INTRAVENOUS ANAESTHETIC Agents

INTRAVENOUS ANAESTHETIC Agents
September 18 INTRAVENOUS ANAESTHETIC Agents Dr. Med. Khaled Radaideh Department of Anesthesiology - Jordan University of Science and Technology Irbid-Jordan Dr. Med. Khaled Radaideh

INTRA VENOUS ANAESTHETIC AGENT Objectives
September 18 1- Properties of the ideal intravenous anesthetic agent 2- Classification of the intravenous anesthetic agent 3- Sodium Thiopental 3.1. Definition 3.2. Classification 3.3. Physical chemical properties 3.4. Pharmacokinetics 3.5. Pharmacodynamics 3.6. Dose and Administration 3.7. Indication, contraindication and precautions 3.8. Side Effects Dr. Med. Khaled Radaideh

September 18 4- Propofol 4.1. Physical and chemical properties 4.2. Dosage 4.3. Effects on organ systems 4.4. Indication and contraindication 5. Ketamine 5.1. definition of dissociative anesthesia 5.2. Physical & chemical Properties 5.3. Pharmacokinetics (Route of administration and Dosage) 5.4. Metabolism 5.5. Mechanism of action 5.6. Pharmacodynamics (effect on organ systems) 5.7. Indications and contraindications Dr. Med. Khaled Radaideh

September 18 6- Benzodiazepines 6.1. Features 6.2. Mode of action 6.3. Midazolam and Diazepam (Uses, differences between them) 6.4. Benzodiazepine antagonists (Flumazenil) 7. Narcotic Agonists 7.1. Origin, Site of action and Receptors 7.2. Pharmacokinetics 7.3. Pharmacodynamics (effect on organ systems) 5.4. Fentanyl And Morphine 8. Narcotic Antagonists (Naloxone) Dr. Med. Khaled Radaideh

PROPERTIES OF THE IDEAL INTRA VENOUS ANAESTHETIC AGENT{1 of 3}
September 18 1-rapid onset: achieved by an agent that is mainly : A- un-ionized at blood ph(7.35 – 7.45) B- highly lipid soluble ** these properties permit penetration of the BBB 2-rapid recovery: -early recovery of consciousness is usually produced by rapid redistribution of the drug from brain into other well-perfused tissues particularly muscles -plasma conc. Of drug decreases & drug diffuses out of the brain along a conc. gradient -quality of the recovery period is more related to the rate of metabolism of the drug * Drugs with slow metabolism are with a more prolonged hangover effect (fatigue, weakness, pain, nuasea vomiting..etc )and accumulate if used in repeated doses or by infusion for maintenance of anesthesia Dr. Med. Khaled Radaideh

PROPERTIES OF THE IDEAL INTRA VENOUS ANAESTHETIC AGENT {2 of 3}
September 18 3- analgesia at sub anesthetic concentrations *analgesia :an absence of the sense of pain without loss of consciousness 4- minimal cardiovascular and resp. depression 5- no emetic effects 6- no excitatory phenomena e.g. coughing .hiccup ,involuntary movements 7-no emergence phenomena e.g. nightmares 8-no interaction with neuromuscular blocking drugs(muscle relaxant) *Neuromuscular blocking drugs relax skeletal muscles and induce paralysis. Dr. Med. Khaled Radaideh

PROPERTIES OF THE IDEAL INTRA VENOUS ANAESTHETIC AGENT {3 of 3}
September 18 9- no pain on injection 10- no venous sequelae(such as thrombosis) 11-no toxic effects on other organs 12- no release of histamine(bronchospasm ..itching) 13- no hypersensitivity reactions 14- water soluble formulation 15- long shelf life : The length of time a product may be stored without becoming unsuitable for use or consumption. 16-no stimulation of porphyria Dr. Med. Khaled Radaideh

Intravenous anaesthetic agents
September 18 1- Barbiturate 1.1. sodium thiopental(used for over 40 years) 2. Non barbiturate 2.1. propofol (newly introduced) 2.2. ketamine (infrequently used) 2.3. Etomidate 4. other adjuvant intravenous anesthetic agents (benzodiazepines, midazolam, diazepam,…) Dr. Med. Khaled Radaideh

Sodium thiopental (pentothal)
Definition: ultra short acting barbiturate Classification: IV anesthetic-hypnotic Physical chemical properties : -It’s a Yellow powder with a sulphuric smell and a bitter taste -highly lipid soluble compound -when combined with sodium carbonate it becomes water soluble September 18 Dr. Med. Khaled Radaideh

-its bacteriostatic in water and has a ph of 10.6 to10.8 -*when injected ,sodium bicarbonate is neutralized and the thiopental is converted to its lipid soluble non ionazed form(40% ionized at ph=7.4) -its highly protien bound by albumen(75%) Which prevents precipition out of solution in vivo September 18 Dr. Med. Khaled Radaideh

September 18 Supplied: thiopental(yellow powder) is dissolved in water& sodium carbonate to make a 2.5% solution (25mg/ml) -Its stable at room temp for 2 weeks Thiopental is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system Dr. Med. Khaled Radaideh

Pharmacokinetics -An IV dose of 3-5 mg/kg results in loss of consciousness -time required to render the patient unconscious is generally 30-60 secs after administration .this is called the “arm brain” circulation time -arm brain circulation time is the time required for the drug to pass from site of injection to the brain as it passes through the right heart ,pulmonary circ., and the left heart September 18 Dr. Med. Khaled Radaideh

Pharmacokinetics -with no other drugs ,the anesthetic state persists for 5-10 mins Its concentration is low enough in the brain such that consciousness returns. So is most commonly used in the induction phase of general anesthesia As with all lipid soluble anesthetic drugs, the short duration of action of Sodium thiopental is almost entirely due to its redistribution away from central circulation towards muscle and fat tissue. September 18 Dr. Med. Khaled Radaideh

September 18 Pharmacokinetics -sulphur containing drugs , acidosis, NSAIDS may displace thiopental from albumen -liver &renal disease may be associated with low albumin levels so result in an increase in free thiopental which inc. the anesthetic toxicity and potency -metabolism occurs primarily in the liver with approximately 10 to 15%of the drug level metabolized per hour -a desulfuration rxn in liver produces pentobarbital which under goes oxidative metabolism yielding 2 compounds with no anesthetic activity -less than 1% of the drug is excreted unchanged in the urine Dr. Med. Khaled Radaideh

September 18 pharmacodynamics CNS: barbiturates interact with chloride ion channels by altering the duration they spend in an open state -this facilitates inhibitory neurotrasmitters such as gama amino butyric acid(GABA) As well as blocking excitatory NTM actions such as glutamic acid -thiopental will decrease both cerebral electrical & metabolic activity So it can be used to stop seizures activity in emergency situations -to maintain depression of cerebral electrical activity very high dose are required -But to maintian seizure control & avoid cv depression from high dose of thiopental other drugs are used (e.g. benzodiazepines) Dr. Med. Khaled Radaideh

September 18 pharmacodynamics CNS: Elevated ICP can quickly be reduced by thiopental BUT The improvement of ICP requires high dose of thiopental to be maintained The reduction of ICP is due to cerebral vasoconstriction, reduced cerb. Metabolism &oxygen requirments associated with dec.cerebral blood volume -theopental has an an anti-analgesic effect, since low dose may decrease pain threshold -Intraocular pressure decreases up to 25% with 3-5mg/kg of thiopental and persists for 3 to 5 minutes Dr. Med. Khaled Radaideh

September 18 Pharmacodynamics CVS:-thiopental causes a dose related depression of myocardial function as measured by CO,SV, and blood pressure -coronary blood flow, heart rate ,&myocardial oxygen uptake all increase following thiopental administration -venous tone decreases (decreased preload) And contributes to the increase in HR and decrease in BP -little change in total peripheral resistance Dr. Med. Khaled Radaideh

September 18 Pharmacodynamics Respiratory:-induction of anesthesia with thiopental may be associated with 2 or 3 large breaths followed by apnea for less than 1min -there is dose related depression of the respiratory response to hypercarbia and hypoxia -laryngospasm and bronchoconstriction may be associated with light levels of thiopental and with airway manipulation or intubation -FRC is reduced by 20% with induction of anasthesia >Functional Residual Capacity (FRC) is the volume of air present in the lungs at the end of passive expiration. Dr. Med. Khaled Radaideh

September 18 Pharmacodynamics GI: enzyme induction may occur with prolonged high dose therapy Hypoalbuminemia will result in an increase in unbound (free) thiopental and an increase in the potency of thiopental GU/pregnancy/fetus: - Thiopental has little or no effect on the kidneys or gravid uterus. -although thiopental crosses the placenta It has no significant effect on the fetus when used for cesarean section (dose used is limited to 4mg/kg) Dr. Med. Khaled Radaideh

September 18 Dose & administration -the usual dose is 3-6 mg/kg - Thiopental should be used with caution for Patients suffering from shock status because normal dose may lead to rapid death -for a short procedure (e.g.cardioversion) a dose of 2 mg/kg is generally sufficient -for frail elderly women with hip fracture mg/kg may induce anesthesia Dr. Med. Khaled Radaideh

Sodium thiopental (pentothal) indications
September 18 1- induction of anesthesia 2- maintenance of anesthesia for short procedures 3- control of convulsive states 4- for supplement of regional anesthesia or low potency anesthesia Dr. Med. Khaled Radaideh

Absolute contraindications 1- airway obstruction 2- porphyria 3- previous hypersensitivity PRECUATIONS 1- CVS disease 2- severe hepatic disease 3- renal diseases September 18 Dr. Med. Khaled Radaideh

Sodium thiopental (pentothal) Side effects
September 18 1- hypotension :if thiopental is administered to hypovolemic, shocked or previously hypertensive pt 2- respiratory depression :when excessive doses are used 3- tissue necrosis : following venous infusion 4- laryngeal spasm 5- bronchospasm :unusual but may be precipitated in asthmatics pts 6- allergic reaction : from cutanous rashes to severe anaphylactic shock with cvs collapse Dr. Med. Khaled Radaideh

Sodium thiopental (pentothal) Side effects
September 18 7- Rarely, intra-arterial injection can occur. The consequences of accidental arterial injection may be severe. The degree of injury is related to the concentration of the drug. Treatment consists of 1. dilution of the drug by the administration of saline into the artery, 2. heparinization to prevent thrombosis, and 3. brachial plexus block. Overall, the proper administration of thiopental intravenously is remarkably free of local toxicity. Dr. Med. Khaled Radaideh

September 18 Dr. Med. Khaled Radaideh

Propofol Intravenous anaesthetic/hypnotic. Akylphenol.
September 18 Intravenous anaesthetic/hypnotic. Akylphenol. Propofol is a sweet drug in the OR, but definitely not for home use. Dr. Med. Khaled Radaideh

Propofol Physical and chemical properties
September 18 Emulsion consists of: 1% propofol 10mg/ml 10% soyabean oil. 2.25 %glycerol 1.2% purified egg phosphatide. Dr. Med. Khaled Radaideh

Propofol Physical and chemical properties
September 18 so Propofol is a highly lipid soluble oil that’s combined with glycerol, egg, and soya bean oil for IV administration. It’s appearance is similar to that of a 2% milk. It has a pH of 7 and is supplied in 20 ml ampoules with a concentration of 10 mg/ml. Neither precipitates histamine release nor triggers malignant hyperthermia. Has no effects on muscle relaxants. Associated with low incidence of nausea & vomiting. Dr. Med. Khaled Radaideh

Propofol Dosage For healthy unpremedicated 2.5-3 mg/kg.
September 18 For healthy unpremedicated mg/kg. For premedicated mg/kg. Elderly patients <= 1 mg/kg. Maintenance of anesthesia ( mcg/kg/min) combined with N2O and Opioids (Continuous Infusion: Total intravenous Anesthesia TIVA) For IV conscious sedation for operative procedures with local anaesthesia mcg/kg/min. Dr. Med. Khaled Radaideh

Propofol Effects on Organ systems
September 18 Cerebral: decreases cerebral blood flow and intracranial pressure. Propofol has antiemetic, antipruritic, and anticonvulsant properties. Cardiovascular: decrease in arterial blood pressure secondary to a drop in systemic vascular resistance, contractility, and preload. Hypotension is more pronounced than with thiopental. Propofol markedly impairs the normal arterial baroreflex response to hypotension. Dr. Med. Khaled Radaideh

Propofol Effects on Organ systems
September 18 Respiratory: propofol causes profound respiratory depression. Propofol induced depression of upper airway reflexes exceeds that of thiopental. Venous irritation: Pain on injection is more common than with thiopental esp. if given in a small vein in the hand. To solve this problem: 1. small doze of lidocaine with propofol. 2. administering propofol through a fast flowing more proximal IV catheter. Dr. Med. Khaled Radaideh

Approved Patient Population
Propofol indications September 18 indication Approved Patient Population Initiation and maintenance of Monitored Anesthesia Care sedation Adults only Combined sedation and regional anesthesia Adults only (See PRECAUTIONS) Induction of General Anesthesia Patients ≥ 3 years of age Mainenance of General Anesthesia Patients ≥ 2 months of age Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Dr. Med. Khaled Radaideh

Propofol Contraindications
September 18 Egg allergy. Lack of resuscitation equipment or knowledge of the drug. Inability to maintain a patent airway. Conditions in which reduction in blood pressure can’t be tolerated. E.g. patients with fixed cardiac output (severe aortic or mitral stenosis, IHSS, pericardial tamponade) and those in shock status. Dr. Med. Khaled Radaideh

Ketamine It’s a dissociative anesthetic agent.
September 18 It’s a dissociative anesthetic agent. by dissociative we mean that the patient is unconscious but appears awake and doesn’t feel pain. It has anesthetic and analgesic effect Dr. Med. Khaled Radaideh

Ketamine Physical & chemical Properties
September 18 chemically related to the psychotropic drug ( e.g. phencyclidine). Water soluble, and 10x more lipid soluble than thiopental. pH= Dr. Med. Khaled Radaideh

Ketamine Pharmacokinetics Route of administration
September 18 I.V. : 2mg/kg IM. Oral. Rectal. Needs higher doze due to extensive first pass metabolism and decreased absorption. Dr. Med. Khaled Radaideh

Ketamine Pharmacokinetics Dosage
September 18 IM  5 – 10 mg/kg. peak plasma level reach approx 15 minutes IV  1 – 2 mg/kg. dissociated stage is noted in 15 seconds. intense analgesia, amnesia & unconciousness occur within minutes subsequent IV doses of 1/3 – ½ of the initial dose maybe required Dr. Med. Khaled Radaideh

KETMINE METABOLISM September 18 It has a rapid absorption and distribution to the vessel rich groups like THIOPENTAL Hepatic metabolism is required for elimination <5% excreted unchanged in urine Dr. Med. Khaled Radaideh

KETMINE Mechanism of action
September 18 There are 3 theories explains the MOA of ketamines : 1 – N-methyl aspartate receptor theory : NMA receptors may represent a subgroup of the sigma opiate receptors (the PCP site) that blocks spinal pain reflexes. 2 – Opiate receptor theory : Ketamine may have some affinity for opiate receptors but it’s effect can’t be reversed with naloxone. 3- Miscellaneous receptor theory : It reacts with muscarinic, cholinergic and serotonergic receptors. Ketamine is a potent analgesic at subanesthetic plasma concentrations. It has a wide margin of safety ( up to 10x the usual dose ) Dr. Med. Khaled Radaideh

KETMINE Pharmacodynamics
September 18 CNS : 1. ketamine increases cerebral oxygen consumption, cerebral blood flow, and intracranial pressure 2- generalized increase in the muscle tone and purposful movements. 3- Unpleasant dreams, hallucinations or frank delirium (esp. females & large doze of ketamine). incidence of dilirium in year old pts is approx. 20% Dr. Med. Khaled Radaideh

September 18 Respiratory system: It preserves laryngeal &pharyngeal airway reflexes. Ketamine is a potent bronchodilator. The CO2 response curve is shifted to the left with its slope unchanged (similar to opiates). FRC  unchaged. Minute ventilation  unchanged. Tidal volume  unchanged. Hypoxic pulmonary vasoconstriction  unchanged. Ketamine causes increased secretions but this can be limited by anti-cholinergic drugs. Dr. Med. Khaled Radaideh

September 18 CVS: It produces central sympathetic stimulation, which increases: arterial blood pressure, heart rate, and cardiac output. Pulmonary artery pressure. Coronary blood flow. Myocardail oxygen uptake. It may cause myocardial depression if the sympathetic nervous sys is exhausted or blocked. Dr. Med. Khaled Radaideh

September 18 GI Minimal anorexia, nausea & vomiting. GU Placental transfer does occur, but neonatal depression hasn’t been observed if the doze is limited to < 1 mg/kg. Muscle system Generalized increase in skeletal muscle tone. Increases the effects of muscle relaxants. Endocrine Sys. Increased sympathetic stimulation  increased blood glucose, increased plasma cortisol, increased heart rate. Dr. Med. Khaled Radaideh

KETMINE Indications September 18 1- sole anesthetic for diagnosis and surgical procedures 2- induction of anesthesia 3- to supplement regional or local anesthetic techniques 4- for anesthetic induction in severe asthmatic pts. Or patients with cardiovascular collapse requiring emergency surgery Dr. Med. Khaled Radaideh

KETMINE Contraindications
September 18 1- lack of knowledge of the drug 2- lack of resuscitative equipment 3- inability to maintain a patent airways 4- allergy to ketamine 5- history of psychosis 6- cerebro-vascular disease 7- Patients. For whom hypertention is hazardous Dr. Med. Khaled Radaideh

2 – minimal cardiarespiretory depressant effect.
Benzodiazepines September 18 Features which result in their popularity as adjuvant IV anaesthetic agents: 1 – amnesia 2 – minimal cardiarespiretory depressant effect. 3 – anticonvulsant activity. 4 – low incidence of tolerance and dependence. Dr. Med. Khaled Radaideh

Benzodiazepines Mode of action
September 18 1 – They inhibit the actions of glycine (by increasing the conc. Of a glycine inhibitory neurotransmitter) which will lead to antianxiety and skeletal muscle relaxant effects. 2 – They facilitate the actions of the inhibitory neurotransmitter GABA which results in the sedative and anticonvulsant effects. Benzodiazepines are highly lipid soluble. They are highly protein bound (albumin). They are metabolized by the liver through conjugation with glucoronic acid and excreted by the kidneys. Midazolam and Diazepam are the most commonly used benzodiazepines during operative procedures. Dr. Med. Khaled Radaideh

Benzodiazepines Midazolam and diazepam
September 18 They are commonly used to provide: 1- IV sedation. 2- amnesia. 3- reducing anxiety. Dr. Med. Khaled Radaideh

The differences between them 1- Midazolam is 2-3 times more potent than diazepam: 2- The dose for IV conscious sedation: 0.5 – 3 mg up to 0.1 mg/kg for midazolam, and mg for diazepam. 3- The dose for inducing anesthesia: 0.2 – 0.4 mg/kg for midazolam , and mg/kg for diazepam. 4- Midazolam has a more rapid onset, greater amnestic effect, less postoperative sedative effects than diazepam. September 18 Dr. Med. Khaled Radaideh

The differences between them 5- Pain on injection and subsequent thrombophlebitis is less likely with midazolam (an emulsion of diazepam) 6- Midazolam is more costly than diazepam). 7- Midazolam’s duration of action is less than diazepam but almost 3 times that of thiopental. 8- Elimination half time for midazolam range from 1-4 hours, and for diazepam from hours. 9- Midazolam is supplied as a clear liquid in concentrations of 1-5 mg/ml. September 18 Dr. Med. Khaled Radaideh

Benzodiazepine antagonists (Flumazenil)
September 18 It’s an imidazobenzodiazepine. It specifically antagonizes benzodiazepine’s central effects by copetative inhibition. It’s elimination half-time is one hour, considerably less than most benzodiazepines; therefore we will need repeated administrations of flumazenil to antagonize a benzodiazepine with a longer half-time. Dr. Med. Khaled Radaideh

Benzodiazepine antagonists (Flumazenil)
Flumazenil is supplied as a colourless liquid in a concentration of 0.1 mg/ml. The usual initial dose is 0.2 mg over 15 seconds, if the desired level of consiousness is not obtained within one minute of administration we can give repeated doses of 0.1 mg every minute up to the maximum of 2 mg, and if sedation recurs we can use infusions of mg/hour. Flumazenil is well tolerated. The most common side is nausea (4% of patients). September 18 Dr. Med. Khaled Radaideh

Narcotic Agonists September 18 Opium derived from dried juice of poppy plant which contains over 20 plant alkaloids. including morphine & codiene. Dr. Med. Khaled Radaideh

Narcotic Agonists Site of Action
Opioid receptors are predominantly located in the: 1. Brain stem (amygdala, corpus striatum, periaqueductal gray matter and medulla). 2. Spinal cord(substantia gelatinosa). 3. GIT. They act on 3 types of receptors: 1. Mu receptors (μ): analgesia, respiratory depression, euphoria, & physical dependence. 2. Kappa receptors (K): analgesia, sedation, respiratory depression, miosis. 3. Segma receptors(a): dysphoria, hallucination, tachypnea, tachycardia. September 18 Dr. Med. Khaled Radaideh

Narcotic Agonists Pharmacokinetics
September 18 Rapid distribution through the body following IV injection. It’s metabolized by the liver and the majority of the inactive metabolites are excreted unchanged in the urine. Dr. Med. Khaled Radaideh

Narcotic Agonists Pharmacodynamics
September 18 CNS: Opioids sedate through interfering with sensory perception of painful stimuli. large doses produce unconsciousness but they are generally incapable of producing anesthesia and it can’t guarantee total amnesia. It may produce nausea & emesis through stimulation of the chemoreceptor trigger zone. Dr. Med. Khaled Radaideh

September 18 Respiratory They result in dose related depression of respiratory rate and minute ventilation and increase the tidal volume which will lead to a slow deep respiration. Reversed by naloxone administration. Dr. Med. Khaled Radaideh

CVS Opioids have little myocardial depressant effect even when administered in high doses. Supplementation with either N2O or benzodiazepines may depress cardiac output. They decrease systemic vascular resistance either by decreasing sympathetic outflow or by releasing histamine (as morphine) which produces vasodilation & decrease SVR. Synthetic opioids are less likely to release histamine. They produce bradycardia by stimulation vagal nucleus in the brain stem. September 18 Dr. Med. Khaled Radaideh

GIT Narcotics slow GI mobility and may result in constipation or post operative ileus. All narcotics increase biliary tract tone which may lead to biliary colic with patients with bile stones. Others Increases the bladder sphincter’s tone  urine retention. Anaphylactic reactions, bronchospasm, chest wall rigidity and pruritis. September 18 Dr. Med. Khaled Radaideh

Narcotic Agonists Fentanyl and Morphine
September 18 Fentanyl is the most narcotic agent used during induction of anaesthesia due to its rapid onset (highly lipid soluble) and predictable duration of action (30 minutes). Morphine is used in the perioperative period to provide long lasting analgesia. And it should be administered slowly at a rate < 5 mg/min to avoid excessive histamine release. Dr. Med. Khaled Radaideh

Narcotic Agonists Fentanyl and Morphine
September 18 Low dose Analgesic dose Potency Ratio mg/kg 10 mg 1 Morphine 0.5 – 3 mic g/kg 100 mcg 100 Fentanyl Dr. Med. Khaled Radaideh

Narcotic Antagonists (Naloxone)
September 18 Naloxone competes with opioids at the mu, delta, kappa and sigma receptors. Ampules of 0.02, 0.4 and 1 mg/ml. Peak effect 1-2 min. Duration of action min. Used in perioperative surgical patients with excessive sedation or respiratory sedation secondary to opioids. Dr. Med. Khaled Radaideh

Narcotic Antagonists (Naloxone)
September 18 Given in small incremental doses. High doses of naloxone will result in sudden reversal of analgesic effects leading to abrupt return of pain resulting in hypertension, tachycardia, pulmonary edema, ventricular dysrhythmias and cardiac arrests. If sedation or respiratory depression recurs, continuous infusion of 3-10 micg/kg/hour of naloxone is required. Dr. Med. Khaled Radaideh

ANAESTHESIA THANK YOU September 18 Dr. Med. Khaled Radaideh

INTRAVENOUS ANAESTHETIC Agents
September 18 Thank you Dr. Med. Khaled Radaideh Department of Anesthesiology - Jordan University of Science and Technology Irbid-Jordan Dr. Med. Khaled Radaideh

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