Intravenous Anesthetic agent

DR. MD. MUSTAFA KAMAL

Associate Professor
Dept. of Anaesthesia, Analgesia and Intensive Care Medicine
Bangabandhu Sheikh Mujib Medical University
Shahbag, Dhaka

Properties of Ideal IVA:

A) Physical Properties: - Drug compatibility & stability in solution.

- Water soluble.
- No pain on injection.
- No vascular or tissue damage following extravasations.

B) Pharmacokinetics: -High Lipid

solubility, a high proportion of unbound & unionized drug to facilitate rapid onset of
action
- Steep
dose response curve to facilitate titration & minimize accumulation.
- Rapid
metabolism to inactive compound (for rapid recovery).

C) Pharmacodynamics: - Rapid
onset of action without excitatory activity.

-Analgesia at sub-anesthetic concentration.

- Lack of organ toxicity (absence of Cardio-respiratory depression,

Hepatotoxicity & Immunosupression).
- Low
potential for histamine release & hypersensitivity reaction.
- Absence
of postoperative nausea, emesis, psychometric reaction
&
hangover.
- No Stimulus
for Porphyria & Malignant hyperpyrexia.
Factors regulating the anesthetic effect of IVA:

1) Protein binding- only unbound drug cross blood-brain barrier. It is reduced by low
plasma protein, low PH

2) Blood flow to brain

3) Extra cellular PH & PK

4) Relative soluble of the drug in lipid & water

5) Speed of injection

Classification of IVA:

On the basis of chemical structure:

A) Barbiturate B) Non-barbiturate

A) Barbiturate : Thiopentone , Methohexitone

B) Non-barbiturate :

1) Dissociative anesthetics- Ketamine

2) Benzodiazepine – Diazepam, Lorazepam, Midazolam

3) Analgesic & neurolepto anesthetic- Haloperidol, Droperidol, Fentanyl, Alfentanile,

Supentanile.

4) Immidazole denivateves- Etomidate

5) Phenol derivatives – Propofol

6) Engenols - Propanidid

7) Steroid – Althesin
Classification of barbiturates:

1) Long acting Estimated half life

e.g. phenoberbitone 24-96 hours

2) Medium acting

e.g. pentoberbitone 21-42 hours

3) Short acting

e.g. secobarbital 20-28 hours

4) Ultra – short acting

e.g. Thiopentol 10-12 hours

Classification of IVA:

On the basis of onset of action:

A) Rapidly action (Primary induction) agents:

 Barbiturate- Thiopentone, Methohexital

 Phenol- Propofol

 Imidazole- Etomidate

 Eugenols- Propanidid

 Steroid- Althesin

B) Slower acting (basal narcotic) agents:

 Phencyclidine- Ketamine

 Benzodiazepines- Diazepum, Midazolam

 Large dose opioids- Fentanyl, Sufentanyl, Alfentanyl, Remifentanyl.

  Neurolept combination- Opioid+ Neuroleptic

TPS
(Thiopental Sodium)

Structure: Sodium 5-ethyl-5-(l-methyl butyl) 2-Thiobarbiturate

Properties:

1) Sulphur analogue of pentobarbital.

2) Yellowish powder with a bitter taste and faint smell of garlic.

3) Stored in nitrogen to prevent chemical reaction with atmospheric carbon-dioxide.

4) Mixed with 6% anhydrous sodium carbonate to its solubility in water

5) Oil /water partition co-efficient- 4.7

6) Pka- 7.6

7) PH- 10.8 (2.5% Solution) (Alkaline)

8) Slightly hypotonic.

Pharmacological action of Thiopental Sodium:

CNS:
1) Produces anesthesia less than 30 sec.
2) Progressive depression of the C.N.S including spinal cord reflex.
3) Potent hypnotic action & poor analgesia.
4) Consciousness regained within 5-10 min.
5) Sub anesthetic blood conc. (i-e low doses, during recovery) ant analgesic effect.
6) Potent anticonvulsant.
7) Reduce cerebral metabolic rate & secondary decrease in CBF, CBV & ICP.
8) Improve cerebral perfusion & compliance in Acute head injury, neurosurgery etc.
CVS:
1) Myocardial contractility is depressed & peripheral vasodilatation.
2) Arterial pressure & profound hypotension in hypovolaemia & cardiac disease.
3) Reflex tachycardia but heart rate may be decreased.
Respiratory:
1) Ventilatory drive is decreased as reduced sensitivity of the resp. centre to co 2
2) Short period of apnoea is common.
3) Increase Bronchial muscle tone.
4) Laryngeal & bronchospasm may occur.

Skeletal Muscle:
1) Muscle tone decreased as suppression of the spinal cord reflex.
2) No effect on NMJ.

Uterus & Placenta:

1) Uterine contraction Suppressed at high dose.
2) Crosses placenta readily but low conc. in fetal blood.

Hepatorenal function:
1) Impaired hepatic & renal function.

Eye:
1) Pupil dilates first then constricts.
2) Light reflex intact until surgical anaesthesia.
3) Corneal, Conjunctival, Eyelash & Eyelid reflex abolished.
4) Intra ocular pressure reduced by 40%.
Pharmacokinetics:
1) 75-85% bond to protein (mostly albumin).
2) Un-ionized state 61% at body PH .
3) Metabolized mainly in Liver & excreted by Kidneys.
4) Elimination Half life 11.5 hours.
5) Clearance- 3.4 mL/Kg/min.
6) Metabolized by zero order kinetics (10-15% per hour).
7) Hangover effect common.
8) In obese, dose according to lean body mass & Elimination impaired due to drug retention
Adipose tissue.

Dose: 3 - 5 mg/Kg. Administrated as 2.5% solution over 15-20 Sec.

 No drug should be mixed with Thiopentone.
 In healthy adult, 1-2 ml of 2.5% solution initially then drug given 4 mg/kg over 15-20 sec
until eyelash reflex abolish. If not abolished 50 – 100mg further given.
 In elderly, dose should be reduced. In very frail patients, 50 mg may be sufficient to
induce sleep.

Adverse effects:
1. Hypotension
2. Respiratory Depression
3. Tissue Necrosis ( perivenous injection).
4. Intra arterial injection- Pain & Severe complication if 5% solution.
5. Laryngeal spasm
6. Bronchospasm
7. Allergic reaction
8. Thromboembolism

Indication:
1) Induction of anesthesia
2) Maintenance of anesthesia- Short procedure.
3) Basel narcosis by rectal administration
4) Rx of status epilepticus
5) Decrease I.C.P
Contraindication (absolute):
1. Airway obstruction.
2. Porphyria.
3. Hypersensitivity reaction.
4. Severe CVS collapse /shock.
5. Status asthmaticus.

Precautions:
1. CVS disease
2. Severe hepatic disease
3. Renal disease
4. Muscle disease
5. Decreased metabolic rate
6. Obstetrics
7. Outpatient anaesthesia
8. Adrenocortical insufficiency
9. Extreme of age
10. Asthma
 Propofol

History: 1st use as anaesthetic agent -1980, Commercially available in 1986.

Structure: 2, 6 Di-iso propyl phenol ( an alkyl phenol compound).

Properties:
1) Extremely lipid soluble & water insoluble.
2) Propofol formulated in a whitish 1% emulsion containing soya bean oil-10%, purified egg
phosphatide-1.2% & glycerol-2.5%.
3) PH- 6-8.5
4) Pka- 11
5) Non-irritant but pain on injection 32-67% case.
6) An antimicrobial, Sodium Metabisulphite (instead of Disodium edetate) cause less
injection pain.

Pharmacological action of Propofol:

CNS:
 1) Anesthesia is induced within 10-30 sec.
2) Delayed disappearance of eyelash reflex and loss of verbal contact is a better end point of
unconsciousness.
3) Reduce Cerebral metabolic rate, Cerebral blood flow & ICP.
4) Rapid recovery & minimal hangover effect.
CVS:
1) Arterial pressure Decreased (More than TPS) due to vasodilatation.
2) Cardiac output decreased slightly.
3) Heart rate increased slightly affect induction.
Respiratory:
1) Apnoea occurs more Commonly after induction.
2) Respiratory rate increased & Tidal volume decreased due to decreased ventilatory
response to co2
3) No effect on Bronchial muscle tone, Laryngospasm is uncommon.
So used in LMA anaesthesia.
Skeletal: Tone is reduced.
GIT: Low incidence of PONV.
Uterus & placenta:
1) No effect on uterine tone.
2) Not recommended in breast feeding mother & Obstetric procedure
(except for termination)
Hepatorenal:
1) Decrease renal function
2) Hepatic blood flow by the in arterial blood pressure
Endocrine: Decrease Plasma conc. of cortisol.

Pharmacokinetics:
1. 98% bond to plasma protein & highly lipophilic.
2. Distribution half life 2-4 min, Intermediate (or first) elimination half life 60-75 min,
Terminal elimination half life 3-4.8 hr (may extend beyond 24 hr).
3. Vd – 600-1000 L
4. Plasma clearance- 20-30 mL/Kg/min.
5. Hepatic & Extra hepatic metabolism.
Kidney excreting metabolites mainly glucoronide & sulphate.

Dose: 1.5 - 2.5 mg/Kg. Infusion rate 2-15 mg/Kg/Hr (according to need)
 Not recommended below 1month of age.
 Infusion not recommended under 14 years in ICU(UK).
Adverse effect:
1) Cardiovascular depression –Profound hypotension (dose dependent).
2) Respiratory depression- Apnoea (more common).
3) Excitatory phenomenon
4) Pain on injection
5) Allergic reaction- Skin rash.

Indication:
1) Induction of anesthesia.
2) Maintenance of anaesthesia.
3) Sedation during surgery.
4) Total IV anaesthesia (TIVA).
5) Sedation in ICU.
6) Useful drug in day case anaesthesia.
7) Hypotensive(Induced) anaesthesia.

Contraindication(absolute):
1) Airway obstruction.
2) Known hypersensitivity reaction.
3) Adrenocortical insufficiency.
4) Below 1month of age.
5) Infusion under 14 years in ICU (UK)
 Ketamine Hydrochloride

History: 1st introduce in 1965

Structure: 2-(o-chlorophenyl)-2 (methylamino)- cyclohexanone hydrochloride.

Properties:
1) Phencyclidine derivatives
2) Produce dissociative anaesthesia and no generalized depression of the CNS
3) Soluble in water containing sodium chloride to produce isotonicity.
 4) PH-3.5-5.5
5) Pka- 7.5
6) It is a N-Methyl D-aspartate receptor antagonist (NMDA).
7) Ketamine molecule has chiral centre producing two optical isomers- S(+) & R(-).
8) Racemic mixture of two isomers available commercially.
9) Benzethonium chloride used as preservative.

Pharmacology:
CNS:
1) Produce anesthesia within 30-60 sec and effective for 10-15 minutes after I.V. injection
also effective within 3-4 minute after I.M.
2) Potent somatic analgesic at sub-anaesthetic blood concentration
3) Amnesia often persists for 1 hour (or 90min).
4) Emergence delirium with restlessness, agitation, disorientation.
5) Unpleasant nightmares or hallucination may occur during recovery
6) Increase Cerebral metabolic rate (CMRO2), CBF & ICP.

CVS:
1) Arterial Blood pressure increases (up to 25%)
2) Heart rate increases (up to 20%)
3) Increased CO & myocardial O2 consumption.
4) Direct myocardial depressor but indirect CVS effect through sympathomimetic effect &
vasomotor center stimulation. Release nor-adrenalin.
5) Increased myocardial sensitivity to Adrenalin.

Respiratory:
1) Transient apnea may occur but ventilations well maintained.
 2) Pharyngeal & laryngeal reflex & patient airway are well maintained.
3) Bronchial muscle dilated & antagonize bronchoconstrictor action of Histamine.

Skeletal muscle : Increased Muscle tone.

GIT: Increased Salivation
Uterus & Placenta :
1) Increased uterine tone & intrauterine pressure both pregnant & non-pregnant uterus.
2) Drugs crosses the placenta quickly
Eye: Increased IOP. Eye movement during surgical anaesthesia.

Pharmacokinetics:
1) 12% Ketamine is bound to protein.
2) Highly lipid soluble.
3) Metabolism mainly in liver by demethylation and hydroxylation of the
cyclohexanone ring.
4) Elimination half life – 2-4 hours (2.5).
5) Norketamine, primary metabolite has 30-50% potency of Ketamine.
6) 80% metabolites of both Ketamine & Norketamine are excreted as glucuronides.

Dose: IV- 1-2 mg/kg. IM - 6-10 mg/kg. Infusion- 50 µg/kg/min.

Oral, Intranasal can be given.

Adverse effect:
1) Emergence delirium, nightmares & hallucination
2) Hypertension & Tachycardia
3) Prolonged recovery
4) Salivation
5) Increased I.C.P & I.O.P
6) Allergic reaction
7) Coughing, Hiccuping, Layngospasm.
Indication :
1) High risk Patient- shocked Patient, Children with cyanotic heart diseases.
2) Paediatric anesthesia
3) Difficult location – war, site of aecedent
4) Analgesia & sedation
5) Developing countries
6) Status asmthaticus.
Absolute contraindication
1) Airway obstruction
2) Increased ICP.
Precaution
1) cardiovascular disease
2) Repeated administration
3) Visceral stimulation
4) Outpatient anaesthesia
Summary of IVA effect on organ system.
IVA Agents Cardiovascular Respiratory Cerebral
HR MAP Vent.Drive Bronchodilation CBF CMRO2 ICP
Barbiturate(Thiopentone)) ↑↑ ↓↓ ↓↓↓ ↓ ↓↓↓ ↓↓↓ ↓↓↓

Benzodiazepines
Diazepum,Lorazepum 0/↑ ↓ ↓↓ ↓↓ ↓↓ ↓↓
Midazolam ↑ ↓↓ ↓↓ ↓↓ ↓↓ ↓↓
Opioids
Pethedinie ↑ ↔ ↓↓↓ ↔ ↓ ↓ ↓
Morphine ↓ ↔ ↓↓↓ ↔ ↓ ↓ ↓
Fentanyl,Sufentanyl ↓↓ ↓ ↓↓↓ 0 ↓ ↓ ↓
Alfentanyl,Ramifentanyl
↓↓ ↓↓ ↓↓↓ 0 ↓ ↓ ↓
Ketamine ↑↑ ↑↑ ↓ ↑↑↑ ↑↑↑ ↑ ↑↑↑
Propofol 0 ↓↓↓ ↓↓↓ 0 ↓↓↓ ↓↓↓ ↓↓↓
Etomidate 0 ↓ ↓ 0 ↓↓↓ ↓↓↓ ↓↓↓

Droperidol ↑ ↓↓ 0 0 ↓ 0 ↓

↔ depend on extent of Histamine release.

 Drugs used to supplement anesthesia
Classification of Opioids:

A) Endgenous: Endorphin, Enkephalin, Dynorphin.

B) Exogenous:

1. Natural: Morphine, Codeine

2. Semisynthetic: Diamorphine, Hydromorphine, Oxymorphine.

Hydrocodone, Oxycodone.

3. Synthetic: Pethedine, Fentanyl, Sufentanyl, Alfentanyl,

Remifentanyl.

 Agonist: Endogenous & Exogenous

 Partial agonist: Buprenorphine

 Opioid agonist/antagonist: Pentazocine, Nalbuphine, Nalorphine.

 Antagonist: Naloxone, Naltraxone.

Opium: Is the derived powder mixture of alkaloid obtained from the unripe seed capsule
of the poppy plant, papaver sominiferum

Opeate: Drugs derived from opium

Opioid: All drugs natural & synthetic that have morphine like properties

Classification Of Opioid Receptor:

Three principle Opioid receptor-
1. mu (μ) receptor- OP3
Subtype- μ 1 & μ 2
2. kappa (κ) receptor- OP2
3. delta (δ) receptor- OP1
Others:
 Sigma(σ) receptor
 Orphan opioid receptor- ORL1 (agonist-nociceptin/orphanon FQ)

Table: Classification of Opioid Receptors & their clinical effect.

RECEPTOR CLINICAL EFFECT AGONISTS ANTAGONISTS

Μ Supra spinal analgesia (μ 1) Morphine
Spinal & Peripheral analgesia Met-enkephalin
Respiratory depression (μ 2) Beta-endorphin Naloxone
Physical dependence Fentanyl Pentazocine
Muscle rigidity
Euphoria
Miosis
Constipation
Somlonence
Tolerance
Κ Sedation Morphine
Spinal &Peripheral analgesia Nalbuphine,Butorphanol,
Dysphoria & Hallucination Dinorphin,Oxycodone Naloxone
Somlonence
Miosis
Constipation
Physical dependence
Tolerance
Δ Spinal analgesia Leu-enkephalin
Behavioral Beta-endorphin
Epileptogenic Naloxone
Ventilatory depression
Constipation
Tolerance
Σ Dysphoria Pentazocine
Hallucination Nalorphine
Respiratory stimulation ketamine
.