1. Intavenous Anaesthetic Agents
Dr.C.N.Chandra Sekhar

2. Intravenous Anaesthetic Agents
Induction with IV Anaesthetic agents is smoother and rapid than inhalational agents

3. Intravenous Anaesthetic Agents
Properties of the Ideal IV Anaesthetic Agent:
Rapid onset – mainly unionized at blood pH highly lipid soluble
Rapid recovery –Rapid redistribution
Analgesic at subanaesthetic Concentration
Minimal CV and Resp. depression
No emetic effects
No emergence phenomena
No Interaction with NMBD

4. Intravenous Anaesthetic Agents
Properties of the Ideal IV Anaesthetic Agent:
No pain on injection
No venous sequelae
Safe if injected inadvertantly into an artery
No toxic effects on other organs
No release of Histamine
No hypersensitivity reactions
Water soluble formulation
Long shelf-life
No stimulation of Porphyrias.

5. Intravenous Anaesthetic Agents
Pharmacokinetics of IV Anaesthetic Agents:
After IV  rapid  in plasma conc. slower decline
Anaesthesia is produced by diffusion of drug from arterial blood across BBB into the brain

6. Intravenous Anaesthetic Agents
Rate of transfer into the brain and anaesthetic effect is regulated by:
1.Protein binding
2.Blood flow to the brain
3.Extracellular pH & pKa of the drug
4.The relative solubilities of the drug in lipid and water
5.Speed of Injection

7. Intravenous Anaesthetic Agents
1.Protein Binding: Only unbound drug is free to cross the BBB
Low plasma protein
Displacement from proteins by other drugs increase free drug conc.
Hyperventilation decreases protein binding and increases anaesthetic effect

8. Intravenous Anaesthetic Agents
2.Blood Flow to the Brain:
Reduced blood flow reduced delivery of the drug.
If CBF is decreased due to low Cardiac output---initial blood conc. Higher than N, i.e Anaesthetic effect may be delayed but enhanced.

9. Intravenous Anaesthetic Agents
3.Extracellular pH & pKa of the drug:
Only non-ionized fraction of the drug penetrates the lipid BBB
The potency of the drug depends on the degree of ionization at the pH of extracellular fluid & pKa of the drug.

10. Intravenous Anaesthetic Agents
4.The relative solubilities of the drug in lipid and Water:
High lipid solubility enhances transfer into brain.
5.Speed of Injection:
Rapid IV adminstration  high initial conc. increases speed of induction and extent of CV and Resp.side effects

11. Pool
Lean
% of Dose
Viscera
Fat
mts

12. Classification of Intravenous Anaesthetics
Rapidly acting agents:
Barbiturates
Methohexital
Thiobarbiturates- thiopental, thiamylal
Imidazole compounds: eg.etomidate
Sterically hindered alkyl phenols: eg. Propofol
Steroids: eg. Eltanalone, Althesin, Minaxolone
Eugenol: eg. Propanidid

13. Classification of Intravenous Anaesthetics
Slower- acting agents:
Ketamine
Benzodiazepines:- Diazepam, flunitrazepam, midazolam
Large-dose opioids:- Fentanyl, Alfentanil, Sufentanil, remifentanil
Neurolept combinations:- Opioid + Neuroleptic

14. O ‖C N R
C=O C R N C ‖ O R

15. Thiopental Sodium Chemical Structure:-
Sodium 5-ethyl – 5(1-methylbutyl) – 2 thiobarbiturate
Physical properties & Presentation:-
Sulphur analogue of pentobarbital
Taste = bitter
Colour = yellowish
State = powder
Smell = garlic

16. Thiopental
Stored in Nitrogen to prevent chemical reaction with atmospheric CO2
6% anhydrous sodium carbonate to increase solubility in water
2.5% solution pH : 10.8
Solution is hypotonic
Prepared solution can be kept for 24 hrs.
Oil/water partition coefficient 4.7
pKa is 7.6

17. Thiopental Central Nervous System:- Onset <30sec after IV injection
delayed if CO is low
Progressive depression of CNS and spinal cord reflexes
Hypnotic action – potent
Analgesic effect – poor
CMR
CBF 
CBV 
ICP 

18. Thiopental - CNS
Recovery of consciousness occurs at high blood concentrations if a large dose is given or if the drug is injected rapidly (acute tolerance)
Consciousness regained in 5-10mts.
At subanaesthetic conc.
Antanalgesic effect
Reduces pain threshold
Potent anticonvulsant
Sympathetic effect depressed more than parasympathetic.
Tachycardia
May represent altered redistribution
Tachycardia at induction may be due to baroreceptor inhibition caused by modest hypotension, partly because of loss of vagal tone.

19. Thiopentone Cardiovascular System:- Myocardial contractility depressed
Peripheral vasodilation
Hypotension
HR

20. Thiopentone Respiratory System:- Ventilatory drive 
In spont.Vent. Vf  & Vt 
 in bronchial muscle tone
Laryngospasm
Ventilatory drive decreases, due to reduced sensitivity of the resp. centre to CO2
-increase in bronchial muscle tone, frank bronchospasm is uncommon
-Laryngeal spasm precipitated by surgical stimulation or presence of secretions, blood or foreign bodies eg.oropharyngeal airway and LMA

21. Thiopentone Skeletal muscle:- Uterus & Placenta:- Eye:-
 tone at high blood concentrations
No direct effect on NMJ
Uterus & Placenta:-
Contractions suppressed at high doses
Crosses the placenta rapidly
Foetal blood conc. Not reach upto mother’s
Eye:-
IOP  by 40%
Pupils = dilates first and then constricts
Light reflex present until surgical anaesthesia is reached
Corneal,conjunctival,eyelash and eyelid reflexes abolished
Decreased skeletal muscle tone is due to suppression of spinal cord reflexes

22. Thiopentone Hepatorenal Function:-
Transient impairement of liver and kidney functions.
Hepatic microsomal enzymes are induced  metabolism & elimination of other drugs.

23. Thiopentone Pharmacokinetics:-
75-85% drug is protein bound (mostly albumin)
Protein binding affected by pH I.e by alkalemia
Conc. Of free drug  in hyperventilation
Diffuses readily into CNS because of high lipid solubility.
Predominantly unionized (61%) at body pH
Consciousness returns when the brain concentration returns to a threshold value( vary from patient to patient)
-More free drug available in Hypoalbuminemia and malnutrition
Phenylbutazone competes for same binding site on protein, so it decreases thiopentone binding.

24. Thiopentone Pharmacokinetics:- (contd….) Metabolism occurs in Liver
Metabolites excreted in Urine
Terminal elimination half-life 11.5 hrs.
Metabolism is a Zero order process
30% of original drug remain after 24 hrs.
Hangover effect common
Elimination impaired in elderly
In obese dose should be based on lean body mass as distribution to fat is slow.
Small portion excreted unchanged in urine

25. Thiopentone Dosage & adminstration:- Adminstered as 2.5% solution
Initially 1-2 ml injected
Healthy adults: 4 mg/kg administered over sec.
Loss of eye reflex within 30sec
Supplementary dose mg slowly
Children 6 mg/kg
Elderly patients 2.5 – 3 mg/kg
Induction smooth, preceded by the taste of garlic
No other drugs should be mixed with Thiopentone

26. Thiopentone Adverse Effects:- Hypotension Respiratory depression
Tissue necrosis
Intra-arterial injection
Laryngospasm
Bronchospasm
Allergic reactions
Thombophlebitis
-Hypotension: should not be administered in sitting position
-Tissue necrosis: perivenous injection ( inject hyaluronidase)
-Median Nerve damage after extravasation drug in the antecubital fossa
-Intra-arterial injection:-Brachial artery, abrrent ulnar artery, intense burning pain- stop injecting the drug.
-forearm and hand blanched & blisters distally
-Intra-arterial thio causes profound contraction of artery accompanied by local release of norepinephrine.
-Crystals of thiopentone formed in arteries leading to thrombosis caused by endarteritis.
-ATP release from damaged redcells & aggregation of platelets result in emboli and may cause ischemia or gangrene of forearm, hand or fingers.
-Treatment:- Leave the needle in the artery- administer vasodilator (Papavarine 20mg)
- stellate ganglion or Brachial plexus block may reduce arterial spasm
- IV heparin & oral anticoagulants after surgery.
-Bronchospasm- precipitated in asthmatics
-Allergic reactions- range from cutaneous rash to fatal anaphylaxis or anaphylactoid reactions with caridovascular collapse.
-Thrombophlebitis- uncommon with 2.5% solution

27. Thiopentone Indications:- Induction of Anaesthesia
Maintenance of Anaestheisa
Treatment of Status epilepticus
Reduce intracranial pressure

28. Thiopentone Absolute Contraindications: Airway Obstruction Porphyria
Hypersensitivity reaction to Baribiturates

29. Thiopentone Precautions:- Cardiovascular disease
Severe hepatic disease
Renal disease
Muscle disease
Reduced metabolic rate
Obstetrics
Outpatient anaesthesia
Adrenocortical insufficiency
Extremes of age
asthma
-Renal disease:- in CRF – protein binding reduced and elimination is not altered
-muscle disease:- resp.depression exaggerated , eg. In pt.s with Myasthenia gravis or dystrophia myotonica
-Reduced metabolic rate:-Myxoedema
-Obstetrics:- excess dose may result in resp. & CVS depression of foetus.
-Outpatient anaesthesia:- persistant drowsiness for hrs.

30. Thiopentone

31. Propofol Indications:
For induction and Maintenance of General anaesthesia
Sedation in Intensive Care Unit and during Regional anaesthesia techniques
For treatment of refractory nausea and vomiting in patients receiving chemotherapy
Treatment of status epilepticus

32. Propofol
Mode of Action:- Unclear Potentiates the inhibitory transmitters glycine and GABA

33. Propofol Routes of Adminstration and Dose:
Intravenous bolus dose 1.5 – 2.5 mg/kg for induction
Maintenance 4-12mg/kg/hour
For children induction dose should be increased by 50% and Manintenance infusion by 25-50%

34. Propofol Consciousness lost in 30 sec.
Recovery about 10mts after a single dose
Plasma concentration of 2-6mcg/ml associated with hypnosis.
Plasma conc. of 0.5 – 1.5 mcg/ml associated with sedation.

35. Propofol- pharmacodynamics
CVS: % drop in Blood pressure and SVR without comp. Increase in HR
-20% decrease in Cardiac output
-attenuates laryngoscopic response
-Vasodilatation due to NO release

36. Propofol- pharmacodynamics
Respiratory System:
Apnea for variable duration
Decreased laryngeal reflexes
Infusion decreases the TV and  RR
Depresses ventilatory response to CO2
Bronchodilatation due to direct effect
Preserves the mechanism of hypoxic pulm.vaso constriction

37. Propofol- pharmacodynamics
Central Nervous System:-
Smooth,rapid induction with rapid and clear headed recovery
Intracranial pressure,cerebral perfusion pressure, cerebral oxygen consumption reduced
GIT:-
Propofol has got intrinsic antiemetic properties, mediated by antagonism of dopamine D2 receptors.

38. Propofol- Pharmacodynamics
Renal:-
Causes reduction in excretion of Na+ ions
Metabolic:-
Longterm use causes hypertriglyceridemia

39. Propofol Toxicity and side effects:-
Pain on injection seen in 28% subjects
Epileptiform movements
Facial parasthesias
Bradycardia
Neurological sequelae in children after longterm use of propofol for sedation
Quinol metabolites give green colour to urine

40. Propofol-Pharmacokinetics
Distribution:-
97% protein bound in plasma
VD is 700 – 1500 L
Distribution half-life is 1.3 – 4.1minutes.
Metabolism:-
Rapidly metabolised in the liver
Primarily to inactive glucuronide and sulphate conjugates and the corresponding quinol.
Renal and hepatic disease have no significant effect on the metabolism.

41. Propofol Chemical:- 2,6 – diisopropylphenol
Presentation:- White oil in water emulsion containing 1 to 2% propofol in soyabean oil and purified egg phosphatide
Main Action:- Hypnotic

42. Ketamine Hydrochloride
1965
Phencyclidine derivative
Dissociative anaesthesia
Chemical structure:-
2(o-chlorophenyl)-2(methylamino)-cyclohexanone hydrochloride

43. Ketamine Physical characteristics & presentation:- Soluble in water
1% with NaCl for istonicity
5 & 10% with benzothonium chloride 0.1mg/kg as preservative
pH of the solution 3.5 – 5.5
pKa of Ketamine 7.5

44. Ketamine Central Nervous System:- Extremely lipid soluble
After IV
Onset: sec
Duration: min
After IM
Onset: 3-4 mts.
Duration: 15-25mts
Potent analgesic at subanaesthetic doses

45. Ketamine Central Nervous System:- (contd…)
Amnesia persists 1 hr. after recovery of consciousness
Induction smooth
Emergence delirium,restlessness,disorientation & agitation
EEG changes – loss of alpha activity & predominant theta activity
CMR
CBF 
CBV 
ICP 

46. Ketamine Cardiovascular System:- Arterial pressure  by 25%
HR  by 20%
CO may increase
Myocardial O2 consumption 
 Myocardial sensitivity to Epinephrine
Vasodilatation in tissues innervated by -adrenergic receptors & vasoconstriction in those with - receptors

47. Ketamine Respiratory System:- Transient apnoea
Pharyngeal & laryngeal reflexes, patent airway maintained
Bronchial muscle is dilated

48. Ketamine Skeletal Muscle:- GI system:- Uterus & Placenta:- Eye:-
Muscle tone 
GI system:-
Salivation is increased
Uterus & Placenta:-
Crosses placenta readily
Eye:-
IOP 

49. Ketamine Pharmacokinetics:- 12% is bound to protein
Initial peak conc.after IV injection decreases after drug distributes
Metabolism is by liver demethylation & hydroxylation of cyclohexanone ring (nor-ketamine is the active metabolite)
80% of injected drug excreted as glucuronides

50. Ketamine Pharmacokinetics:- contd…… 2.5% excreted unchanged in urine
Elimination half-life 2.5hrs.
Peak conc. Achieved after 20 mts. After IM inj.
-(slowered if given with halothane,benzodiazepines or barbiturates)

51. Ketamine Dosage & administration:- Induction of Anaesthesia:-
2mg/kg IV, mg/kg required every 5-10mts.
8-10mg/kg IM.
mg/kg or 50g/kg/min infusion for analgesia without loss of consciousness

52. Ketamine Adverse effects:
Emergence delirium,nightmares & hallucinations
Hypertension & tachycardia
Prolonged recovery
Increased salivation
Increased ICP
Allergic reactions

53. Ketamine Indications:- High risk patients:- (shocked patients)
Paediatric anaesthesia
Difficult locations
Analgesia & sedation
Developing countries

54. Ketamine Absolute contraindications:- Precautions:- Airway obstruction
Raised ICP
Precautions:-
Cardiovascular diseases
Repeated administration
Visceral stimulation
Outpatient anaesthesia (not suitable for adults)

55. Total Intravenous Anaesthesia
Indications:
Rapid recovery and minimal hangover
Minimal cardiovascular depression
To deliver High oxygen concentration
To avoid nitrous oxide

56. Methohexital Sodium Chemical Structure:-
Sodium-α-dl-5-allyl-1-methyl-5(1-methyl-2-pentynyl) barbiturate
Physical Properties & Presentation:-
Two asymmetrical carbon atoms
White powder
Mixed with 6% anhydrous Na2CO3
1% solution pH , pKa 7.9
Single dose vial 100mg & multidose vials.5&2.5gm.
Stable in solution for about 6 wks.(allowed only 24hrs)

57. Methohexital Sodium Pharmacodynamics:- Central Nervous System:-
Induction 15-30sec.
Recovery more rapid than thio (2-3mts.)
Drowsiness persists for several hours
Epileptiform activity in EEG seen in epileptic patients.
In sufficient doses acts as anticonvulsant

58. Mthohexital Sodium CVS:- RESP:- Pharmacokinetics:-
Hypotension less than thio
HR increases
RESP:-
Moderate hypoventilation
Pharmacokinetics:-
More is unionized at body pH( 75%) than thio
Elmination half life is shorter( appx. 4hrs)

59. Methohexital Sodium Dose & Administration:- Adverse effects:-
1- 1.5mg/kg
Adverse effects:-
CVS and Resp. depression
Excitatory phenomena during induction
Epileptiform activity
Pain on injection
Tissue damage
Intraarterial injection
Allergic reaction
Thrombophlebitis

60. Etomidate Chemical Structure:-
D-Ethyl-1-(α-methylbenzyl)-imidazole-5-carboxylate
Physical characteristics and presentation:-
Soluble but unstable in water
Contains 35% propylene glycol
10ml ampoule contains 20mg
pH is 8.1

61. Etomidate Pharmacology:- Rapidly acting Duration of action 2-3 mts.
Less cardiovascular depression
Large doses may produce tachycardia
Respiratory depression is less
Impairs synthesis of cortisol from adrenal gland.
Longterm infusion in ICU leads to increased infection and Mortality.

62. Etomidate Pharmacodynamics:- 76% bound to protein
Metabolised in liver mainly by esterase hydrolysis
Terminal elimination half life 75mts.

63. Etomidate Dose & administration:- Adverse effects:- 0.3mg/kg
Suppression of synthesis of cortisol
Excitatory phenomenon
Pain on injection
Nausea and vomiting
Emergence phenomena
Venous thrombosis

64. Incidence of Adverse reactions:
Thiopentone : 1: :20000
Methohexital : 1: :7000
Althesin : 1:400- 1:11000
Propanidid : 1:500- 1:1700
Etomidate :1:
Propofol :1: