4mg/kg/hr. - Analgesia: 0.1-0.5mg/kg/hr IV, 3-5mg/kg IM. - Intrathecal & epidural routes also used. ## Ketamine ### Mode of action - It is an n-methyl -d-aspartate receptor antagonist (NMDA). - More lipid soluble and less protein bound than thiopentone. ### Metabolism - In the liver to norketamine with 20% potency. - Excreted in urine. - Induces enzymes so may lead to tolerance & dependence. ## Ketamine ### CNS - Extremely lipid soluble. - Dissociative anaesthesia - intense analgesia (even at subanaesthetic level) with superficial sedation. - Dissociates the thalamus from the limbic system. - Cerebral blood flow (CBF) increased - Intra-cranial pressure (ICP) increased - Intra-ocular pressure (IOP) increased - Cerebral metabolic oxygen consumption (CMRO2) increased ### CNS - Potent analgesia - Hallucination go away upon treatment. - Delusions - Delirium - Nightmares - Emergence phenomena reduced by: - Avoidance of noise and touch. - Opioids & benzodiazepines. - Nightmares may persist for a long time. Keep in a quiet place, hydrate, give benzos/opioids. - Increased sympathetic tone from ↓NA reuptake - EEG - epileptiform spikes ### CVS - Stimulates the CVS by central sympathetic activity →: - Heart rate (HR) increased by 20% - Systemic vascular resistance (SVR) increased - Blood Pressure increased by 25% - Cardiac output (CO) increased and increased myocardial O2 requirements. - Direct cardiac muscle depressant ### Respiratory system - Airway reflexes are retained in low doses but may be depressed in high doses. - Bronchodilation - (antagonising serotonin and histamine, ↑catecholamines) - Secretions increased ### GIT - Salivation. Give atropine. - Nausea and vomiting. ### Muscle - Hypertonus - Clonic tonic activity ## Ketamine ### Uses - Induction of anaesthesia in poor-risk patients, asthmatics, difficult airway. - TIVA - Burns dressing, radiotherapy - Adjunct analgesia - Epidural analgesia - Field situations (outside hospital) ## Ketamine contraindications - Hypertension & ischaemic heart disease - Epilepsy - Intra-cranial pressure (ICP) increased - Intra-ocular pressure (IOP) increased - Cerebrovascular accident (CVA) - Penetrating eye injury - Head injury - Psychosis ## Propofol - Image of a vial of Propofol ## Propofol - IVA was introduced in 1980, commercially available in 1986. - Chemical name - 2,6-di-isopropyl phenol. - Presentation - 1% or 2% solution of a milky white emulsion - In 10, 20, 50 or 100ml vials and ampoules. - Contains - Soya bean oil 1% - Egg phosphatide 1.2% (good culture medium, so disodium edetate or sodium metabisulfite added as antimicrobials) use within 6 hours - Glycerol – 2.25% - The pH is 4.5 - 6.4. - The pKa is 11. - It is preservative free, must be used within 6 hours of opening the vial. ## Propofol - pharmacokinetics - Induction by IV only. - Mechanism of action - thought to be GABA-mediated. - Very lipid soluble, almost insoluble in water. - 97-98% protein bound. - Metabolised in the liver to inactive glucuronides. - Excreted in urine. 0.3% excreted unchanged. - Minimal hangover. - Good for day-care surgery. - Talk - to know you're at the end point of induction for other drugs - eyelash reflex (accrue slowly). ## Propofol ### Induction doses - Less than 60 years: 2-2.5mg/kg. - More than 60 years, very ill patients ASA III/IV: 1-1.5mg/kg. - Children more than 3 yrs: 3-3.5mg/kg. - Not licensed for use in children less than 1 month old. - Infusion: 3-12 mg/kg/hr. - Metabolites are inactive. ## Propofol ### Induction characteristics - Rapid induction and recovery. - Cannot use the eyelash reflex to assess unconsciousness as with barbiturates. Loss of verbal contact is more reliable. - Pain at the site of injection. - Pain relieved by: - Cooling drug. - Adding LA or fentanyl. - Using a large vein. - Injecting while IV fluid is running. - Involuntary muscle movements. - Cough. - Duration of action: 3-10mins ### CNS - Onset of action usually 20 - 40 secs. - Sedation. - Hypnosis. - Cerebral blood flow (CBF) decreased. - Intra-cranial pressure (ICP) decreased. - Intra-ocular pressure (IOP) decreased. - Cerebral metabolic oxygen consumption (CMRO2) decreased. - Convulsions (very rare, caution when using in epileptics) ### CVS - Cardiac output decreased by 20%. - Systemic vascular resistance (SVR) decreased. - Severe bradycardia and asystole may occur. - Blood pressure (BP) decreased by 15-20% leading to secondary tachycardia. - Depression of the laryngeal reflexes causing attenuation of the haemodynamic response to laryngoscopy and intubation. ### Respiratory system - It obtunds airway reflexes so a laryngeal mask airway device can be passed without patient coughing or laryngospasm. It is therefore, the drug of choice when the LMA is to be used. - Apnoea of variable duration. - Tidal volume decreased and minute ventilation decreased. - Bronchospasm may occur if the patient reacts to egg. ## Propofol - Antiemetic. - No effect on the gravid uterus. - Reduced muscle tone (central effect), makes intubation easy. - Prolonged infusion of high-dose (> 5 mg/kg/hour) for > 48 hours leads to Propofol infusion syndrome. - This is rare, but fatal. - It is characterized by: - Severe metabolic acidosis. - Hyperkalaemia. - Lipidaemia. - Rabdomyolysis. - Hepatomegaly. - Cardiac failure. - Renal failure. - Propofol infusion syndrome may also follow large-dose, short-term infusions during surgical anaesthesia. ## Propofol ### Uses - Induction of anaesthesia. - Day care anaesthesia. - Sedation. - During surgery under the LA technique. - For endoscopy. - In ICU. - TIVA (Total Intravenous Anaesthesia). It can be used alone, for analgesia, and for muscle relaxation. ## Propofol ### Side effects: - Pain on injection - add local anaesthetic / cool it before. - CVS depression. - Resp depression. - Myoclonus. - Allergic rxns - skin rashes, anaphylaxis (rare). - Propofol infusion syndrome. ## Etomidate - CVS issues/critically ill ## Benzodiazepines - Used for co- induction with propofol in very ill people. - These are drugs that produce sedation and hypnosis by depressing the limbic system. - They act by causing hyperpolarisation of the nerve membranes by binding to GABA receptors. ## Benzodiazepines ### Types - Short acting - Midazolam - Intermediate acting - Temazepam - Long acting - Diazepam - Lorazepam is very long acting, not recommended for children. ## Benzodiazepines - They all have good oral bioavailability. - Distribution is extensive because most are very lipid soluble at body pH. - High protein binding. - Metabolism is by oxidation and glucuronidation in the liver. This may yield active metabolites. ## Benzodiazepines ### Excretion - Metabolites are excreted in urine. - Enterohepatic circulation may cause a second plasma peak 6 - 12hrs later. ## Benzodiazepines ### CNS - Sedative. - Hypnotic. - Anticonvulsant. - Muscle relaxant. - Cerebral blood flow (CBF) decreased. - Intra-cranial pressure (ICP) decreased. - Intra-ocular pressure (IOP) decreased. - Cerebral metabolic oxygen consumption (CMRO2) decreased. - Anterograde amnesia (for premedication) ## Benzodiazepines ### Uses - Premedication - anxiolysis, sedation, amnesia. - Insomnia. - Agitation. - Induction of anaesthesia. - Co-induction with propofol. - Muscle relaxant properties especially for spastic conditions. - Anticonvulsant. ## Benzodiazepines ### Midazolam - Short acting. - Imidazo-benzodiazepine. - Water soluble. - 99% metabolized, 1% excreted unchanged. - One active metabolite - alpha-hydroxymidazolam t½ less than midazolam itself. - It can be given orally, IV, IM, intrathecally, epidurally. - Dose - IV 0.07 - 0.15mg/kg, oral 0.05 - 0.1mg/kg. - May cause a slight fall in BP and cardiac output, especially in the elderly. ## Midazolam ### Uses - Premedication. - Sedation. - Co-induction. - Maintenance of anaesthesia. - Anticonvulsant. ## Neuroleptics - Alcohol with neuroleptics is used rarely. ## Thank you Any questions?