Jonathan C. Caranzo M.D.

QCGH-MC

Introduction Mode of Action Pharmacokinetics Pharmacodynamics Individual Drug Discussion Maintenance Conclusion

General anesthesia is not limited to the use of inhalation agents. Numerous drugs administered intravenously augment or produce an anesthetic state within thier therapeutic dosage range. Induction and even maintenance of anesthesia can be achieved with total intravenous anesthesia technique.

Earlier Thiopental quickly became the gold standard of IV anesthetics

1.) Drug compatibility ( water solubility) and stability in solution 2) Lack of pain on injection, veno-irritation, and local tissue damage following following extravasation 3) Low potential to release histamine or precipitate hypersensitivity reactions. 4. Rapid and smooth onset of hypnotic action without excitatory activity.

5.) Rapid metabolism to pharmacologically inactive metabolites 6.) A steep dose response relationship to enhance titratability and minimize tissue reaction 7.) Lack of acute cardiovascular and respiratory depression

8.) Decreases in cerebral metabolism and intracranial pressure 9) Rapid and smooth return of consciousness and cognitive skills with residual analgesia. 10.) Absence of postoperative nausea and vomiting, amnesia, psychomimetic reactions, dizziness, headache, or prolonged sedation(hangover effects)

Lack of a particular property =Disadvantages = restricted indications Optimal clinical properties are not equally important in every clinical situation, the anesthesiologist must make the choice of the IV anesthetic drug that best fits the needs of the individual patient and the operative procedure.

Drug-surface receptor interaction => inhibitory pharmacologic effect. Exogenous drugs - incidental passengers 3 classes of cell surface receptors

G-protein coupled receptor Ligand- gated ion channel Receptor-linked enzymes

Excitable Transmembrane Proteins

Voltage-sensitive ion channels Ligand-gated ion channels(ionotropic receptors)

Inv. primarily in fast synaptic transmission bet. cells Receptor-ion channel complexes Ion channel is an integral part of a larger more complex transmembrane protein.
2 Cationselective(excitatory) nAChRs, 5HT3 receptor 2 Anionselective(inhibitory) GABAa, glycine receptor Glutamate principal excitatory nerotransmitter in the CNS

MECHANISM OF ACTION IV anesthetics exert their primary sedative and hypnotics effects through interaction with GABA neurotransmitter system. GABA type A activation transmembrane chloride conductance increases resulting in hyperpolarization of postsynaptic cell membrane and functional inhibition of postsynaptic neuron

Different combinations of subunits form ligand-gated ion channels that are activated by selective ligands: NMDA, Kainate etc.

Benzodiazepines bind to specific repceptor types that are part of the GABA-A receptor complex.

Increases the efficiency of the coupling between the receptor and the chloride ion channel. Increases the frequency of opening of chloride channel

DOSE-DEPENDENT CNS DEPRESSION

20% receptor occupancy - anxiolysis 30 % - 50% - amnesia and sedation 60% - hypnosis/unconciousness

Barbiturates and Propofol binding with specific membrane structures decreases the rate of dissociation of GABA from its receptor, thereby increasing the duration of GABA-activated opening of the chloride ion channel.

Barbiturates also mimic GABA by directly activating the chloride channels Thiopental- competitive inhibition at the nicotinic acetylcholine receptor in the CNS. Etomidate augments GABA-gated chloride currents (indirect modulation) but at higher concentration produces direct activation of the chloride channel without activating GABA.

Ketamine does not interact with GABA - antagonistic activity at NMDA receptor - also inhibits neuronal sodium channels(local anesthetic action) and calcium channel(cerebral vasodilatation)

Lipid solubility facillitates diffusion of IV anesthetics across cellular membranes and BBB Non-ionized form only form that is able to readily cross the neuronal membrane Rapid action

Lipid solubility High proportion of cardiac output (20%) perfusing the brain

Pharmavokinetics of IV anesthetics are characterized by rapid distribution and subsequent redistribution into several hypothetical compartments followed by elimination

Concentration of drug in the central compartment rapidly declines below hypnotic threshold => short emergence time Slow return of the anesthetic from the deep compartment contributes little to the concentration of the drug in the central compartment which is rapidly cleared.

Tissue Group Vessel-rich

Composition Brain,Heart, Liver, Kidney,Lungs Musacle, skin Fat Bone,ligament, cartilage

Body Mass(%) 10%

Cardiac Output(%) 75

Muscle Fat Vessel-poor

50 20 20

19 6 0

Primary mechanism of terminating central effect after induction:

Redistribution from central highly perfused compartment (Brain) to the larger but less well perfused compartments (muscle, fat).
Elimination does not usually play a major role, after induction, in terminating CNS effect.

During Maintenance
Blood level of anesthetic equals that of the brain
so that elimination now plays a role in maintenance/termination of CNS effect.

Metabolism 1. Primarily Hepatic - conversion into more water- soluble metabolites. 2.Renal Metabolites with pharmacologic activity - oxazepam, desmethyldiazepam, norketamine, pentobarbital Slow elimination partly due to high degree of protein binding.

Steady state concentration during infusion depends on rate of drug aministration and clearance rate. When an infusion is discontinued

Rate at which plasma concentration decreases depends on clearance rate as reflected by the half life value.

higher clearance = shorter the half-life = faster recovery

Degree of protein binding Efficiency of hepatic and renal elimination Physiologic changes with aging Pre-existing disease states Drug interaction

Hepatic disease can influence pharmacokinetics of drug

Delayed arousal is due to decreased detoxification Altering the plasma protein content and changing the degree of protein binding Decreasing the hepatic blood flow Depressing the metabolic enzyme activity of the liver

Brain

Decreaed brain mass Body Water 61%->53% Lean Body Mass 19% -> 25% Body Fat 26-33 38 - 45

Effects of Aging

Liver
Dec. Liver mass and blood flow Dec. Hepatic extraction No change in hepatic microsomal enzyme activity Serum albumin = 4.7 -> 3.8

Kidney
Weight
100 -> 80 <GFR

Principal pharmacologic effect Most sedative-hypnotic drugs cause a proportional reduction in cerebral metabolism (CMRO2)and cerebral blood flow(CBF) = decrease in ICP. Some hypnotics possess cerebroprotective potential Lower intraocular pressure except Ketamine

Possible epileptogenic properties Dose dependent respiratory depression (except ketamine and etomidate) Cardiovascular changes Lack intrinsic analgesic effect except ketamine and dexmedetomidine.

Thiopental (Pentotal) Thiamylal (Surital)- slightly more potent but similar pharmacologic profile

S(-) isomer, R(-) isomer

Methohexital (Brevital) B-L isomer 4x-5x more potent than a-L isomer but produces excessive motor response. All three are available as sodium salt and must be dissolved in isotonic sodium chloride(0.9%) or water to prepare solutions 2.5% thiopental 1-2% methohexital 2% thiamylal

Barbiturates + LR/acidic solution = precipitation occlude IV catheter Thiopental (2.5%) = rare venoirritation Methohexital (1%) = (+) venoirritation Intra-arterial injection =>serious complication treated with lidocaine, regional anesthesia induced sympathectomy, heparinization

Thiopental metabolized in the liver -> hydroxythiopental and carboxylic acid derivatives. High doses -> desulfuration reaction -> pentobarbital

Decrease in CMRO2 and CBF => ICP Decrease in systemic arterial pressure is less than the reduction in ICP => improved cerebral perfusion and compliance Thiopental

widely used to improve brain relaxation during neurosurgery Improve cerebral perfusion pressure (CPP) after brain injury

Dose dependent respiratory depression

But causes Broncho/Laryngospasm after low dose induction

Decreases in cardiac output, systemic arterial pressure and peripheral vascular resistance

Potent anticonvulsant activity

Used to treat refractory status epilepticus

Antianalgesic effect
Lower pain threshold Immunosuppression impair neutrophil function inhibits nuclear trascription factor KB(central regulator of immune response BM depression and leukopenia Allergic reaction

Benzene ring fused to a seven-membered diazepine ring(5-aryl benzodiazepine structure) Parenteral benzodiazepines:
Diazepam (Valium) Lorazepam (Ativan) Midazolam (Versed) - water-soluble, acidified aqueous solution PH 3.5 - intramolecular reaarangement at physiologic PH more lipid soluble - higher affinity for benz receptor 2x-3x more potent

Hepatic metabolism via oxidation and glucuronide conjugation

Diazepam

Metabolized to active metabolites (desmethyldiazepam, 3-hydroxydiazepam) Cimetidine inhibit the oxidative metabolism of diazepam Severe liver disease reduces diazepam protein binding and hepatic clearance rate -> volume distribution -> prolongs the t1/2 value.

Diazepam

Chronic renal disease -> protein binding and the free drug fraction -> enhanced hepatic metabolism -> shorter t1/2 value Elderly -> clearance rate is decreased -> prolong t1/2 to 75-150 hours

Midazolam
Undergo extensive oxidation by hepatic enzymes to form water soluble hydroxylated metabolites which are excreted in urine. Primary metabolite = 1-hydroxymethylmidazolam mild CNS depressant activity Hepatic clearance rate is 5x > than lorazepam and 10x > than diazepam. Age has relatively little influence on elimination half life.

Lorazepam
Directly conjugated to glucuronic acid to form pharmacologically inactive metabolites. Severe hepatic disease -> clearance rate Age and renal disease have little influence on the kinetics

Distribution volumes are similar, differ clearance rate The context-sensitive half-times for diazepam and lorazepam are very long. Only midazolam should be used by continuous infusion to avoid excessive accumulation

PROPERTIES:

ANXIOLYTIC ANTEROGRADE AMNESIA SEDATIVE-HYPNOTIC ANTICONVULSANT SPINALLY MEDIATED MUSCLE RELAXANT PROPERTIES

COMPARED WITH BARBITURATES

More specific CNS effect Higher therapeutic index Greater margin of safety after an overdose Less tendence to produce tolerance Less potential for abuse Elicit fewer and less serious drug interactions

Primarily used as premedicants and adjuvant drugs Midazolam is the most commonly used premedicant. Midazolam 0.4 0.8mg/kg oral = excellent premedicant before parenteral separation in children.

100-200ng/ml = unconsciousness in Midazolam <50ng/ml = awakening occur Midazolam and opiods analgesics = synergistic 0.1-0.2 mg/kg IV = premedicated induction dose

Onset of unconsciousness is facilitated by small dose of opioids 1-3 mins prior to Benz

0.25-1mg/kg/min = infusion rate Higher maintenance infusion rates and prolonged administration -> accumulation and prolonged recovery times. Ceiling Effect

Decrease both CMRO2 and CBF (analogous to the barbiturates and Propofol) Dose dependent respiratory depression Depress the swallowing reflex and decrease upper airway reflex activity

Midazolam and Diazepam = SVR and BP when large doses are administered for induction.

May increase HR by mechanism similar to thiopental Maybe beneficial in improving cardiac output in the presence of congestive heart failure decreased preload and afterload

BP lowering effect are marked in hypovolemic patients.

Anticonvulsant Anti-platelet activity

Inhibit PAF-induced aggregation

FLUMAZENIL

1,4-imidazobenzodiazepine derivative Competitive antagonist Agonist antagonist activity Absence of phenyl group and replaced by carboxyl group Half life = 1 hour Duration of action = 30 60 mins 1-3mg IV = 45-90 minutes antagonism

FLUMAZENIL
Resedation may occur after a single dose Not associated with adverse cardiovascular effect Does not change CBF and CMRO2 following midazolam anesthesia in craniotomy

2,6-disopropylphenol Insoluble in aqueous solution Cromophor EL formulation = anaphylactic reactions Egg lecithin emulsion formulation (Diprivan)

10% soybean oil 2.25% glycerol 1.2% egg phosphatide

32-67% experience pain on injection which can be minimized by:

Injection in larger veins Prior administration of lidocaine, fentanyl or remifentanil Diluting the formulation with additional solvent (Intralipid) or changing the lipid carrier (Lipofundin) New formulation with sodium metabisulphite instead of disodium edentate as antimicrobial

Aquavan
Water soluble prodrug Rapidly hydrolyzed by plasma alkaline phosphates in the circulation Slower onset but similar recovery profile Transient burning sensation on perineal region following IV injection

Clearance rate (20-30 ml/kg/min) exceeds hepatic blood flow Long elimination half life Induction dose 1.5-2.5 mg/kg 25-75 ug/kg/min- sedation 100-300ug/kg/min recommended maintenance infusion rate for hypnosis Unconsciousness 2-6 ug/ml blood level 1 to 1.5 ug/ml - awakening

Same with barbiturates

children require induction and maintenance doses elderly require induction and maintenance doses

More profound cardiovascular depressant effect Alters baroreflex mechanism Decrease CMRO2, CBF and ICP Neuroprotectant

Phenolic hydroxyl group scavenges free radicals and inhibits lipid peroxidation Prevents reperfusion injury during CABG Scavenges phenoxynitrites potent reactive metabolite for the initiation of lipid peroxidation, potent bactericidal agent involved in phagocytosis.

Dose dependent respiratory depression = 25%35% of patients after indcution of anesthesia Decreases IOP Inhibits platelet aggregation

TXA2 and PAF inhibition

Allergy
Phenyl nucleus and diisopropyl side chain dermatologic preparations

Anticonvulsant property 1mg/kg Produce bronchodilation in patient with COPD

Except preparation with metabisulfite

Anti emetic properties

Direct depressant effect on vomiting center Depression of subcortical center Treatment of post op N/V - 10 to 15mg IV 10mg IV

Decrease pruritus produced by spinal opiods

Occasional excitatory motor activity (nonepileptic myoclonia) Does not trigger malignant hyperthermia Produce subjective feeling of well being and even euphoria abused by health care professionals

Ketalar or Ketaject Phencyclidine derivative Dissociative anesthesia Chiral center produces two optical isomers

S(+) left handed isomer

More intense analgesia More rapid metab and recovery Less salivation Lower incidence of emergence reactions

R(-) right handed isomer

Analgesia (0.2 0.5mg/kg IV)

thalamic and limbic systems responsible for the interpretaion of painful signals Inhibition of spinal NMDA receptors

Dissociative anesthesia

Electrophysiologic inhibition of Thalamocortical pathways and stimulation of the limbic system

Extensively metabolized by hepatic microsomal cyctochromeP450 enzymes Norketamine primary metabolite 1/3 to 1/5 as potent than parent compound High hepatic clearance rate 1 L/min and large distribution volume 3L/kg

Dose dependent CNS depression (dissociative anesthesia)

Profound analgesia amnesia

6mg/kg = used for premedication for pediatric patient, PO. 1-2 mg/kg IV or 4-8mg/kg IM following benzodiazepine can be used for induction of anesthesia. Onset 45 60 s IV, 2-4mins IM Return of consciousness 10 20mins, full orientation additional 60 90mins. Longer after repeated IV of continuous insusion.

Psychomimetic reactions during early recovery period

Hallucination Nightmares Altered short term memory and cognitionsonality problem or frequent dreaming >15yo,female,>2mg/kgIV,hx of p

CMRO2, CBF and ICP Anticonvulsant property Possible myoclonic/seizure like activity in normal nonepileptic patient

Bronchodilator activity Protective airway reflexes preserved Increased secretions

Both salivary and tracheobronchial mucous glands

Prominent cardiovascular stimulating effect

Direct stimulation of SNS Only anesthetic that peripheral arteriolar resistance Systolic increase 20 to 40mmHg
Inc. During first 3-mins Predrug level: 10-20 mins

Increased: systemic pressure, pulmonary art pressure, HR, CO, cardiac work,myocardial O2 requirement. Beneficial in patient with hypovolemia, but note the possble myocardial depressant effect.

Contraindicated in patient with:

Severe coronary artery disease Patient with poor right ventricular reserve Can be used in patient with malignant hyperthermia Used extensibly for burn dressing changes, dbridments, and skingrafting procedures. The excellent analgesia and ability to maintain spontaneous ventillation in an airway that might otherwise be altered by burn-scar contractures are important advantages of ketamine in these patients

Carboxylated immidazole containing anesthetic compound D isomer/R(+) posses anesthetic activity Analogous to Midazolam Aqueous preparation (Amidate)

Formulated in 0.2% solution with 35% propylene glycol

incidence of pain on injection Venoirritation hemolysis

Metabolized by hydrolysis of the ethyl side chain to its carboxylic acid ester

Hepatic microsomal enzyme and plasma esterazes

Standard induction dose 0.2-0.3mg/kg IV Involuntary myoclonic movements(50-80%) Decrease CMBRO2(35%-45%), CBF and ICP
Lowers a previously increased ICP Hemodynamic stability maintain adeguate CPP Used both for induction and maintenance in neurosurgery

Inhibitory effect on adrenocortical synthetic functions 11B-hydroxylase

single induction dose produces adrenal suppression which persists for 5-8 minutes Not for long-term tx of increased ICP

Anticonvulsant properties

Used to terminate status epilepticus

Minimal cardiorespiratory depression even in the presence of cardiovascular and pulmonary disease Used in patients with reactive airway disease

High incidence of postoperative nausea and emesis Inhibit platelet function

Valuable induction drug for specific indications

Patients with severe cardiovascular disease Cerebrovascular disease

Highly selective 2 adrenoreceptor agonist Blunt the acute hemodynamic response to laryngoscopy and intubation. Potentially useful adjuvant during local and regional anesthesia Provide comparable sedation to midazolam Slower onset and offset of sedation than propofol Improved the quality of both intra and postoperative analgesia.

Traditional intermittent bolus Continuous IV infusions:

Provide more stable blood and brain concentration Improve anesthetic conditions Hemodynamic stability Decrease side effects and recovery times

Required plasma concentration depends on:

Desired pharmacologic effects Concomitant use of other adjunctive drugs Type of operation Patients sensitivity to the drugs Preexisting diseases

In general, children have higher clearance rates while elderly have reduced clearance rates. Infusion scheme should be tailored to provide peak drug concentration during the periods of the most intense stimulation.

Intraoperative interventions transiently increase the anesthetic requirements:

Laryngoscopy Tracheal intubation Skin incision Entry into body cavities

Thiopental and Methohexital = most cost effective IV anesthesia in situation in which a rapid recovery is not essential Methohexital
more rapid recovery Excitatory side effects (myoclonus, hiccoughing) Anesthetic of choice for electroconvulsive therapy procedures

Propofol
IV drug of choice when rapid and smooth recovery is essential Absence of a hang over effect Reduced postoperative nausea and vomiting symptoms Combine with potent, rapid and short acting opiods analgesics (Remifentanil) facilitate the use of TIVA techniques

Etomidate
Minimal CV and respiratory deppression Extremely useful induction agents in high risk patients Used as an alternative in methohexital in electroconvulsive therapy procedures Side effects:

Pain on injection Excitatory phenomenon Adrenocortical suppression High incidence of postoperative nausea and vomiting

Ketamine

Unique IV anesthetic that produces a wide spectrum of pharmacologic effects

Sedation Hypnosis Somatic analgesia Bronchodilation Sympathetic nervous system stimulation

Alternative to an inhalation induction when IV access is difficult to establish

Ketamine is indicated in patient with:

Severe hypovolemic shock Acute bronchospastic states Cardiac tamponade

Useful part of coinduction and maintenance anesthetic techniques when avoiding opiods analgesia is desirable

The shorter context-sensitive half life values of the newer sedative-hypnotic drugs make these compounds more useful as continuous infusions for maintenance of anesthesia and sedation.

While the search for the ideal IV anesthetics continues, the major challenge for anesthesiologists is to choose the sedativehypnotic drugs that most closely matches the patients needs in specific clinical situations.

HAPPY BIRTHDAY DRA. KWONG