Intravenous Anesthetic Agents-1

INTRAVENOUS ANAESTHETIC

AGENTS

Dr. Med. Khaled Radaideh

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

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INTRA VENOUS ANAESTHETIC AGENT

OBJECTIVES1- Properties of the ideal intravenous anesthetic agent

2- Classification of the intravenous anesthetic agent

3- Sodium Thiopental

3.1. Definition

3.2. Classification

3.3. Physical chemical properties

3.4. Pharmacokinetics

3.5. Pharmacodynamics

3.6. Dose and Administration

3.7. Indication, contraindication and precautions

3.8. Side Effects

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OBJECTIVES4- Propofol4.1. Physical and chemical properties4.2. Dosage4.3. Effects on organ systems4.4. Indication and contraindication5. Ketamine5.1. definition of dissociative anesthesia5.2. Physical & chemical Properties5.3. Pharmacokinetics (Route of administration and Dosage)

5.4. Metabolism5.5. Mechanism of action5.6. Pharmacodynamics (effect on organ systems)5.7. Indications and contraindications

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OBJECTIVES6- Benzodiazepines

6.1. Features

6.2. Mode of action

6.3. Midazolam and Diazepam (Uses, differences between them)

6.4. Benzodiazepine antagonists (Flumazenil)

7. Narcotic Agonists

7.1. Origin, Site of action and Receptors

7.2. Pharmacokinetics

7.3. Pharmacodynamics (effect on organ systems)

5.4. Fentanyl And Morphine

8. Narcotic Antagonists (Naloxone)

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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 BBB2-rapid recovery: -early recovery of consciousness is usually produced by rapid

redistribution of the drug from brain into other well-perfused tissues particularly muscles

-plasma conc. Of drug decreases & drug diffuses out of the brain along a conc. gradient

-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, nuasea vomiting..etc )and accumulate if used in repeated doses or by infusion for maintenance of anesthesia

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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 phenomenae.g. coughing .hiccup ,involuntary movements

7-no emergence phenomenae.g. nightmares

8-no interaction with neuromuscular blocking drugs(muscle relaxant)*Neuromuscular blocking drugs relax skeletal muscles and induce

paralysis.

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

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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

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

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INTRAVENOUS ANAESTHETIC AGENTS1- Barbiturate1.1. sodium thiopental(used

for over 40 years)2. Non barbiturate2.1. propofol (newly

introduced)2.2. ketamine (infrequently

used) 2.3. Etomidate4. other adjuvant intravenous

anesthetic agents (benzodiazepines, midazolam, diazepam,…)

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SODIUM THIOPENTAL (PENTOTHAL) Definition:

ultra short acting barbiturate

Classification:

IV anesthetic-hypnotic

Physical chemical properties :

-It’s a Yellow powder with a sulphuric smell and a bitter taste

-highly lipid soluble compound

-when combined with sodium carbonate it becomes water soluble

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SODIUM THIOPENTAL (PENTOTHAL)

-its 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 ionazed form(40% ionized at ph=7.4)

-its highly protien bound by albumen(75%)

Which prevents precipition out of solution in vivo

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Supplied: 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

- Thiopental is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system

Sodium thiopental (pentothal) 2

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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

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Pharmacokinetics-with no other drugs ,the anesthetic

state persists for 5-10 minsIts 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.

Sodium thiopental (pentothal) 2

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Pharmacokinetics-sulphur containing drugs , acidosis, NSAIDS may displace

thiopental from albumen

-liver &renal disease may be associated with low albumin levelsso result in an increase in free thiopental which inc. the anesthetic

toxicity and potency

-metabolism occurs primarily in the liver with approximately 10 to 15%of the drug level metabolized per hour

-a desulfuration rxn in liver produces pentobarbital which under goes oxidative metabolism yielding 2 compounds with no anesthetic activity

-less than 1% of the drug is excreted unchanged in the urine

Sodium thiopental (pentothal)2

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pharmacodynamicsCNS: barbiturates interact with chloride ion channels by

altering the duration they spend in an open state-this facilitates inhibitory neurotrasmitters such as gama amino

butyric acid(GABA)As well as blocking excitatory NTM actions such as glutamic acid

-thiopental will decrease both cerebral electrical & metabolic activitySo 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 maintian seizure control & avoid cv depression from high

dose of thiopental other drugs are used (e.g. benzodiazepines)

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pharmacodynamics

CNS: 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 cerb. Metabolism &oxygen requirments associated with dec.cerebral blood volume

-theopental has an an anti-analgesic effect, since low dose may decrease pain threshold

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

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PharmacodynamicsCVS:-thiopental causes a dose related depression

of myocardial function as measured by CO,SV, and blood pressure

-coronary blood flow, heart rate ,&myocardial oxygen uptake all increase following thiopental administration

-venous tone decreases (decreased preload)

And contributes to the increase in HR and decrease in BP

-little change in total peripheral resistance

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PharmacodynamicsRespiratory:-induction of anesthesia with

thiopental may be associated with 2 or 3 large breaths followed by apnea for less than 1min

-there is dose related depression of the respiratory response to hypercarbia and hypoxia

-laryngospasm and bronchoconstriction may be associated with light levels of thiopental and with airway manipulation or intubation

-FRC is reduced by 20% with induction of anasthesia

>Functional Residual Capacity (FRC) is the volume of air present in the lungs at the end of passive expiration.

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Pharmacodynamics GI: enzyme induction may occur with

prolonged high dose therapy - Hypoalbuminemia will result in an increase in

unbound (free) thiopental and an increase in the potency of thiopental

GU/pregnancy/fetus:- Thiopental has little or no effect on the kidneys

or gravid uterus.-although thiopental crosses the placentaIt has no significant effect on the fetus when

used for cesarean section (dose used is limited to 4mg/kg)

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Dose & administration

-the 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

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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

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Absolute contraindications1- airway obstruction

2- porphyria

3- previous hypersensitivity

PRECUATIONS1- CVS disease

2- severe hepatic disease

3- renal diseases

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SIDE EFFECTS1- 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

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SIDE EFFECTS7- 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.

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PROPOFOL Intravenous

anaesthetic/hypnotic. Akylphenol. Propofol is a sweet drug

in the OR, but definitely not for home use.

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PROPOFOL PHYSICAL AND CHEMICAL PROPERTIES

Emulsion consists of:

1% propofol 10mg/ml

10% soyabean oil.

2.25 %glycerol

1.2% purified egg phosphatide.

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PROPOFOL PHYSICAL AND CHEMICAL PROPERTIES

so Propofol is a highly lipid soluble oil that’s combined with glycerol, egg, and soya bean oil for IV administration.

It’s 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.

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PROPOFOL DOSAGE

For healthy unpremedicated 2.5-3 mg/kg.

For premedicated 1.5-2 mg/kg.

Elderly patients <= 1 mg/kg.

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

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

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PROPOFOL EFFECTS ON ORGAN SYSTEMS

Cerebral: decreases cerebral blood flow and intracranial

pressure. Propofol has antiemetic, antipruritic, and anticonvulsant properties.

Cardiovascular: decrease in arterial blood pressure secondary to a

drop in systemic vascular resistance, contractility, and preload. Hypotension is more pronounced than with thiopental. Propofol markedly impairs the normal arterial baroreflex response to hypotension.

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PROPOFOL EFFECTS ON ORGAN SYSTEMS

Respiratory:

propofol causes profound respiratory depression. Propofol induced depression of upper airway reflexes exceeds that of thiopental.

Venous irritation: Pain on injection is more common than with thiopental

esp. if given in a small vein in the hand.

To solve this problem:

1. small doze of lidocaine with propofol.

2. administering propofol through a fast flowing more proximal IV

catheter.

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PROPOFOL INDICATIONS

indication Approved Patient Population

Initiation and maintenance of Monitored Anesthesia Care sedation

Adults only

Combined sedation and regional anesthesia

Adults only (See PRECAUTIONS)

Induction of General Anesthesia Patients ≥ 3 years of age

Mainenance of General Anesthesia Patients ≥ 2 months of age

Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients

Adults only

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PROPOFOL CONTRAINDICATIONS

1. Egg allergy.

2. Lack of resuscitation equipment or knowledge of the drug.

3. Inability to maintain a patent airway.

4. Conditions in which reduction in blood pressure can’t be tolerated. E.g. patients with fixed cardiac output (severe aortic or mitral stenosis, IHSS, pericardial tamponade) and those in shock status.

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KETAMINE

It’s a dissociative anesthetic

agent.

by dissociative we mean that

the patient is unconscious but

appears awake and doesn’t

feel pain.

It has anesthetic and

analgesic effect

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KETAMINE PHYSICAL & CHEMICAL PROPERTIES 2

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chemically related to the psychotropic drug ( e.g. phencyclidine).

Water soluble, and 10x more lipid soluble than thiopental.

pH=3.5 - 5.5

KETAMINE PHARMACOKINETICS

ROUTE OF ADMINISTRATION

I.V. : 2mg/kgIM.Oral.Rectal. Needs higher doze due to

extensive first pass metabolism and decreased absorption.

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KETAMINE PHARMACOKINETICS

DOSAGE

IM 5 – 10 mg/kg. peak plasma level reach approx 15 minutes

IV 1 – 2 mg/kg. dissociated stage is

noted in 15 seconds. intense analgesia, amnesia & unconciousness occur within 45-60 minutes

subsequent IV doses of 1/3 – ½ of the initial dose maybe required

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KETMINE METABOLISM

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

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

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KETMINE 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 it’s effect can’t 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 )

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KETMINE 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 dilirium in 15-35 year old pts is approx. 20%

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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.

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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. Myocardail oxygen uptake. It may cause myocardial depression if the

sympathetic nervous sys is exhausted or blocked.

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GI Minimal anorexia, nausea & vomiting.

GUPlacental transfer does occur, but neonatal depression hasn’t

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.

Endocrine Sys. Increased sympathetic stimulation increased blood

glucose, increased plasma cortisol, increased heart rate.

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KETMINE INDICATIONS

1- sole anesthetic for diagnosis and surgical procedures

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

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KETMINE CONTRAINDICATIONS

1- lack of knowledge of the drug

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. For whom hypertention is hazardous

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BENZODIAZEPINES

Features which result in their popularity as adjuvant IV anaesthetic agents:

1 – amnesia2 – minimal cardiarespiretory

depressant effect.3 – anticonvulsant activity.4 – low incidence of tolerance and

dependence.

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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.

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.

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BENZODIAZEPINES MIDAZOLAM AND DIAZEPAM

They are commonly used to provide:

1- IV sedation.

2- amnesia.

3- reducing anxiety.

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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.

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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- Midazolam’s 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.

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BENZODIAZEPINE ANTAGONISTS (FLUMAZENIL)

It’s an imidazobenzodiazepine.

It specifically antagonizes benzodiazepine’s central

effects by copetative inhibition.

It’s elimination half-time is one hour, considerably less

than most benzodiazepines; therefore we will need

repeated administrations of flumazenil to antagonize a

benzodiazepine with a longer half-time.

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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).

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NARCOTIC AGONISTS

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

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NARCOTIC AGONISTSSITE 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 (μ): analgesia, respiratory depression, euphoria, & physical dependence.

2. Kappa receptors (K): analgesia, sedation, respiratory depression, miosis.

3. Segma receptors(a): dysphoria, hallucination, tachypnea, tachycardia.

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NARCOTIC AGONISTS PHARMACOKINETICS

Rapid distribution through the body

following IV injection.

It’s metabolized by the liver and the

majority of the inactive metabolites are

excreted unchanged in the urine.

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NARCOTIC AGONISTS PHARMACODYNAMICS

CNS:Opioids sedate through interfering with sensory perception of painful stimuli.

large doses produce unconsciousness but they are generally incapable of producing anesthesia and it can’t guarantee total amnesia.

It may produce nausea & emesis through stimulation of the chemoreceptor trigger zone.

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RespiratoryThey 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.

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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.

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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.

Others Increases the bladder sphincter’s tone urine

retention. Anaphylactic reactions, bronchospasm, chest

wall rigidity and pruritis.

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NARCOTIC AGONISTSFENTANYL AND MORPHINEFentanyl 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.

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NARCOTIC AGONISTSFENTANYL AND MORPHINE

Potency Ratio Analgesic dose Low dose

Morphine 1 10 mg 0.05 - 0.2 mg/kg

Fentanyl 100 100 mcg 0.5 – 3 mic g/kg

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NARCOTIC ANTAGONISTS (NALOXONE)

Naloxone competes with opioids at the mu, delta,

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.

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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.

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ANAESTHESIA THANK YOU

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INTRAVENOUS ANAESTHETIC

AGENTS

Thank you

Dr. Med. Khaled Radaideh

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

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Date post:	27-Jan-2016
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Intravenous Anesthetic Agents-1

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