INTRAVENOUS ANAESTHETIC AGENTS

Department of Anesthesiology - Jordan University of Science and Technology Irbid-Jordan

INTRAVENOUS ANAESTHETIC AGENTS

1- Barbiturate 1.1. sodium thiopental(used for over 40 years) 2. Non barbiturate 2.1. propofol (newly introduced) 2.2. ketamine (infrequently used) 2.3. Etomidate 3. other adjuvant intravenous anesthetic agents (benzodiazepines, midazolam, diazepam,)

PROPERTIES OF THE IDEAL INTRA VENOUS ANAESTHETIC AGENT{1 OF 3}

1-rapid onset: achieved by an agent that is mainly : A- un-ionized at blood ph(7.35 7.45) B- highly lipid soluble ** these properties permit penetration of the BBB 2-rapid recovery: -early recovery of consciousness is usually produced by rapid redistribution of the drug from brain into other well-perfused tissues particularly muscles -quality of the recovery period is more related to the rate of metabolism of the drug * Drugs with slow metabolism are with a more prolonged hangover effect (fatigue, weakness, pain, nausea, vomiting..etc )and 3 accumulate if used in repeated doses or by infusion for maintenance of anesthesia

PROPERTIES OF THE IDEAL INTRA VENOUS ANAESTHETIC AGENT {2 of 3}

3- analgesia at sub anesthetic concentrations *analgesia :an absence of the sense of pain without loss of consciousness
4- minimal cardiovascular and resp. depression 5- no emetic effects 6- no excitatory phenomena e.g. coughing .hiccup ,involuntary movements 7-no emergence phenomena e.g. nightmares 8-no interaction with neuromuscular blocking drugs(muscle relaxant) *Neuromuscular blocking drugs relax skeletal muscles and induce paralysis.
4

PROPERTIES OF THE IDEAL INTRA VENOUS ANAESTHETIC AGENT {3 of 3} 9- no pain on injection 10- no venous sequelae(such as thrombosis) 11-no toxic effects on other organs 12- no release of histamine(bronchospasm ..itching) 13- no hypersensitivity reactions 14- water soluble formulation 15- long shelf life :
The length of time a product may be stored without becoming unsuitable for use or consumption.

16-no stimulation of porphyria

SODIUM THIOPENTAL (PENTOTHAL)

Definition: ultra short acting barbiturate Classification: IV anesthetic-hypnotic Physical chemical properties : -Its a Yellow powder with a sulphuric smell and a bitter taste -highly lipid soluble compound -when combined with sodium carbonate it becomes water soluble
6

SODIUM THIOPENTAL (PENTOTHAL)

-bacteriostatic in water and has a ph of 10.6 to10.8 -*when injected ,sodium bicarbonate is neutralized and the thiopental is converted to its lipid soluble non ionized form(40% ionized at ph=7.4) -its highly protein bound by albumen(75%) Which prevents precipitation out of solution in vivo
7

Sodium thiopental (pentothal)

thiopental(yellow

powder) is dissolved in water& sodium carbonate to make a 2.5% solution (25mg/ml)

Its stable at room temp for 2 weeks

SODIUM THIOPENTAL (PENTOTHAL)

Pharmacokinetics
-An IV dose of 3-5 mg/kg results in loss of consciousness
-time required to render the patient unconscious is generally 30-60 secs after administration .this is called the arm brain circulation time

-arm brain circulation time

is the time required for the drug to pass from site of injection to the brain as it passes through the right heart ,pulmonary circ., and the left heart

Sodium thiopental (pentothal)

Pharmacokinetics
-with

no other drugs ,the anesthetic state persists for 5-10 mins Its concentration is low enough in the brain such that consciousness returns.
So is most commonly used in the induction phase of general anesthesia

As with all lipid soluble anesthetic drugs, the short duration of action of Sodium thiopental is almost entirely due to its redistribution away from central circulation towards muscle and fat tissue.
10

Sodium thiopental (pentothal)

Pharmacokinetics
-sulphur containing drugs , acidosis, NSAIDS may displace thiopental from albumen -liver &renal disease may be associated with low albumin levels so result in an increase in free thiopental which increase the anesthetic toxicity and potency -metabolism occurs primarily in the liver with approximately 10 to 15%of the drug level metabolized per hour -desulfuration reaction in liver produces pentobarbital which undergoes oxidative metabolism yielding 2 compounds with no anesthetic activity -less than 1% of the drug is excreted unchanged in the urine
11

SODIUM THIOPENTAL (PENTOTHAL)

pharmacodynamics
CNS:
1-interact with chloride ion channels facilitate GABA ( inhibitory NTM) 2- Block glumatic acid (excitatory NTM) 3-thiopental will decrease both cerebral electrical & metabolic activity (So it can be used to stop seizures activity in emergency situations) -to maintain depression of cerebral electrical activity very high dose are required -but to maintain seizure control & avoid cv depression from high dose of thiopental other drugs are used (e.g. benzodiazepines)
12

SODIUM THIOPENTAL (PENTOTHAL)

pharmacodynamics

CNS:
4-Elevated ICP can quickly be reduced by thiopental BUT The improvement of ICP requires high dose of thiopental to be maintained The reduction of ICP is due to cerebral vasoconstriction, reduced cerebral Metabolism &oxygen requirements associated with decrease cerebral blood volume 5-Anti-analgesic effect, since low dose may decrease pain threshold

6-Intraocular pressure decreases up to 25% with 35mg/kg of thiopental and persists for 3 to 5 minutes
13

SODIUM THIOPENTAL (PENTOTHAL) Pharmacodynamics

CVS:

1-thiopental causes a dose related depression of myocardial function as measured by CO,SV and blood pressure 2-coronary blood flow, heart rate ,&myocardial oxygen uptake all increase following thiopental administration 3-venous tone decreases (decreased preload) And contributes to the increase in HR and decrease in BP 4-little change in total peripheral resistance 14

SODIUM THIOPENTAL (PENTOTHAL)

Pharmacodynamics
Respiratory

1-induction of anesthesia with thiopental may be associated with 2 or 3 large breaths followed by apnea for less than 1min 2-there is dose related depression of the respiratory response to hypercarbia and hypoxia 3-laryngospasm and bronchoconstriction may be associated with light levels of thiopental and with airway manipulation or intubation 4-FRC is reduced by 20% with induction of anesthesia >Functional Residual Capacity (FRC) is the volume of air present
in the lungs at the end of passive expiration.
15

SODIUM THIOPENTAL (PENTOTHAL)

Pharmacodynamics

GI:

1-enzyme induction may occur with prolonged high dose therapy 2-Hypoalbuminemia will result in an increase in unbound (free) thiopental and an increase in the potency of thiopental GU/pregnancy/fetus: 1- Thiopental has little or no effect on the kidneys or gravid uterus. 2-although thiopental crosses the placenta It has no significant effect on the fetus when used for cesarean section (dose used is limited to 4mg/kg)

16

SODIUM THIOPENTAL (PENTOTHAL) Dose & administration

- Usual dose is 3-6 mg/kg - Thiopental should be used with caution for Patients suffering from shock status because normal dose may lead to rapid death - For a short procedure (e.g.cardioversion) a dose of 2 mg/kg is generally sufficient - For frail elderly women with hip fracture .5-1 mg/kg may induce anesthesia

17

SODIUM THIOPENTAL (PENTOTHAL)

INDICATIONS
1- induction of anesthesia 2- maintenance of anesthesia for short procedures 3- control of convulsive states 4- for supplement of regional anesthesia or low potency anesthesia

18

SODIUM THIOPENTAL (PENTOTHAL)

Absolute contraindications
1- airway obstruction

2- porphyria
3- previous hypersensitivity

PRECAUTIONS
1- CVS disease 2- severe hepatic disease

3- renal disease
19

SODIUM THIOPENTAL (PENTOTHAL)

SIDE EFFECTS
1- hypotension :if thiopental is administered to
hypovolemic, shocked or previously hypertensive pt

2- respiratory depression :when excessive doses are

used

3- tissue necrosis : following venous infusion 4- laryngeal spasm 5- bronchospasm :unusual but may be precipitated in
asthmatics pts

6- allergic reaction : from cutanous rashes to severe

anaphylactic shock with cvs collapse
20

SODIUM THIOPENTAL (PENTOTHAL)

SIDE EFFECTS
7- Rarely, intra-arterial injection can occur.
The consequences of accidental arterial injection may be severe. The degree of injury is related to the concentration of the drug. Treatment consists of 1. dilution of the drug by the administration of saline into the artery, 2. heparinization to prevent thrombosis, and 3. brachial plexus block. Overall, the proper administration of thiopental intravenously is remarkably free of local toxicity.
21

PROPOFOL
Intravenous anaesthetic/hypnotic. Alkylphenol. Propofol is a sweet drug in the OR, but definitely not for home use.

22

PROPOFOL

PHYSICAL AND CHEMICAL PROPERTIES

Emulsion consists of: 1% propofol 10mg/ml 10% soyabean oil. 2.25 %glycerol 1.2% purified egg phosphatide.

23

PROPOFOL

PHYSICAL AND CHEMICAL PROPERTIES

Propofol is a highly lipid soluble Its appearance is similar to that of a 2% milk.

It has a pH of 7 and is supplied in 20 ml ampoules with a concentration of 10 mg/ml. Neither precipitates histamine release nor triggers malignant hyperthermia. Has no effects on muscle relaxants. Associated with low incidence of nausea & vomiting.
24

PROPOFOL DOSAGE
For For

healthy unpremedicated 2.5-3 mg/kg. premedicated 1.5-2 mg/kg. patients <= 1 mg/kg.

Elderly

Maintenance

of anesthesia (50-150 mcg/kg/min)

combined with N2O and Opioids (Continuous Infusion: Total intravenous Anesthesia TIVA)
For

IV conscious sedation for operative procedures

25

with local anaesthesia 25-75 mcg/kg/min.

PROPOFOL
EFFECTS ON ORGAN SYSTEMS

Cerebral:
1-decreases cerebral blood flow and intracranial pressure. 2-Propofol has antiemetic, antipruritic, and anticonvulsant properties.

Cardiovascular:
1-decrease in arterial blood pressure secondary to a drop in systemic vascular resistance, contractility, and preload. 2-Hypotension is more pronounced than with thiopental. Propofol markedly impairs the normal arterial baroreflex response to hypotension.

26

PROPOFOL
EFFECTS ON ORGAN SYSTEMS

Respiratory:
1-profound respiratory depression. 2-induced depression of upper airway reflexes exceeds that of thiopental.

Venous irritation:

Pain on injection esp. if given in a small vein in the hand.

To solve this problem:

1. small dose of lidocaine with propofol.

2. administering propofol through a fast flowing more proximal IV catheter.
27

PROPOFOL
INDICATIONS
indication Initiation and maintenance of Monitored Anesthesia Care sedation Combined sedation and regional anesthesia Induction of General Anesthesia Maintenance of General Anesthesia Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Approved Patient Population Adults only

Adults only Patients 3 years of age Patients 2 months of age

Adults only

28

PROPOFOL
CONTRAINDICATIONS
1. 2.

3.
4.

Egg allergy. Lack of resuscitation equipment or knowledge of the drug. Inability to maintain a patent airway. Conditions in which reduction in blood pressure cant be tolerated. E.g. patients with fixed cardiac output (severe aortic or mitral stenosis, IHSS, pericardial tamponade) and those in shock status.
29

KETAMINE

Its a dissociative anesthetic agent.

30

by dissociative we mean that

the patient is unconscious but

appears awake and doesnt feel pain.

It has anesthetic and

analgesic effect

KETAMINE
PHYSICAL & CHEMICAL PROPERTIES
chemically

related to the psychotropic drug ( e.g. phencyclidine). soluble, and 10x more lipid soluble than thiopental. - 5.5

31

Water

pH=3.5

KETAMINE
PHARMACOKINETICS
ROUTE OF ADMINISTRATION
I.V. IM. Oral.

: 2mg/kg

32

Rectal. Needs higher dose due to extensive first pass metabolism and decreased absorption.

KETAMINE
PHARMACOKINETICS DOSAGE
IM

5 10 mg/kg. peak plasma level reach approx 15 minutes 1 2 mg/kg. dissociated stage is noted in 15 seconds. intense analgesia, amnesia & unconciousness occur within 4560 minutes subsequent IV doses of 1/3 of the initial dose maybe required

33

IV

KETAMINE METABOLISM

It has a rapid absorption and distribution to the vessel rich groups like THIOPENTAL

34

Hepatic metabolism is required for elimination <5% excreted unchanged in urine

KETAMINE
MECHANISM OF ACTION
There are 3 theories explains the MOA of ketamines : 1 N-methyl aspartate receptor theory : NMA receptors may represent a subgroup of the sigma opiate receptors (the PCP site) that blocks spinal pain reflexes. 2 Opiate receptor theory : Ketamine may have some affinity for opiate receptors but its effect cant be reversed with naloxone. 3- Miscellaneous receptor theory : It reacts with muscarinic, cholinergic and serotonergic receptors. Ketamine is a potent analgesic at subanesthetic plasma concentrations. It has a wide margin of safety ( up to 10x the usual dose )

35

KETAMINE
PHARMACODYNAMICS
CNS : 1. ketamine increases cerebral oxygen consumption, cerebral blood flow, and intracranial pressure 2- generalized increase in the muscle tone and purposful movements. 3- Unpleasant dreams, hallucinations or frank delirium (esp. females & large doze of ketamine). incidence of delirium in 15-35 year old pts is approx. 20%

36

KETAMINE
PHARMACODYNAMICS

Respiratory system:
It preserves laryngeal &pharyngeal airway reflexes. Ketamine is a potent bronchodilator. The CO2 response curve is shifted to the left with its slope unchanged (similar to opiates). FRC unchaged. Minute ventilation unchanged. Tidal volume unchanged. Hypoxic pulmonary vasoconstriction unchanged. Ketamine causes increased secretions but this can be limited by anti-cholinergic drugs.
37

KETAMINE
PHARMACODYNAMICS

CVS:
It produces central sympathetic stimulation, which increases: 1. arterial blood pressure, heart rate, and cardiac output. 2. Pulmonary artery pressure. 3. Coronary blood flow. 4. Myocardial oxygen uptake. It may cause myocardial depression if the sympathetic nervous sys is exhausted or blocked.

38

KETAMINE
PHARMACODYNAMICS

GI

Minimal anorexia, nausea & vomiting.

39

GU
Placental transfer does occur, but neonatal depression hasnt been observed if the doze is limited to < 1 mg/kg.

Muscle system

Generalized increase in skeletal muscle tone. Increases the effects of muscle relaxants. Increased sympathetic stimulation increased blood glucose, increased plasma cortisol, increased heart rate.

Endocrine system

KETAMINE INDICATIONS
1- sole anesthetic for diagnosis and surgical procedures
40

2- induction of anesthesia 3- to supplement regional or local anesthetic techniques 4- for anesthetic induction in severe asthmatic pts. Or patients with cardiovascular collapse requiring emergency surgery

KETAMINE
CONTRAINDICATIONS
1- lack of knowledge of the drug
41

2- lack of resuscitative equipment 3- inability to maintain a patent airways 4- allergy to ketamine 5- history of psychosis

6- cerebro-vascular disease
7- patients with hazardous hypertension

BENZODIAZEPINES
Features

which result in their popularity as adjuvant IV anaesthetic agents: 1 amnesia 2 minimal cardiarespiretory depressant effect. 3 anticonvulsant activity. 4 low incidence of tolerance and dependence.

42

BENZODIAZEPINES MODE OF ACTION

1 They inhibit the actions of glycine (by increasing

the conc. of a glycine inhibitory neurotransmitter) which will lead to antianxiety and skeletal muscle relaxant effects. 2 They facilitate the actions of the inhibitory neurotransmitter GABA which results in the sedative and anticonvulsant effects.

43

Benzodiazepines are highly lipid soluble. They are highly protein bound (albumin). They are metabolized by the liver through conjugation with glucoronic acid and excreted by the kidneys. Midazolam and Diazepam are the most commonly used benzodiazepines during operative procedures.

BENZODIAZEPINES MIDAZOLAM AND DIAZEPAM

They

are commonly used to provide:

44

1- IV sedation. 2- amnesia. 3- reducing anxiety.

BENZODIAZEPINES MIDAZOLAM AND DIAZEPAM

THE DIFFERENCES BETWEEN THEM

1- Midazolam is 2-3 times more potent than diazepam: 2- The dose for IV conscious sedation: 0.5 3 mg up to 0.1 mg/kg for midazolam, and 1-10 mg for diazepam. 3- The dose for inducing anesthesia: 0.2 0.4 mg/kg for midazolam , and 0.15-1.5 mg/kg for diazepam. 4- Midazolam has a more rapid onset, greater amnestic effect, less postoperative sedative effects than diazepam.
45

BENZODIAZEPINES MIDAZOLAM AND DIAZEPAM

THE DIFFERENCES BETWEEN THEM

5- Pain on injection and subsequent thrombophlebitis is less likely with midazolam (an emulsion of diazepam) 6- Midazolam is more costly than diazepam). 7- Midazolams duration of action is less than diazepam but almost 3 times that of thiopental. 8- Elimination half time for midazolam range from 1-4 hours, and for diazepam from 21-37 hours. 9- Midazolam is supplied as a clear liquid in concentrations of 1-5 mg/ml.

46

BENZODIAZEPINE ANTAGONISTS (FLUMAZENIL)

Its an imidazobenzodiazepine.

It specifically antagonizes benzodiazepines central

effects by copetative inhibition. Its elimination half-time is one hour, considerably less than most benzodiazepines; therefore we will need repeated administrations of flumazenil to antagonize a

47

benzodiazepine with a longer half-time.

BENZODIAZEPINE ANTAGONISTS (FLUMAZENIL)

Flumazenil

is supplied as a colourless liquid in a concentration of 0.1 mg/ml. The usual initial dose is 0.2 mg over 15 seconds, if the desired level of consiousness is not obtained within one minute of administration we can give repeated doses of 0.1 mg every minute up to the maximum of 2 mg, and if sedation recurs we can use infusions of 0.1-0.4 mg/hour. Flumazenil is well tolerated. The most common side is nausea (4% of patients).

48

NARCOTIC AGONISTS
Opium

derived from dried juice of poppy plant which contains over 20 plant alkaloids. including morphine & codiene.

49

NARCOTIC AGONISTS SITE OF ACTION

Opioid receptors are predominantly located in the: 1. Brain stem (amygdala, corpus striatum, periaqueductal gray matter and medulla). 2. Spinal cord(substantia gelatinosa). 3. GIT. They act on 3 types of receptors: 1. Mu receptors (): analgesia, respiratory depression, euphoria, & physical dependence. 2. Kappa receptors (K): analgesia, sedation, respiratory depression, miosis. 3. Segma receptors(a): dysphoria, hallucination, tachypnea, tachycardia.

50

NARCOTIC AGONISTS PHARMACOKINETICS

Rapid

distribution through the body

51

following IV injection.
Its

metabolized by the liver and the

majority of the inactive metabolites are excreted unchanged in the urine.

NARCOTIC AGONISTS PHARMACODYNAMICS

CNS:
52

Opioids sedate through interfering with sensory perception of painful stimuli. large doses produce unconsciousness but they are generally incapable of producing anesthesia and it cant guarantee total amnesia. It may produce nausea & emesis through stimulation of the chemoreceptor trigger zone.

NARCOTIC AGONISTS PHARMACODYNAMICS

Respiratory
They

result in dose related depression of respiratory rate and minute ventilation and increase the tidal volume which will lead to a slow deep respiration. Reversed by naloxone administration.

53

NARCOTIC AGONISTS PHARMACODYNAMICS

CVS

Opioids have little myocardial depressant effect even when administered in high doses. Supplementation with either N2O or benzodiazepines may depress cardiac output. They decrease systemic vascular resistance either by decreasing sympathetic outflow or by releasing histamine (as morphine) which produces vasodilation & decrease SVR. Synthetic opioids are less likely to release histamine. They produce bradycardia by stimulation vagal nucleus in the brain stem.

54

NARCOTIC AGONISTS PHARMACODYNAMICS

GIT
Narcotics

slow GI mobility and may result in constipation or post operative ileus. All narcotics increase biliary tract tone which may lead to biliary colic with patients with bile stones.

55

Others
Increases

the bladder sphincters tone urine

retention. Anaphylactic reactions, bronchospasm, chest wall rigidity and pruritis.

NARCOTIC AGONISTS FENTANYL AND MORPHINE

Fentanyl

is the most narcotic agent used during induction of anaesthesia due to its rapid onset (highly lipid soluble) and predictable duration of action (30 minutes). Morphine is used in the perioperative period to provide long lasting analgesia. And it should be administered slowly at a rate < 5 mg/min to avoid excessive histamine release.

56

NARCOTIC AGONISTS FENTANYL AND MORPHINE

Potency Ratio Analgesic dose Low dose
57

Morphine

10 mg

0.05 - 0.2 mg/kg

Fentanyl

100

100 mcg

0.5 3 mic g/kg

NARCOTIC ANTAGONISTS (NALOXONE)

Naloxone competes with opioids at the mu, delta,

58

kappa and sigma receptors.

Ampules of 0.02, 0.4 and 1 mg/ml.

Peak effect 1-2 min.

Duration of action 30-60 min. Used in perioperative surgical patients with excessive sedation or respiratory sedation secondary to opioids.

NARCOTIC ANTAGONISTS (NALOXONE)

Given

in small incremental doses. High doses of naloxone will result in sudden reversal of analgesic effects leading to abrupt return of pain resulting in hypertension, tachycardia, pulmonary edema, ventricular dysrhythmias and cardiac arrests. If sedation or respiratory depression recurs, continuous infusion of 3-10 micg/kg/hour of naloxone is required.

59

60

THANK YOU