INTRVENOUS INDUCTION AGENTS

[Link] REKHA DEPT. OF ANAESTHESIOLOGY

Overview
Classification Mechanisms of action Pharmacological principles Individual agent overviews Pharmacokinetics Induction characteristics Organ effects

CLASSIFICATION OF IV INDUCTION AGENTS RAPID ACTINGBarbiturates- thiopental, methohexitone Propofol Etomidate SLOW ACTING Ketamine- Dissociative anaesthesia Benzodiazapines

How do they work?

Major inhibitory neuro-transmitter in the CNS = GABA Active GABA receptor => Cl- influx => hyperpolarisation Propofol & Barbiturates acts on GABAA receptor Barbiturates-GABA mimetic Benzodiazepines -GABA facilitator Etomidate- GABA facilitator Ketamine - NMDA receptor antagonism.

These lead to sedative & hypnotic effects

Distribution & Elimination

Single-injection Kinetics

SINGLE INJECTION ELIMINATION KINETICS

ELIMINATION HALF TIME

ELIMINATION HALF LIFE

Context-sensitive Half-Time
Time necessary for plasma drug concentration to decrease by 50% after discontinuing a continous infusion of a specific duration.

Pharmacodynamics
Increasing dose => sedation => hypnosis All iv anaesthetics affect other organ systems
Potential for respiratory depression Potential for CVS depression Potential for altered CBF/ICP

Hypovolaemia => severe haemodynamic effects seen due to decreased blood pool

Thiopental
Thiobarbiturate- introduced by lundy & waters in 1935 Derived from Barbituric acid-cyclic compound obtained by combinatin of urea& malonic acid Precipitates with acidic drugs e.g. NMBs Extravascular injection => pain + tissue injury Intra-arterial injection => crystals + ischaemia Chemical structure- 5 ethyl,5[methyl,butyl]2 thiobarbiturate.

 Metabolism- in liver -side chain oxidation -hydroxylation,desulphuration -ring cleveage to form urea -products are thiobarbituricacid,pentobarbitone -80% excreted through kidney

 USESInduction and maintainance. Anticonvulsant. Cerebral protection in trauma pts. CONTRAINDICATIONS ABSOLUTE- Porphyria. RELATIVE- Bronchial asthma Myxoedema pts Hepatic or Renal diseases.

COMPLICATIONS LOCAL -Thrombophlebitis. -Arterial spasm. GENERAL - Laryngeal spasm - Bronchospasm

Management of intra-arterial injection of Thiopental Stop injection but leave needle or cannula in place Dilute with immediate injection of saline Give intra-arterial LA + vasodilator Lidocaine 50mg (5 ml of 1% solution) Phenoxybenzamine (a blocker) 0.5 mg bolus or 50-200 mg/minute infusion

Consider systemic papaverine 40-80 mg

Consider sympathetic blockade (stellate ganglion or brachial plexus block) Start iv heparin infusion Consider intra-arterial hydrocortisone Postpone non-urgent surgery Liaise with vascular surgeon

Propofol
CHEMICAL STRUCTURE -2,6-diisopropylphenol Emulsion with 10% soybean oil, 2.25% glycerol and 1.2% lecithin (egg yolk phosphatide - ? allergen) METABOLISM- In liver conjugation to sulphate& glucuronide Also ring hydroxylation- 4-hydroxy propofol . Induction dose higher in childrn, lower in elderly Wake-up due to redistribution, not metabolism

USES -Day care surgeries -Significant vasodilatation -Pressor response is less than thiopentone. -Antiemetic[10-15 mg i.v] -Suppresses laryngeal reflexes -sedation in icu -Antipruritic effects[10mg iv] .

COMPLICATIONS-

-allergic respose-to emulsifying agent.

-Pain on injection -Hypotensive episodes -Tendency for apnoea -Propofol infusion syndrome

 Caused by propofol in critically ill pediatric pts or on long term infusion [>48 hrs] or at high doses[>5mg/kg/hr] MECHANISM- Inc. triglycerides, impaired E.C chain FEATURESMetabolic acidosis Multiple organ failure Hepato megaly Rhabdomyolysis Hyperkalemia.

PROPOFOL INFUSION SYNDROME

Etomidate

CHEMICAL STRUCTURE-Imidazole derivative, D(+) isomer Poorly soluble in H2O => 35%propylene glycol used METABOLISM Metabolised by ester hydrolysis Wake-up due to redistribution Minimal haemodynamic effects, short half-life

 High incidence of PONV (35-40%) May activate seizure foci, myoclonus in 50% Adrenocortical suppression Dose-dependent 11 b-hydroxylase inhibition Lasts 4-12 hrs after single dose (much longer in critically ill)

Ketamine

CHEMICAL STRUCTURE-Phencyclidine derivative Racemic mixture: S-isomer fewer adverse effects METABOLISM- high hepatic clearence n-demethylation,hydroxylation

USES- Significant analgesia at sub-anaesthetic doses -Bronchodilatation -Preserves larengeal & pharyngeal reflexes -Choice in shock. -IV ketamine for labour analgesia- 10mg bolus and then 0.5mg/min.

 SIDE EFFECTS-Secretions -Vomiting -Epileptogenic -Hypertension and tachycardia -Vivid dreams -Hallucinations

Benzodiazepines
IV prep: midazolam, diazepam, lorazepam Midazolam has imidazole ring Ring protonated => water soluble at acid Ph In body, ring unprotonated => lipid soluble At pH 4 only 9% of MDZ rings are open (75% at pH 2)

 Bind specific site between a + g subunits of GABAA receptor METABOLISM-IN LIVER -hydroxylation -conjugation with glucuronic acid USES induction and sedative agent -sedative supplement in regional blocks -sedative in icu pts -Anticonvulsant -Total intravenous anaesthesia [midazolam+propofol+fentanyl]

 SIDE EFFECTS- may cause respiratory depression. Avoided in pregnancy Avoided in acute narrow angle glaucoma Avoided with cemitidine and ranitidine

Overdose is treated with FLUMAZENIL

Single dose pharmacokinetics

Drug
Redistribution T1/2 (min) Protein binding % VdSS l/kg Clearance ml/kg/min Elimination T1/2 (hrs)

Thiopental Methohexital Propofol

2-4 5-6 2-4

85 85 98

2.5 2.2 2-10

3.3 11 20-30

11 4 4-23

Midazolam
Diazepam Lorazepam Etomidate Ketamine

7-15
10-15 3-10 2-4 11-16

94
98 98 75 12

1.1-1.7
0.7-1.7 0.8-1.3 2.5-4.5 2.5-3.5

6.4-11
0.2-0.5 0.8-1.8 18-25 12-17

1.7-2.6
20-50 11-22 2.9-5.3 2-4

Induction Characteristics
Drug Induction dose (mg/kg) Onset (secs) Duration (mins) Excitation Injection pain Heart rate BP

Thiopental Methohexital Propofol

3-6 1-3 1.5-2.5

<30 <30 15-45

5-10 5-10 5-10

+ ++ +

0/+ + ++

+ ++ 0/-

--

Midazolam
Diazepam Lorazepam Etomidate Ketamine

0.2-0.4
0.3-0.6 0.03-0.06 0.2-0.3 1-2

30-90
45-90 60-120 15-45 45-60

10-30
15-30 60-120 3-12 10-20

0
0 0 +++ +

0
+/+++ ++ +++ 0

0
0 0 0 ++

0/0/0/0 ++

CNS effects of IV anaesthetics

Drug CMRO2 CBF CPP ICP Anticonvulsant

Thiopental
Methohexital Propofol Etomidate Benzodiazepines Ketamine

----+

----+ ++

+
+ + 0 +

---+

Yes
No Yes No Yes No

CMRO2 = cerebral metabolic rate for oxygen CBF = cerebral blood flow CPP = cerebral perfusion pressure ICP = intracranial pressure

CVS Effects of IV Anaesthetics

Drug MAP HR CO Contractility SVR Venous dilatation

Thiopental Methohexital Propofol Etomidate Diazepam Midazolam Ketamine

-0 0/0/++

+ ++ 0 + + ++

0 0 0/+

0 0 0 +

+ + -0 -/0 -/0 +

++ + ++ 0 + + 0

RS Effects of IV Anaesthetics
Drug Ventilation Respiratory rate CO2 response Hypoxia response Propofol -----/---

Thiopental

--

--

Ketamine

Unchanged

Unchanged

Unchanged

Midazolam

Unchanged

Unchanged

Etomidate

Propofol SBP Decrease 0/Decrease Decrease Decrease

Thiopental Decrease Increase Decrease Decrease

Ketamine Increase Increase Increase Unchanged

Etomidate Decrease Decrease Decrease Unchanged

CVS

Heart rate SVR Ventilation

RESP

Resp rate
CO2 response CBF CMRO2

Decrease
Decrease Decrease Decrease Decrease Yes? No No

Decrease
Decrease Decrease Decrease Decrease Yes No No

Unchanged
Unchanged Unchanged/Increa se Unchanged/increa se Unchanged/Increa se Unclear No Yes

Unchanged
Unchanged Unchanged Unchanged/Decre ase Unchanged

CNS

ICP Anticonvulsant Anxiolysis Analgesia

Yes? No?

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