Intravenous induction agents used in anesthesia

1. IV INDUCTION
AGENTS

2. MAIN DRUGS TO STUDY
 BARBITURATES
 BENZODIAZEPINES
 KETAMINE
 ETOMIDATE
 PROPOFOL
 DEXMEDITOMEDINE

3. BARBITURATES
 MECHANISM OF ACTION :
 Depress RAS ( reticular activating system ) in brainstem
 Bind to GABAA receptor .
 Potentiate the action of GABAA -> increase the duration of opening of chloride
specific ion channel .
 STRUCTUE ACTIVITY RELATIONSHIP :
 Phenyl group in phenobarbital -> anticonvulsive
 Methyl group in methohexital -> not anticonvulsive
 Useful for anaesthesia for electroconvulsive therapy .
 Sodium salts of barbiturates are water soluble but markedly alkaline

4.  PHARMACOKINETICS :
 ABSORBTION :
 Thiopental , thiamylal , methohexital – iv
 Rectal methohexital – in children .
 DISTRIBUTION :
 Duration of induction dose is determined by redistribution , not by metabolism
or elimination .
 Thiopental : great lipid solubility and high non ionized fraction ( 60%)
 Rapid brain uptake ( within 30 sec )
 If central compartment is contracted , serum albumin is low or non ionized
fraction is increased – larger brain and heart concentration achieved

5.  Redistribution lowers plasma and brain concentration to 10% of peak
levels within 10-20 min .
 Typically lose consciousness within 30 sec and awaken within 20 min
 Induction dose depends on wt and age .
 Reduced dose for elderly
 Rapid initial distribution t1/2 but elimination t1/2 is prolonged . ( 10-12 h)
 Repetitive administration / infusion  saturates peripheral compartments
 then duration of action depends on elimination . ( context sensitivity )
 Context sensitivity : also seen in other lipid soluble agents .

6.  BIOTRANSFORMATION :
 Via hepatic oxidation to inactive water soluble metabolites
 EXCRETION :
 Renal excretion is limited to water soluble end products ( exception –
phenobarbital )
 Methohexital – excreted in feces
 EFFECTS ON ORGAN SYSTEM :
 CARDIOVASCULAR SYSTEM :
 Cause decrease in blood pressure and increase in heart rate .
 Tachycardia d/t central vagolytic effect and reflex response to decrease in bp

7.  In situations where baroreceptor response is blunted ( hypovolemia , congestive
heart failure , beta adrenergic blockade )  cardiac output and bp fall drastically
d/t uncompensated peripheral pooling of blood and direct myocardial depression .
 RESPIRATORY
 Barbiturates depress medullay ventilatoy center  decreasing ventilatory response
to hypercapnia and hypoxia .
 Apnea often follows induction dose
 During awakening – tidal volume and resp rate are decreased .
 Incompletely depresses airway reflex responses to laryngoscopy and intubation
 May lead to bronchospasm ( in asthmatic patients ) or laryngospasm in lightly anesthetised
pts .

8.  CEREBRAL :
 Constrict cerebral vasculature  decrease in cerebral blood flow , cerebral blood
volume , intracranial pressure .
 CPP ( cerebral perfusion pressure ) : [cerebral artery pressure - greater of jugular
venous pressure/ intracranial pressure ]
 CPP usually increases .
 Induce greater decline in cerebral oxygen consumption ( upto 50%)
 May protect from transient episodes of focal ischemia ( cerebral embolism ) but do not
protect from global ischemia ( cardiac arrest )
 EEG burst suppression .
 No analgesic action , no muscle relaxation ( methohexital may cause involuntary
skeletal muscle contration )
 Can be used to control grand mal seizures .

9.  Reduce renal blood flow and GFR in proportion to fall in bp
 Hepatic blood flow is decreased
 Chronic exposure -> induction of hepatic enzymes & increased rate of metabolism .
 Promote synthesis of aminolevulinic acid synthetase  increase formation of
porphyrin  precipitate intermittent porphyria or variegate porphyria .
 DRUG INTERACTIONS
 Contrast media , sulfonamides – occupy same protein binding site  displace
thiopental  potentiating the effect
 Ethanol , opioids , antihistaminics or other cns depressants potentiate the sedative
effects of barbiturates .

11. BENZODIAZEPINES
 MECHANISM OF ACTION :
 Binds to same receptors as barbiturates but at different site
 Increase the frequency of opening of chloride channel
 Flumzenil : specific bzd –receptor antagonist  reverses most of the cns
effects of BZDs .
 STRUCTURE – ACTIVITY RELATIONSHIP :
 Imidazole ring in midazolam  water solubility at low pH .
 Diazepam and lorazepam  insoluble in water , parenteral preparation contain
propylene glycol ( can cause venous irritation ) .

12.  PHARMACOKINETICS :
 ABSORBTION :
 Orally or intravenously
 Diazepam and lorazepam : well absorbed from GIT
 IV midazolam ( 0.05- 0.1 mg/kg ) : for anxiolysis before sx is ubiquitous
 Oral midazolam ( not FDA approved ) but used for premedication in pediatrics
 Intranasal , buccal, sublingual midazolam provide preoperative sedation .
 IM midazolam & lorazepam well absorbed .

14.  DISTRIBUTION :
 Diazepam - lipid soluble and readily penetrates BBB
 Midazolam – water soluble at reduced pH , but lipid soluble at physiological pH
.
 Redistribution is rapid  can cause awakening .
 All are highly protein bound .
 BIOTRANSFORMATION :
 Liver : into water soluble glucuronidated end products
 Phase 1 end products are metabolically active
 Diazepam : Slow hepatic extraction and large volume of distribution Vd long
elimination T1/2 .

15.  Lorazepam : low hepatic extraction , but lower lipid solubility limits its Vd
resulting in shorter T1/2
 But clinical duration of lorazepam is prolonged -> d/t increased receptor affinity
 Shows the limited utility of T1/2 in guiding clinical practise .
 EXCRETION :
 In urine
 Enterohepatic circulation secondary peak in diazepam plasma conc .
 EFFECTS ON ORGAN SYSTEMS :
 CARDIOVASCULAR :
 Minimal depressant effects

16.  But when co admininstered with opioids  myocardial depression and hypotension
 RESPIRATORY :
 Depress ventilatoy response to CO2 .
 Although apnea is uncommon , even small iv doses can result in resp arrest .
 Steep dose response curve
 Ventilation must be monitored in all pts
 CEREBRAL :
 Reduce cerebral O2 consumtion ( not to the extent of barbiturates do )
 Effective to control grand mal seizures .
 Sedative doses : often a/w anterograde amnesia.
 Mild muscle relaxing action – at spinal cord level .

17.  Lower doses : antianxiety , amnestic , sedative
 Induction doses : slower rate of loss of consciousness , longer recovery .
 No analgesic property
 DRUG INTERACTION :
 Cimetidine binds to cytochrome P 450 – reduce metabolism of diazepam
 Erythromycin inhibit metabolism of midazolam – prolongation of effects
 Combination of BZDs and opioids – reduce bp and peripheral vascular
resistance .
 Reduce MAC of volatile anesthetics by 30% .
 Ethanol , barbiturates and other cns depressants  potentiate sedative effects
of BZDs

18. KETAMINE
 MECHANISM OF ACTION :
 Multiple effects throughout nervous system
 Inhibit NMDA channels , HCN1 Channels
 Dissociative anaesthesia : dissociate sensory impulses from limbic cortex
 Patient appear conscious .
 STRUCTURE ACTIVITY RELATIONSHIP :
 Structural analogue of phencyclidine
 Used for iv induction of anaesthesia  when sympathetic stimulation is useful (
hypotension , trauma )
 When IV access is not available : IM in children & no cooperative adults .

19.  Combined with other agents ( propofol , midazolam)  for conscious sedation
( for nerve root block , endoscopy)
 Can cause hallucinations (clinically we can use midaz for amnesia and sedation
prior to ketamine )
 PHARMACOKINETICS:
 ABSORBTION :
 Nasally , rectaly , orally , s/c , epidurally
 Clinically – IV / IM
 DISTRIBUTION :
 Highly lipid soluble
 Ketamine induced inc in CBF ,CO  rapid brain uptake and redistribution-
awakening .

20.  BIOTRANSFORMATION :
 In liver : norketamine retains anesthetic activity
 Repeated doses : develop tolerance
 Extensive hepatic uptake  short elimination T1/2 ( 2h)
 EXCRETION : end products excreted renaly
 EFFECTS ON ORGAN SYSTEMS :
 CVS :
 Increases BP , HR , CO
 d/t central stimulation of sympathetic nervous system & inhibition of reuptake of
norepinephrine
 Increase in pulmonary artery pressure & myocardial work

21.  Caution in pts with CAD , uncontrolled HTN , CHF , arterial aneurysms
 Direct myocardial depressant effects unmasked by sympathetic blockade ( spinal
cord transection ) exhaustion of catecholamine stores ( severe end stage shock )
 RESPIRATORY :
 Minimally affected
 Combination with opioids produce apnea
 Racemic mixture – potent bronchodilator
 Good induction agent for asthmatic patients
 Upper airway reflexes remain largely intact  increased risk of aspiration pneumonia
 Increased salivation : premedication with glycopyrrolate .

22.  CEREBRAL :
 Increases CBF , ICP
 Not used in pts with SOL, head trauma .
 Can b
 e used in combination with BZDs
 Psychotomimetic side effects ( disturbing dreams , delirium ) less with children ,
pts given premedication with BZDs or in pts taking ketamine in combination
with propofol in TIVA .
 Ketamine comes closest to complete anesthetic : induce analgesia , amnesia ,
unconsciousness
 DRUG INTERACTION :
 Synergestic with volatile anesthetics

23.  Additive way with propofol , BZDs etc .
 Diazepam & midazolam attenuate its cardiostimulatory effects
 Concurrent infusion of ketamine & propofol ( 1:10 mg )  sedation in regional
or general anaesthesia in office based settings

24. ETOMIDATE
 MECHANISM OF ACTION :
 Depress RAS & mimics inhibitory effects of GABA
 Disinhibitory effects on extrapyramidal motor activity
 30-60% incidence of myoclonus with induction
 STRUCTURE – ACTIVITY RELATIONSHIP :
 Dissolved in propylene glycol for injection
 Pain on injection  prior iv injection with lignocaine .
 PHARMACOKINETICS :
 ABSORPTION
 Only for IV – for induction of anaesthesia
 Brief production of sedation – prior to placement of retrobulbar block .

25.  DISTRIBUTION :
 Highly protein bound
 very rapid onset of action d/t high lipid solubility and large non ionized fraction
 Hepatic microsomal enzymes & plasma esterases rapidly hydrolyse etomidate
 End products are excreted renaly
 EFFECTS ON ORGAN SYSTEMS :
 CVS :
 Minimal effects
 Mild reduction in peripheral vascular resistance  slight dec in BP .
 Do not release histamine
 Even with large dose : relatively light anaesthesia for laryngoscopy and marked inc in HR , BP when giving alone
for induction
 RESPIRATORY :
 Even induction dose : do no cause apnea unless opioids also given

26.  CEREBRAL :
 Decrease CBF , ICP ,CMR
 CPP well maintained .
 Post operative nausea and vomiting more common .
 No analgesic properties
 ENDOCRINE :
 Transiently inhibit enzymes involved in cortisol and aldosterone synthesis
 Infusion produce adrenocortical suppression  increased mortality in critically ill pts .
 DRUG INTERACTION :
 Fentanyl increases the plasma level -> prolongs action
 Opioids decrease the myoclonus

27. PROPOFOL
 MECHANISM OF ACTION :
 Facilitation of inhibitory neurotransmission mediated by GABA A
 Allosterically increase affinity of GABA for GABA A .
 Coupled with chloride channel  cause hyperpolarization of nerve membrane .
 STRUCTURE –ACTIVITY RELATIONSHIP :
 Phenol ring substituted by 2 isopropyl groups
 No water soluble
 1% acques soln is available – oil in water emulsion containing soybean oil , glycerol ,
egg lecithin
 Cause pain during injection .
 Formulations support bacterial growth
 Should be administered within 6H .

28.  PHARMACOKINETICS :
 ABSORPTION :
 Only IV : moderate to deep sedation
 DISTRIBUTION :
 Rapid onset of action
 Awakening – d/t rapid initial distribution T1/2 .
 Recovery : more rapid , less hangover
 Good anesthetic for ambulatory sx
 Smaller dose in elderly because of smalled Vd
 BIOTRANSFORMATION :
 Clearance of propofol exceeds hepatic blood flow  means extrahepatic metabolism .
 Rapid recovery after continuous infusions .
 Conjugation in liver  inactive metabolite  excreted renally
 But do not affected in obesity , cirrhosis , kidney failure
 Propofol infusion for long term sedation : a/w sporadic cases of lipemia , metabolic acidosis , death
 PROPOFOL INFUSION SYNDROME

29.  Excretion in urine , but end stage kidney disease does not affect the clearance .
 EFFECT ON ORGAN SYSTM :
 CVS :
 Decrease BP d/t drop In vascular resistance , preload , cardiac contractility
 Hypotension following induction reversed by laryngoscopy and intubation
 Markedly impairs normal arterial baroreflex response to hypotension .
 Bradycardia : rarely d/t drop in cardiac filling vagally mediated reflex
 Changes in HR , CO transient and insignificant in healthy pts .
 Severe in pts of extremes of ages , pts receiving beta blockers , impaired ventricular function
 Although myocardial o2 consumption and coronary blood flow decreases comparably 
some mismatch between myocardial o2 supply and demand .

30.  RESPIRATORY SYSTEM :
 Profound respiratoy depression
 Apnea following induction dose
 Inhibits hypoxic ventilatory drive and depress normal response to hypercarbia .
 Depression of laryngeal reflexes  allow intubation , endoscopy , LMA placement in absence of
neuromuscular blockade .
 Can cause histamine release
 Low incidence of wheezing in asthmatic compared to barbiturates , etomidate .
 CEREBRAL :
 Decrease CBF , CBV , ICP .
 In pts with elevated ICP , propofol causes critical reduction in CPP ( <50mmhg )
 Action should be taken to increase mean BP .
 Propofol and thiopental : similar degree of cerebral protection during focal ischemia
 Antipruritic and anti emetic property

31.  Anticonvulsant , safely used in epileptic
 Decrease IOP
 Tolerance : not developed after long term use
 DRUG INTERACTION :
 Small amount of midazolam ( 30 mcg/kg ) prior to induction with propofol
 Decrease dose of propofol by 10%
 Often combined with remifentanil or ketamine for TIVA
 FOSPROPOFOL :
 Water soluble prodrug .
 More complete amnesia and better conscious sedation for endoscopy than
midazolam plus fentanyl
 Slower onset and slower recovery

32. DEXMEDETOMIDINE
 Alpha2 agonist  for anxiolysis, sedation , analgesia
 Used in combination with LA to prolong Regional blocks
 As premedication by nasal (1-2 mcg/kg ), or oral (2.5-4 mcg/kg) in children
 Used in procedural sedation ( awake craniotomy , fiberoptic intubation ) , ICU sedation
 To reduce the likelihood of emergence delirium after inhalational anesthetic ( in children
)
 To treat alcohol withdrawal and side effects of cocaine intoxication
 IV dexmedetomidine : 1 mcg/kg loading dose given over 5-10 min followed by
maintanence infusion of 0.2 – 1.4 mcg/kg /hr .
 Very rapid redistribution , short elimination T1/2
 Metabolized In liver by CYP 450 through glucuronidation .
 Excreted in urine