Tutor: Dr. Sohail Anjum By: Dr. Muhammad Haqqi Dr. Fahad Mahmood Dr. Saqib Hussain Khan Dr. Zahid Bashir

Introductiony General Anesthesia is not limited only to Inhalational agents y A lot of effective Intravenous agents have been devised as well y

Properties of an IDEAL I/V Anesthetic: Stable in the solution Absence of pain Low potential to release Histamine Rapid Onset Prompt metabolism to inactive compounds Efficient Clearance & redistribution Benign CVS & Respiratory Effects Decrease in cerebral blood flow (CBF) & Metabolism (CMRO2) Complete return of Consciousness Absence of Adverse PostOp effects like Nausea , Vomiting , Headache

Factors affecting Heamodynamics after I/V Induction:y Drugs y Blood volume y Sympathetic nervous system y Speed of Injection y Cardiovascular Drugs y PreAnesthetic medication y Direct effect on Cardiac Contractility or Peripheral Vasculature

List Propofol Barbiturates : 1) Thiopental Sodium

2) Methohexital 3) Thiamylal 4) Secobarbital 5) Pentobarbital Benzodiazepines: 1) Diazepam 2) Midazolam Ketamine Etomidate

Mechanism of ActionACTIVATION OF GABA RECEPTORS:

GABA is the principle inhibitory neurotransmitter of CNS

Propofol exerts its effect by binding to beta subunit of GABAA receptor: decreases the rate of dissociation of GABA from its receptors --------> increasing the duration of GABA activated Cl- ion channels----------> hyperpolarization of postsynaptic cell membrane---------------------> functional inhibtion of postsynaptic neuron.

ION CHANNEL BLOCKING EFFECTS IN CEREBRAL CORTEX BLOCKING OF NICOTINIC Ach RECEPTORS INHIBITORY EFFECTS ON LYSOPHOSPHATIDATE SIGNALING IN LIPID MEDIATING RECEPTORS

STRUCTURE 2,6-diisopropylphenol

an Alkylphenol

compound

Alkylphenol side chain

length influences the potency , induction and recovery characteristics .

FormulationPrepared as 1% isotonic Oil in Water Emulsion(10mg/ml) containing:y 10% Soyabean Oil y 2.25% Glycerol y 1.2% Egg Lecithin y 0.005% Disodium Edetate or 0.025% Sodium Metabisulfite to retard bacterial growth

Painful Injection 1% Lignocaine can be added or an Opiod like Fentanyl can be given prior injecting AMPOFOL: less lipid formulation (5% soyabean oil & 0.6% egg lecithin) AQUAVAN : Water Soluble Prodrug Hydrolyzes by Plasma Alkaline Phosphatases releasing the free propofol

PHARMACOKINETICS ROUTE: INTRAVENOUS DOSES: Induction ---> 1 -- 2.5 mg/kg Maintainance infusion---> 50 -- 200 g/kg/min Sedation infusion---> 25 -- 100 g/kg/min DISTRIBUTION: Highly lipid soluble Initial Distribution Half life ---> 2 -- 8 min. Elimination Half life ---> 2 24 hrs. Protein Binding -- > 98%

Cont Metabolism: Rapid distribution to tissues Clearance Rate 20 30 ml/kg/min. Conjugation: Rapid Hepatic clearance by Oxidative metabolism by cytP-450 resulting in inactive water soluble metabolites like Suphates and Glucoronic acid These are eliminated by Renal Clearance. ExtraHepatic Elimination Route: Lungs Pharmacokinetics mildly change in CRF and CLD.

PHARMACODYNAMICS

I. II. III. IV. V.

Cardiovascular System:Direct Myocardial depressant Arterial & Venodilator Decreases Mean arterial pressure Blunts Baroreceptor Reflex Heart Rate is minimally affected

I.II. III. IV. V. VI. VII.

Central Nervous System:Decreases Cerebral Metabolism Decreases ICP Decreases Cerebral Blood Flow Decreases Cerebral perfusion pressure as MAP decreases Supresses the EEG activity Decreases IOP Dose not trigger Malignant Hyperthermia

Cont

I. II. III. IV. V.

Respiratory System:Respiratory Depressant causing APNEA (esp. after Intubating Dose) Tidal volume Decreases and R/R increases in maintainance infusion Inhibits the Hypoxic Ventilatory Drive Depression of Upper Airway Reflexes (Helps intubation or LMA placement without Paralysis) Can produce mild Bronchodilation in COPD patients

ANTI-EMETIC:Depresses the ChemoReceptor trigger Zone(CMZ) & Vagal nuclei Reduction of Serotonin Concentration in AREA POSTREMA Dose : 10 20 mg

No ANALGESIC EFFECT

Clinical Usesy Good Induction agent y Ideal agent for Day Care Surgery y Sedation y Antiemetic (in subanesthetic doses) y AntiPruritic y Anticonvulsant(Status Epilepticus) y Total Intravenous Anesthesia: Propofol is an Ideal agent for TIVA Infusion Dose : 50 -- 200 g/kg/min Safe and good alternative to Standard Inhalational Technique.

Cautions: Cautiously given in patients suffering from Lipid

Metabolism Disorder Hyperlipidemia Pancreatitis PROPOFOL SYNDROME:

Etiology: Prolonged infusion in critically ill patients leading to high lipid load characterized by: Myocardial Failiure Metabolic Acidosis Rhabdomyolysis

Thiobarbiturates :Thiopental Sodium Thiamylal Oxybarbiturates : Methohexital Phenobarbital Secobarbital Pentobarbital

Mechanism of ActionDepresses the Reticular Activating Centre Competitive Inhibitor at Acetylecholine Receptors in CNS suppressing the Excitatory neurotransmission GABA mediated Cl- ions conductance Enhancing the Inhibitory neurotransmission

StructurePhenoBarbitaly Barbituric acid derivatives y Substitution at 5 Carbon

Determines hypnotic & anticonvulsant effects e.g.: Phenyl group in Phenobarbital is anticonvulsant but methyl group in Methohexital is not

Cont5- t t iy Replacing the Oxygen at 2

l-5[1- t l r it ric ci

t l]2-

carbon with a Sulfur atom increases its Lipid Solubility.y Thiopental & Thiamylal more

lipid soluble

Pharmacokinetics(Thiopental Sodium)Formulation: 2.5% solution should prepared in Isotonic NaCl or Water (not with Ringer s lactate) pH 9 (Highly Alkaline) Route: I/V Rectal for Children Doses: Induction 3 6 mg/kg I/V Sedation 0.5 1.5 mg/kg I/V

ContDistribution: Highly Lipid soluble Protein Binding 80 85% Distribution half life 2 4 min Elimination half life 11 hrs Metabolism: Hepatic Oxidation to inactive water soluble compounds like, I. Hydroxythiopental II. Carboxylic acid derivative

These are then excreted by kidneys Hepatic and Renal pathology results in decreased protein binding and increasing its free fraction

Pharmacodynamics:Cardiovascular System: Decrease in Blood Pressure Decreased Venous return due to peripheral pooling of blood ( via Medullary Vasomotor Centre ) Decrease Cardiac Output Direct Myocardial Depression Heart rate increases via Baroreceptor Reflex Hypotension exagerates in CCF & Hypovolemic patients. Respiratory System: Dose Dependant Respiratory Depression Depression of Medullary Ventilatory Centre Decrease Response to Hypoxia & Hypercarbia Tidal volume & Respiratory Rate Decreases Bronchospasm & Laryngospasm in Asthamatics or under lighter anesthetic plane. Apnea can occur for 30 90 min after sedative dose

ContCentral Nervous System: CNS depression ranges from Mild Sedation to Unconsciousness Constricts Cerebral Vasculature causing: I. Decreased Cerebral blood flow II. Decreased ICP III. Decrease in CMRO2 IV. Increase in CPP V. Robbin Hood Effect (reverse steel phenomenon) EEG changes at high doses Do not produce Muscle Relaxation Renal System: Decrease Renal Blood flow Decrease in GFR Hepatic System: Hepatic Blood flow Decreases Hepatic Enzyme ( Cyt P-450 )Inducer e.g. Digoxin

Clinical Uses:Induction agent AntiConvulsant Ideal I/V agent for Electroconvulsive Therapy Cerebroprotective agent during incomplete brain ischemia conditions like: Carotid endarterectomy Temporary occlusion of cerebral arteries profound Hypotension Cardiopulmonary bypass

Drug Interactions: Sulfonamides occupy the same protein binding site as

that of thiopental increasing free fraction of drug and prolonged organ effects All of the following potentiate the system depressant

effects of barbiturate: Ethanol Opioids AntiHistamines

Adverse Effects Allergy:Do not administer in patients with any History of Barbiturate Allergy

Porphyria: Absolutely contraindicated in patients suffering with Acute intermittent Porphyria Induction of - aminolevullinic acid synthetase ,a rate limiting step in porphyrin

synthesis precipitating an acute attack.

Venous irritation & Tissue damage occurs as its highly ALKALINE Intra Arterial irritation can cause severe pain , tissue damage & necrosis Treatment: Heparinization & Regional sympathetic block

Myoclonus & Hicoughing ; esp after Methohexital Histamine Release : esp by sulfur containing compounds

STRUCTUREy 2-(o-chlorophenyl)-2-

(methylamino) cyclohexanone y Structural analogue of Phencyclidine (PCP)y It retains PCP s

Psychotomimetic effect

FORMULATION Recaemic mixture of S+ and R- isomers, where S+

isomer is a more active and potent Anesthetic & Analgesic Profile Water soluble Available in 1%, 5% & 10% Aqueous solutions pH 3.5 5.5 Benzethonium Chloride added as a preservative

PHARMACOKINTICSRoute: I/V , I/M , Doses: Induction : 1 2 mg/kg I/V 3 5 mg/kg I/M Analgesia : 0.1 0.5 mg/kg I/V 50 g/kg/min I/V infusion Distribution: More lipid soluble & less protein bound ( only 12%) Distribution Half life : 10 - 15 min Elimination Half life: 2 4 hrs.

ContBiotransformation: High Hepatic Uptake Metabolized by Hepatic microsomal cyt P-450 enzymes to NORKETAMINE Norketamine 1/3rd as potent as Ketamine Norketamine undergoes Conjugation & Hydroxylation and excreted by Kidneys as water soluble compounds Distribution and elimination are slower with concurrent use of Benzodiazipines, Barbiturates

Mechanism Of Actiony Acts as antagonist on N-methyl-D-aspartate (NMDA) Receptor y Dissociates the neuronal activity of THALAMUS from the Cortex resulting in

DISSOCIATIVE ANESTHESIA

y Also stimulates the Limbic system y

It also binds to: Non-NMDA glutamate receptors Muscarinic receptors Monoaminarigic receptors Opioid receptors Sodium Channels Calcium Channels

PharmacodynamicsCentral Nervous system:o o o o o o o

Increases ICP Increases CBF Increases Cerebral Metabolic Rate Blocks Polysynaptic Reflexes in spinal cord Dissociative Anesthesia ( Muscle tone and Respiration maintained) Analgesia Amnesia ( up to 1 hour after recovery)

Cardiovascular System:o

Stimulates the Sympathetic Nervous System & Inhibit Reuptake of Norepinephrine causing: Increases Heart rate Increases Arterial Blood Pressure Increases Cardiac output Increases the Myocardial work and Oxygen demand

Cont These effects are often beneficial in ACUTE Hypovolemic Shock

Should be Avoided in patients with IHD ,CCF, uncontrolled HTN, Arterial Aneurysms It has shown Myocardial depressant effects in seriously ill patients with depleted Catecholamine reserves.

Respiratory System: Mildly Depresses the Respiratory Rate & Tidal Volume Potent Bronchodilator Upper Airway Reflexes remain Intact Response to Hypercarbia is minimally affected Good Analgesic & Sedative for Asthamatics even when used with Midazolam

Clinical Usesy Ideal Induction agent in Heamodynamically Unstable

Patientsy Good Analgesic esp. in Opioid Resisitant Chronic Pain

States.y Mild AntiConvlusant Activity

y Potent Bronchodilator

Adverse Effectsy Oral Secretions ( can be treated with glycopyrolate) y Muscle Tone is increased y Emotional Disturbances like: Restlessness Agitation Emergence Delirium ( Reduced by pre medication with Benzodiazepines) Hallucinations Nightmares Short term memory loss and Cognition

Cont Increases ICP so relatively contraindicated in Head

Trauma or Intracranial hypertension Eye Movements : Nystagmus Diplopia Blephrospasm Increases IOP So should not be used in Ophthalmic Surgeries

Anesthetic Depth difficult to assess

Drug Interactiony If administered with Tricyclic Antidepressants , can y y y y

produce Severe Hypotension, MI and Heart Failure as both inhibit Nor Epinephrine Uptake Potentiates Non Depolarizing NMBA Can predispose Seizures if used with THEOPHYLLINE Propranolol, Phenoxybenzamine can unmask its Myocardial depressant effects Lithium can prolong its duration of action

Mechanism of Action & Structure:y Agonist at GABAA Receptors & Depresses

the Reticular Activating System.

y Disinhibit the CNS that control

Extrapyramidal motor system Imidazole

y It is an Ethyl Ester of a Carboxylated y R-(+)-ethyl-1-(alpha-methyl-

benzyl)imidazole-5-carboxlyate acidic solution & lipid Solubilty at Physiological pH

y Imidazole Ring gives Water solubility in

Pharmacokinetics:y Formulation: 0.2% aqueous sol. with 35% propylene glycol y pH: 8.1 y Route: I / V y Dose: Induction: 0.2 0.5 mg/kg I/V y Distribution Half Life: 2 4 min. y Elimination Half life: 2.9 5.3 hrs y Protein Binding: 75% y Highly lipid soluble y Biotransformation: Hepatic Microsomal enzymes and Plasma Esterases rapidly

Hydrolyze it into water soluble compounds These compounds are excreted Renally Severe Hepatic Disease leads to prolong elimination half life.

PharmacodynamicsCentral Nervous system: Decreases Cerebral metabolic rate Decreases CBF Decreases ICP Lacks Analgesic property CardioRespiratory system: Mild Reduction in Peripheral Vascular Resisitance Mildly Reduce MAP Ventilation is not affected Dose not release Histamine.

Clinical Uses:y Best Induction Agent esp. for severe Cardiovascular &

Cerebrovascular Diseasey Anti-Convulsant esp.in Status Epilepticus

Adverse Effects:y Myoclonus .Can be lessened by Opioids. y PostOp. Nausea & Vomiting .Can be lessened by premedication by any

AntiEmetic

y Venous Irritation can occur. Can be lessened by Inj.Lignocaine prior

its administeration

y ADRENAL Suppression: It inhibits the activity of 11- -Hydroxylase, enzyme necessary for

synthesis of: I. Cortisol II. Aldosterone III. 17-hydroxyprogesterone

Cont

Single Induction dose causes this suppression for 5 8 hrs. Longterm Infusions associated with increased mortality in critically ill patients.

y Inhibit Platelet Function leading to prolongation of Bleeding time y Amnesia

BENZODIAZEPINESo o

Diazepam Midazolam Lorazepam,

Mechanism of Actiony They act on Specific receptor

(BZD receptors)site that are a part of GABAAreceptors y Binds GABA receptor and increases membrane Cl- ions conductance y They enhance the inhibitory effect of Various Neurotransmitters in CNS esp.Cortex

Structure of DiazepamBenzodiazepines include a Benzene ring

Structure of MidazolamLipid Soluble Water Soluble

y Imidazole ring contributes to

its Water Solubility at low pH.y At Physiological pH , ring

close thus making it Lipid Soluble.

Pharmacokinetics: Formulation:

Diazepam in Lipid emulsion Midazolam is Water Soluble Route: I/M, I/V & Oral Midazolam Intranasal, Sublingual & Buccal preparations are also available .

Doses: Diazepam: Premedication

Sedation 0.04 Induction 0.3 Midzolam: Premedication Sedation 0.01 Induction 0.1

0.2 0.5 mg/kg Oral 0.2 mg/kg I/V 0.6 mg/kg I/V 0.07 0.5 mg/kg I/M 0.1 mg/kg I/V 0.4 mg/kg I/V

Cont Distribution: Diazepam is very Lipid Soluble and is rapidly distributed. Midazolam is Water Soluble at low pH but Imidazole ring closes at Physiological pH increasing its Lipid Solubility. Distribution Half Life: Diazepam: 10 15 min. Midazolam: 7 15 min. Elimination Half life: Diazepam: 20 50 hrs Midazolam: 1.7 2.6 hrs.

Cont Protein Binding : 90 98% Biotransformation:Diazepam: Hepatic Metabolism via Oxidation & Conjugation. Metabolized to 3- Hydoxydiazepam ,which is an active compound. This undergoes Secondary Conjugation water soluble inactive products Severe liver disease reduce its Metabolism H2 Blockers like Cimetidine inhibit its Oxidation CRF decreases Protein binding free fraction of drug

ContMidazolam: it undergoes Oxidation by Hepatic Enzymes Water Soluble end products. Primary Metabolite of Midazolam 1-hydroxymethymidazolam has mild CNS depressant effect Hepatic clearance 10 times that of Diazepam.

PharmacodynamicsCardiovascular System: Decrease in Systemic Vascular Resistance & Blood pressure Mild Decrease in Heart Rate & Cardiac Output Heamodynamic changes are more prominent in Hypovolemic Patients Midazolam tends to reduce BP and PVR more than Diazepam Respiratory System: Dose dependant Respiratory depression Decrease in Tidal Volume & Respiratory Rate Depresses Swallowing & Upper airway reflex activity Respiratory depression will be more marked if used with Opioids esp. in COPD patients

ContCentral Nervous System: Decrease CBF ,Cereb. Metabolic Rate ,ICP Unconsciousness at Induction Doses. Mild Muscle Relaxant property at Spinal Cord Level not at NMJ No direct Analgesic Property Amnesia

Clinical Usesy Induction agent y As Pre- Medicant y Sedation in ICU y Anxiolytic y Anti Convulsant esp. Grand Mal Seizures (Diazepam) y Hypnotic y Sedative

Drug Interactions: Sodium Valproate & Diazepam can precipitate

Psychotic episode. Cimetidine can reduce metabolism of Diazepam. Erythrocine can inhibit metabolism of Midazolam Heparin displaces Diazepam from its protein binding site Opioids & Diazepam can markly decrease Blood pressure & PVR in Ischemic & Valvular Heart disease. Ethanol & Barbiturates can increase the sedative effects of Benzodiazepines.

Adverse Effectsy Reduce Ventilatory response to Hypercarbia y Resp. Depression at relatively low dose y Birth Defects: Cleft lip & Palate y Crosses the placenta and leads to Neonatal Depression