General Anesthetics

General Anesthetics

-        Explain briefly about pre-anesthetic agents

-        Identify the main inhalation anesthetic agents and describe their PD properties

-        Explain relationship of blood-gas partition coefficient of an inhalation anesthetic with its speed of onset of anesthesia and its recovery

-        Describe the major PK and PD characteristics of the IV anesthetic agents

-        Ideal properties of modern anesthetic agents.

-        History

-        Pre-anesthetic Agents

-        Role of Pre-anesthetics

-        To relieve anxiety and apprehension

-        To induce amnesia for preoperative and postoperative events

-        To administer analgesic that potentiate the effect of anesthetics

-         

-        To decrease vagal stimulation & secretion

-        To reduce acidity & volume of gastric juice

-        To induce gastric peristalsis to promote gastric content emptying

-        The uses of pre-anesthetic agents

1. Opioids: Morphine or pethidine

ü to relieve anxiety and apprehension

ü To reduce the dose of anesthetic required & to supplement poor analgesic

2. Anti-histaminic / emetic, sedative:

ü Promethazine:- for children

3. Sedative-hypnotics:

ü Diazepam or lorazepam produce loss of recall of pre-operative events

ü Midazolam for short period maintaining GA and calm the patient before operation

4. Anti-cholinergic agents:

ü To reduce salivary & bronchial secretion, to prevent HPN & laryngospasm (atropine or hyoscine)

5. H2 blockers (ranitidine or famotidine):

ü To prevent risk of aspiration pneumonia

6. Metoclopramide: In emergency surgery

     I.            Drugs affect anesthesia

  II.            Antimicrobial agents: additive to non-depolarizing drugs (aminoglycosides)

III.            Steroids: may be collapse of patient (prolonged use)

IV.            NSAIDs & anticoagulants: Oozing of wounds

 V.            Antihypertensive drugs: [but continue]

VI.            CCBs: Verapamil- heart with halothane

VII.            Digoxin- Arrhythmias

VIII.            Diuretics: Hypokalemia- potentiate NM blocking  and GAs

IX.            OCPs : Thromboembolism

  X.            Antipsychotic drugs: synergize with opioid, hypnotics and GA.

XI.            Beta blockers: prevent homeostatic sympathetic cardiac response to cardiac depressant anesthetic

XII.            Ant-depressants: MAO-I potentiate pethidine, sympathomimetics. TCA potentiate catecholamines

XIII.            General Anesthetic Agents

XIV.            General Anesthesia

XV.            Analgesia,

XVI.            Amnesia,

XVII.            Skeletal muscle relaxation

XVIII.            Unconsciousness 

XIX.            & loss of reflexes.

XX.            Stages of general anesthesia

XXI.            Protocols

XXII.            Minor procedures: Conscious sedation techniques (IV agents with LA).

XXIII.            Balanced anesthesia: short acting IV agents + opioids & nitrous oxide + O2

XXIV.            Major surgery: IV drugs to induce the anesthesia; inhaled anesthesia for maintaining , and NM blocking agents to effect muscle relaxation.

XXV.            Mechanism of Action

XXVI.            Increase threshold  for firing of CNS neurons

XXVII.            Potency of inhaled anesthetic- to their lipid solubility

XXVIII.            Effect on ion channels by interaction with membrane lipids or proteins- on endogenous  mechanism

XXIX.            List of group of GA

A. Inhaled anesthetic agents:

ü Gases: Nitrous oxide, Xenon

vVolatile liquids:

ü Halothane, Methoxyfurane, desofurane

ü Enfurane, Isofurane, sevofurane

B. Intravenous agents:

Barbuturates: Thiopental, methohexital

Benzodiazepine: Midozolam, diazepam

Propofol

Opioid analgesics: morphine, meperidine

Skeletal muscle relaxants: Depolarizing and non-depolarizing agents

Neurolept anesthetics: fentanlyl or alfentanyl, or remifentanyl, etc. with droperidol & nitrous oxide

Dissociative anesthetic: Ketamine, etc

oPharmacokinetics

A. Gases:

Partial pressure (tension) in inhaled air or in blood or tissues, is measure of their conc.

Atmospheric pressure ~ 750 mmHg at sea level

50% of nitrous oxide in air [ PP of 380 mmHg]

B. The speed of induction :

Solubility: > rapidly a drug equilibrates with blood, >> quickly passes into the brain.

Inspired gas partial pressure: a HP of the gas in lungs results in > rapid achievement of anesthetic level in blood

Ventilation rate: >> the ventilation the > rapid the rise of alveolar & BPP of agents

Pulmonary blood flow: At HPBF, the GPP rises at a slower rate. The speed of onset of anesthesia is reduced.

Arterio-venous concentration gradient:

oThe uptake of soluble anesthetic into highly perfused tissues may decrease gas tension in mixed venous blood

HPBF: high pulmonary blood flow; GPP: gas pulmonary pressure

Elimination

Redistribute from brain to the blood & eliminate through the lungs

The rate of recovery: an agents with low blood gas partition co-efficient is faster > of anesthetic with high blood solubility

Halothane & methoxyflurane- metabolized in liver-a minor influence on the speed of recovery, but < toxicity

MAC value

The concentration of drug in alveolar is required to eliminate the response to a standardized painful stimulus in 50% of patients

Roles: Variable among different patients like on age, CVS status and use of adjuvant drugs

MAC for infants & old age are lower

Effects of Inhaled Anesthetic

1. CNS effects: Slowed brain metabolism

Reduce the PVR- Increase in cerebral blood flow (increase ICP)

Enflurane:  Spike and wave activity  and muscle twitching in high dose

Nitrous oxide: Marked analgesic & amnesic actions (high MAC)

2. CVS: Decrease arterial pressure

CO is low (enflurane, halothene)

Isoflurane: Peripheral vasodilatation

Nitrous oxide less likely to lower BP.

Blood flow to liver & kidney [decreased by most inhaled drugs]

Halothane: Arrhythmias sometimes

3. Respiratory effects:

Rate of respiration may be increased, but tidal volume & MV are decreased – increased in arterial CO2 tension

Decrease ventilatory response to hypoxic drive.

Less effect on ventilation [nitrous oxide]

Adverse effects

Postoperative hepatitis- by halothane

Methoxyflurane and flurane (prolonged anesthesia)- renal insufficiency

Nitrous oxide (prolonged)- megaloblastic anemia (due to decrease in methonine synthase)

Malignant hyperthermia (some patients)- by halogenated anesthetics

Benzodiazepines

Midazolam:  As a adjunctive agent with inhaled anesthetic and opioids

CNS effects is slower than that of thiopental and longer duration of action

Postoperative respiratory depression have occurred (over dose)

Antidote- flumazenil

Note: In detail see in sedative hypnotics

Opioids

Used with other CNS depressants  [nitrous oxide or BDZ] to avoiding high risk GA

Chest wall rigidity: Impairs ventillation & respiratory depression (IV)- antidote is naltrexone

Neuroleptic: Analgesia & amnesia- by Fentanyl, droperidol &  nitrous oxide

Propofol

Anesthesia as with IV thiopental & recovery is more rapid

An anti-emetic and recovery is not delayed after prolonged infusion

Indications: For Total IV anesthesia and in outpatient surgery.

Loading: 6-9 mg/kg/h by infusion for  5 min or 0.5-1 mg/kg by slow injection over 1-5 minute

Maintenance doses: 1.5 – 4.5 mg/kg/h infusion for ventilated patient

Contraindications: hypersensitivity of the drugs, ECT, Pregnancy & lactation

Pharmacokinetics

TB-CL > hepatic blood flow

Alpha T1/2 ~ 2-8 m & beta t1/2 ~ 30-60 m

Metabolism: Glucuronidation & sulfation [1% in urine]

Adverse effects: HPN, anaphylaxis, involuntary muscle movements, apnea, etc.

Total I/V anesthesia

The use of a computer controlled syringe driver [pump] to infuse “Propofol” through out  duration of surgery, removing the need for a volatile anesthetics

Advantages: no malignant hyperthermia

Faster recovery & Reduced incidence of post-operative nausea/vomiting

Nitrous Oxide

Advantages:

Non-irritant, non-inflammable, rapid induction and recovery

Potent analgesic

No CVS, RS, Liver & Kidney toxicity

Adverse effects

The collection of air in pleural, pericardiac or peritoneal space.

Intestinal obstruction, arterial air embolism

Contraindications: in 

COPD or emphysema

Megaloblastic anemia, abortion & teratogenicity

Halothane

Volatile anesthetic

Reversible CNS depression: SANS > PANS

Depresses Respiration

HPN: Both systolic & diastolic pressure

Reduced HR, CO & coronary flow

Adverse effects or disadvantages:

Hypotension, Inadequate muscle relaxation, Arrhythmias with epinephrine

Respiratory depression

Less analgesic action

Elevation of ICP, MH with suxamethonium

Recovery time: prolonged & shivering

Uses: for

Induction GA: 2-4% v/v in O2 or mixture of nitrous oxide

For maintenance: increase by 0.5% v/v to required level

Malignant hyperthermia

Results from massive release of calcium from the sarcoplasmic reticulum, leading to uncontrolled contraction and stimulation of metabolism in skeletal muscles

1:4500 or 1:60,000 procedure involving GA

Causative factors:

Autosomal dominant disorder due mutation of ryanodine receptor gene (RYR-1)

All volatile anesthetics and  NMJ blocking agents

Clinical features

Muscular rigidity

Increased O2 consumption and  CO2 production

Tachycardia

Hyperthermia 

rhabdomyolysis & electrolyte misbalance & red-brownish urine

Management 

A. Supportive measure: correcting

the hyperthermia

Electrolyte

Acidosis: NaHCO3

B. Medication:

Prompt stoppage of triggering agents

IV dantrolene or azumolene (antidote)

Thiopental sodium

Ultra-short acting: (20-30 seconds)

Mode of action: (sedative-hypnotics)

Decreases ICP

Highly lipid soluble: the rapid entry into brain & redistributed to muscle and fat leading to return of consciousness in 10-15 minutes

Redistribution

Disadvantages

Metabolized slowly and accumulated in body fat

No analgesic effect

Weak muscle relaxant

Apnea, cough, hiccup, laryngospasm and bronchospasm

Respiratory or myocardiac depression

Produces gastro-esophageal reflex

Nerve palsy

Pain, necrosis & gangrene at injection site

Contraindications:

Severe cardiac diseases & COPD

Addison’s disease

Myxoedema & H/O porphyrias

Indications & dosages

Induction of GA: 100-150 mg of a 3- or 5% injected over 10-15 sec. Repeat every 30-60 sec according to response.

Maintenance dose: repeated or infusion of 0.2 or 0.4% solution

Children: 2-7 mg/kg

Neuroleptic Analgesia

Combination of Fentanyl citrate (0.05 mg)            & neuroleptic Droperidol (2.5 mg)

Psychic and  intense analgesia without producing unconsciousness

The patient is in state of analgesia & amnesia but co-operative

Ketamine

Dissociative anesthesia: The state of sedation, immobility, amnesia and marked analgesia

Properties:

-        Resembles to phencyclidine, but less euphoria, & sensory destructions

-        Blocks glutamate receptors (NMDA-r)

High incidence of dysphoria, hallucination during recovery

Advantages:

-        Effect lasts for 15 minutes

-        Good analgesic

-        Less vomiting and hypotension

-        No broncho-spasm or slight

Uses of Ketamine

In dressing of burns

Minor surgeries

In radiotherapy procedures

For induction of anesthesia prior to administration of inhaled anesthetic

Dosage regimens

Intravenous:

Induction: 1-4.5 mg/kg iv injection or 0.5-2mg/kg in infusion.

Maintenance: 10-45 mcg/kg/min infusion rate treated according to response

Surgical anesthesia: 2 mg/kg over 60 sec

I/M: for diagnostic propose 4mg/kg & surgical anesthesia: 10 mg/kg within 3-4 min

Contraindications

Relative: in CVD and cardiac failure

Not used in abdominal surgery (not effective in visceral pain)

Absolute: Alcohol intoxications, pregnancy [pre-eclampsia & eclampsia], psychosis, & barbiturate incompatibility

Questions

List drugs used as general anesthesia. Mention effects and adverse effect of Halothane.

Write short notes on:

PK properties of inhaled anesthetic agents

Ideal properties of modern anesthetic agents

Effects of inhaled anesthetic agents

Thiopental sodium or Propafol or nitrous oxide

Ketamine

Succinylcholine or pancuronium

MAC value

Preanesthetic agents

Pharmacological basis

Oxygen in anesthesia

Nitrous oxide in anesthesia

Total intravenous anesthesia

Enflurane in anesthesia

Ketamine in anesthesia