Ketamine

Ketamine is phencyclidine derivative. Ketamine is the closest to being a "complete" anesthetic as it induces analgesia, amnesia, and unconsciousness.

Mechanisms of Action

· Ketamine functionally "dissociates" the thalamus from the limbic cortex .Thalamus relays sensory impulses from the reticular activating system to the cerebral cortex and limbic cortex is involved with the awareness of sensation.

· Ketamine produces dissociative anesthesia. The patient appear conscious (eg, eye opening, swallowing, muscle contracture) but unable to process or respond to sensory input and in a state of dissociation from surroundings.

· Ketamine is an N-methyl-D-aspartate receptor (a subtype of the glutamate receptor) antagonist.

· Ketamine blocks polysynaptic reflexes in the spinal cord and inhibits excitatory neurotransmitter effects in selected areas of the brain.

Pharmacokinetics

Absorption

Ketamine is administered intravenously or intramuscularly. Peak plasma levels are usually achieved within 10–15 min after intramuscular injection.

Distribution

Ketamine is more lipid soluble and less protein bound than thiopentone. Distribution half-life is 10–15 min. Awakening is due to redistribution.

Metabolism

Ketamine is metabolized in the liver; some of the metabolites (eg, norketamine) have anesthetic activity. Development of tolerance is seen which is due to hepatic enzyme induction. Elimination half-life is short 2 hours.

Extensive hepatic uptake (hepatic extraction ratio of 0.9) explains ketamine's relatively short .End products of biotransformation are excreted renally.

Effects on body Systems

Cardiovascular

1. Ketamine increases arterial blood pressure, heart rate, and cardiac output due to central sympathetic stimulation and inhibition of norepinephrine reuptake. So it is the induction agent of choice for patients in shock.

2. Ketamine is avoided in patients with coronary artery disease, uncontrolled hypertension, congestive heart failure and arterial aneurysms.

3. Direct action of ketamine is myocardial depressant at high doses.

Respiratory

1. Respiration is minimally affected by induction doses of ketamine.

2. Ketamine is a potent bronchodilator, making it a good induction agent for asthmatic patients. Although upper airway reflexes remain intact, But not sufficient to prevent aspiration pneumonia in high risk (like potentially full stomach) patients.

3. Salivation is increased with ketamine. Premedication with an anticholinergic agent (glycopyrolate or atropine) can prevent it.

Cerebral

1. Ketamine increases cerebral oxygen consumption, cerebral blood flow, and intracranial pressure.

2. Ketamine should be avoided in patients with space-occupying intracranial lesions.

3. Ketamine hallucination-

· Ketamine may cause psychotomimetic side effects (eg, illusions, disturbing dreams, and delirium) during emergence and recovery.

· Less common in children.

· Premedication with benzodiazepines can prevent it.

Propofol

Propofol is chemically described as 2, 6-diisopropylphenol and has a molecular weight of 178.27.

The structural and molecular formulas are:

.

Available emulsion contains 10 mg/mL of propofol.

Propofol is slightly soluble in water and, thus, is formulated in a white, oil-in-water emulsion of pKa 11 that contains

· Soybean oil (100 mg/ml),

· Glycerol (22.5 mg/ml),

· Egg lecithin (12 mg/ml);

· Disodium edetate (0.005%); with sodium hydroxide to adjust pH to 7-8.5. or sodium metabisulphite 0.25%

Once opened it should be used within 6 hours - Available preparation contains either no preservative or some newer preparation contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, for up to 12 hours but as it is not an antimicrobially preserved product under USP standards and can still support the growth of microorganisms. Microbial contamination can lead to fever, infection/sepsis, other life-threatening illness, and/or death. Strict aseptic technique must always be maintained during handling.

Propofol can be used in patients allergic to eggs. (Egg allergies are due to protein, propofol does not contain egg protein it contains egg lecithin.) Propofol infusion may cause hyperlipidemia.

I.V. Injection of propofol is painful (less common in elderly patients).Pain can be decreased by prior injection of lidocaine or by mixing lidocaine with propofol prior to injection (2 mL of 1% lidocaine in 18 mL propofol).

Doses of Intravenous Propofol

Induction of GA	1-2.5 mg/kg IV dose reduced with increasing age
Maintenance of GA	50-150 µg/kg/min IV combined with N2O or an opiate
Sedation	25-75 µg/kg/min IV
Antiemetic	10-20 mg IV, can repeat every 5-10 min or infusion of 10 µg/kg/min

Mechanisms of Action- Facilitation of inhibitory neurotransmission mediated by beta subunit of GABA

· Produces sedation/hypnosis rapidly (within 40 sec) and smoothly with minimal excitation; termination of action is due to redistribution.

· It has anti pruritic and anti emetic property.

· Decreases IOP and systemic vascular resistance;

· Rarely is associated with malignant hyperthermia and histamine release;

· Suppresses cardiac output and respiratory drive.

· During induction there may be muscle twitching, spontaneous movement, opisthotonus, or hiccupping due to subcortical glycine antagonism. This may mimic tonic-clonic seizure although propofol is predominantly anticonvulsant.

Pharmacokinetics

· Rapid rate of distribution - The drug is highly lipophilic and rapidly and extensively distributed. Crosses blood brain barrier and placenta; distributes into breast milk. Protein binding is 95% to 99%. T _½ of rapid distribution is 2 to 4 min. T _½ of slower distribution is 30 to 64 min.

· Metabolism - Liver conjugation to inactive metabolites.

· Elimination - 50% of dose is excreted in the kidney (metabolites). Clearance is 23 to 50 mL/kg/min.

· Onset - Rapid onset, usually within 40 sec from start of injection.

· Duration - 3 to 5 min (single bolus).

· In elderly the dose requirement decreases because of occurrence of higher peak plasma concentrations.

Effects on body Systems

Cardiovascular

1. Propofol decreases arterial blood pressure due to a reduction in systemic vascular resistance (inhibition of sympathetic vasoconstrictor activity), cardiac contractility, and preload.

2. Hypotension is more than with thiopentone but is usually reversed by the stimulation due to laryngoscopy and intubation.

3. Factors exacerbating the hypotension include large doses, rapid injection, and old age.

4. Aarterial baroreflex response to hypotension is impaired, particularly in conditions of normocarbia or hypocarbia.

5. Might cause vegally mediated bradycardia(less common)

Changes in heart rate and cardiac output are usually transient and insignificant in healthy patients but may be severe enough to lead to asystole, particularly in patients at the extremes of age and patients with impaired ventricular function.

Respiratory

1. Propofol causes profound respiratory depression resulting in apnea following an induction dose.

2. Propofol inhibits hypoxic ventilatory drive and depresses the normal response to hypercarbia.

3. Depression of upper airway reflexes is more than thiopentone.

4. Propofol is better than thiopentone for induction in asthmatics. It causes lower incidence of wheezing in asthmatic and nonasthmatic patients compared with barbiturates or etomidate.

Cerebral

1. Cerebral blood flow and intracranial pressure is reduced by propofol. In patients with raised ICP, propofol can cause a critical reduction in Cerebral Perfusion Pressure (< style="mso-bidi-font-weight:normal">protects brain from focal ischemia.

2. Propofol have anticonvulsant properties (i.e. burst suppression), has been successfully used to terminate status epilepticus, and safely used in epileptic patients.

3. Propofol has antipruritic and antiemetic (at blood propofol concentration 200 ng/mL) properties.

On eye

· Propofol decreases intraocular pressure. Tolerance does not develop after long-term propofol infusions.

Indications and Usage

1. Induction and maintenance of anaesthesia in adults

2. Induction agent of choice for day care surgery (Outpatient anaesthesia).

3. Induction anaesthesia in children at least 3 yr of age; maintenance anaesthesia in children at least 2 mo of age

4. Initiation and maintenance of monitored anaesthesia care sedation in adults

5. Sedation in intubated or respiratory-controlled adult ICU patients.

Adverse Reactions

· Cardiovascular: hypotension, bradycardia, decreased cardiac output; hypertension (especially in children), Myocardial ischemia.

· CNS: Amorous behavior; movement hypotonia; hallucinations; neuropathy; opisthotonus.

· Respiratory - Apnea; respiratory acidosis during weaning.

· Metabolic- Hyperlipidemia.

· Dermatologic: Rash.

· Eye: Conjunctival hyperemia; nystagmus.

· Miscellaneous - Asthenia; burning, stinging, or pain at injection site; fever.

Propofol infusion syndrome is a rare Complication with Potentially Fatal Results

1. It is associated with high doses and long-term use of propofol.(>4mg/kg/hr for more than 24 hours or infusion more than 48 hours)

2. More common in children. Critically ill patients receiving catecholamines, glucocorticoids are at high risk.

3. Severe metabolic acidosis, rhabdomyolysis, hyperkalemia, hypertriglyceridemia, renal failure, hepatomegaly and cardiovascular collapse are key features.

4. Treatment – Supportive. Early recognition of the syndrome and discontinuation of the propofol infusion reduces morbidity and mortality.

Etomidate

Mechanisms of Action

Depression of reticular activating system and GABA mimetic inhibitory effects. Etomidate binds to GABA type A receptor. Unlike barbiturates, it may have disinhibitory effects on the parts of the nervous system that control extrapyramidal motor activity. This disinhibition is responsible for a 30–60% incidence of myoclonus.

Structure–Activity Relationships

Structurally it is a carboxylated imidazole compound. Etomidate is dissolved in propylene glycol. This solution often causes pain on injection that can be lessened by a prior injection of lidocaine.

Pharmacokinetics

Absorption

Etomidate is available only for intravenous administration and is used primarily for induction of general anesthesia (see Table 8–7).

Distribution

Although it is highly protein bound, etomidate is characterized by a very rapid onset of action due to its high lipid solubility and large nonionized fraction at physiological pH. Redistribution is responsible for decreasing the plasma concentration to awakening levels.

Biotransformation

Hepatic microsomal enzymes and plasma esterases rapidly hydrolyze etomidate to an inactive metabolite. The rate of biotransformation is five times greater for etomidate than for thiopental.

Excretion

The end product of hydrolysis is primarily excreted in the urine.

Effects on Organ Systems

Cardiovascular

Etomidate has minimal effects on the cardiovascular system. A mild reduction in peripheral vascular resistance is responsible for a slight decline in arterial blood pressure. Myocardial contractility and cardiac output are usually unchanged. Etomidate does not release histamine.

Respiratory

Ventilation is affected less with etomidate than with barbiturates or benzodiazepines. Even induction doses usually do not result in apnea unless opioids have also been administered.

Cerebral

Etomidate decreases the cerebral metabolic rate, cerebral blood flow, and intracranial pressure to the same extent as thiopental. Because of minimal cardiovascular effects, CPP is well maintained. Although changes on EEG resemble those associated with barbiturates, etomidate enhances somatosensory evoked potentials. Postoperative nausea and vomiting are more common than following barbiturate induction, but can be minimized by antiemetic medications. Etomidate is a sedative-hypnotic but lacks analgesic properties.

Endocrine

Induction doses of etomidate transiently inhibit enzymes involved in cortisol and aldosterone synthesis. Long-term infusions lead to adrenocortical suppression that may be associated with an increased mortality rate in critically ill patients.

Drug Interactions

Fentanyl increases the plasma level and prolongs the elimination half-life of etomidate.

Opioids decrease the myoclonus characteristic of an etomidate induction.

Barbiturates

Barbiturates

Barbiturates are derivatives of barbituric acid. Depending upon the presence of oxygen or sulphur atom with 2^nd carbon they are called

· Oxybarbiturates (eg. Methohexitol) – Oxygen at 2^nd position

· Thiobarbiturates (eg. Thiopentone) - Sulphur at 2^nd position

Thiobarbiturates are more lipid soluble, more potent and having shorter duration of action than oxybarbiturates.

Substitution at 5^th carbon atom with phenyl group increases anticonvulsant activity. (Phenobarbitone)

Thiopentone

Thiopental was introduced clinically by Waters and Lundy. It is an ultra short-acting barbiturate that depresses the central nervous system (CNS) to produce hypnosis and anaesthesia without analgesia.

Preparation

Thiopentone sodium is available as white powder (mixed with6 % anhydrous sodium carbonate) in nitrogen environment. (I.e. Air in vial is replaced by nitrogen.)

It should be reconstituted with either water or normal saline to produce a 2.5% solution of thiopental. This solution is highly alkaline (pH >10) and relatively unstable (2 week shelf life when refrigerated). Injections should be freshly prepared and used within 24 hours after reconstitution. Solutions of higher concentration are not recommended as it causes pain on injection and venous thrombosis.

Any factor or condition that tends to lower the pH of thiopental injections, such as diluents that is too acid (Ringer Lactate) or the absorption of carbon dioxide, which combines with water to form carbonic acid, causes precipitation of thiopental acid. 6% anhydrous sodium carbonate is added to prevent precipitation of thiopentone due to CO2 absorption.

Thiopentone should not be mixed with medications that have an acid pH like succinylcholine, tubocurarine. They cause precipitation.

Pharmacokinetics and pharmacodynamics

After i.v. injection onset of action is within one arm brain circulation time (15 sec) patient become unconscious within 30-40 sec and patients awaken within 20 minutes. Termination of action is due to rapid redistribution of the drug to peripheral compartment (mainly muscle) and reduction of concentration in brain. From muscle it is redistributed to adipose tissue.

Time to peak concentration after Intravenous administration: Brain: within 30 seconds. Muscles: 15 to 30 minutes. Fat: Several hours. Very highly perfused tissues such as the brain, heart, liver, and kidneys achieve concentrations equal to peak plasma concentrations. Rapid induction is due to high lipid solubility and higher initial brain concentration.

The elimination half life of thiopentone is 12 hours. So it takes about 48 hours for complete elimination of the drug and patient is drowsy. So thiopentone is not preferred for day care surgery. (Propofol is the choice)

· Distribution: Because of their high lipid solubility and low degree of ionization, thiopentone rapidly cross the blood-brain barrier and are rapidly redistributed from the brain to other body tissues, first to highly perfused visceral organs (liver, kidneys, heart) and muscle, and later to fatty tissues.
When barbiturate anesthetics are administered repeatedly or by continuous infusion, accumulation in and slow release from lipoidal storage sites may result in prolonged anesthesia, somnolence, and respiratory and circulatory depression. Concentrations of thiopental in fatty tissues may be six to twelve times greater than in plasma.

· Volume of distribution: 1.7 to 2.5 L/kg

· Protein binding: 72 to 86%.

· Onset of action: Intravenous—30 to 40 seconds, Rectal—within 8 to 10 minutes.

Following intravenous administration of induction doses of thiopental, muscle relaxation occurs about 30 seconds after unconsciousness is attained, the depth of anaesthesia increase for up to 40 seconds and then decrease progressively until consciousness returns. Hypnosis occurs Within 10 to 40 seconds of intravenous injection.

· Duration of action: 10 to 30 minutes

· Half-life: Redistribution half life: 4.6 to 8.5 minutes, Elimination half life: 3 to 8 hours after a single intravenous dose, the elimination half-life is longer after prolonged administration (10 to 12 hours). The elimination half-life increases with increasing age, during pregnancy at term and in obese patients. At low doses it follow 1^st order kinetics but at higher doses it follow zero order kinetics.

· Biotransformation: Primarily hepatic; also, biotransformed to a small extent in other tissues, especially the kidneys and brain. Although most of thiopental's metabolites are inactive, about 3 to 5% of a dose is desulfurated to pentobarbital, which is cleared from the body much more slowly than thiopental.

Action on Central Nervous system –

Thiopentone is CNS depressant; it causes sedation, hypnosis, unconsciousness. It has anticonvulsant property.

It has antanalgesic property and lowers the pain threshold.

No muscle relaxation.

Mechanism of action –

· Thiopentone depresses the reticular activating system in brainstem which is responsible for consciousness.

· It (1) enhances the synaptic actions of inhibitory neurotransmitters (mainly acts on GABA_A receptor), and (2) blocks the synaptic actions of excitatory neurotransmitters (glutamate and acetylcholine).

Thiopentone is cerebro-protective and the induction agent of choice in neurosurgery.

It reduces the cerebral oxygen requirement (CMRO2) and reduces intra cranial tension (ICT) and thus increases cerebral perfusion.

It shunts blood from non ischemic to ischemic areas of brain so it protects brain from focal ischemia (But not from global ischemia). This phenomenon is called reverse still phenomena or Robin Hood effect. (Inhalational anaesthetics like halothane causes the opposite effect ie. Shunts blood from ischemic to non ischemic areas and it is called still phenomena or Luxury perfusion.)

Action on other body systems

Cardio Vascular System -

· On i.v. administration it causes hypotension and tachycardia. Too rapid injection may cause a severe drop in blood pressure, possibly to shock levels, especially in patients who are hypovolemic.

Respiratory System -

· Barbiturate anaesthetics are potent respiratory depressants, apnea may occur immediately after intravenous injection, especially in the presence of hypovolemia, cranial trauma, or opioid premedication.

· During induction of anaesthesia or in lightly anesthetized patients, laryngospasm may be induced by a variety of stimuli such as surgical stimulation, the premature insertion of the laryngoscope blade or airway. Laryngospasm is treated with IPPV and small dose of scholine

Hepatic-

Thiopentone induces of amino levulinic acid synthetase, which stimulates the formation of porphyrin, and may precipitate acute intermittent porphyria or variegate porphyria in susceptible patients.

Action on thyroid – thiopentone depress thyroid function. (So it is preferred in patients with increased thyroid activity)

Immunological –

In vitro thiobarbiturates may release histamine from mast cell. So oxybarbiturates (methohexitone) or propofol is preferred over thiopentone in asthmatic and atopic patients. True anaphylaxis has been reported to occur with barbiturate but it is rare.

Barbiturate anaesthetics rapidly cross the placenta; also, after administration of large doses, thiopental is distributed into breast milk.

Indications

1. Thiopentone is indicated primarily for the induction of general anaesthesia.

2. Sole anaesthetic as intramuscular, intravenous, or rectal anaesthesia for brief surgical procedures with minimal painful stimuli and to produce hypnosis during balanced anaesthesia with other agents such as analgesics or muscle relaxants

3. It is used as the sole sedative agent for diagnostic procedures (e.g., computerized axial tomography [CAT] scans or magnetic resonance imaging [MRI]) in children.

4. Treatment of convulsions —Thiopentone is used for short-term control of status epilepticus resistant to other drugs and to control convulsive states during or following inhalation anaesthesia, local anaesthesia, or other causes

5. To reduce ICT — It is indicated in the treatment of increased intracranial pressure if adequate ventilation is provided. It is useful in the management of conditions associated with acutely increased intracranial pressure, such as Reye's syndrome, cerebral edema, acute head injury and during neurosurgical procedures.

6. Cerebo-protection - Thiopental for injection is indicated to protect the brain from the effects of hypoxia and ischemia following head injuries and other related conditions

7. Narcoanalysis—it is used for narcoanalysis.

Accidental Intra-arterial injection of thiopentone is a serious complication and can lead to significant morbidity

Commonly occurs at anticubital vein accidentally injected to ulnar artery. Many patients complain of immediate discomfort (often within seconds), ranging from local irritation to intense pain distal to the site of injection. Patients may report sensory problems such as tingling, burning, and paresthesias; altered motor function (involuntary muscle contractures and muscle weakness) and cutaneous manifestations (flushing, mottling).

There is crystal formation of thiopentone, which blocks the microcirculation and causes vasospasm ieading to necrosis and gangrene

Management:

1. STOP the injection

2. LEAVE the cannula/needle in place

3. Immediately inject 0.9% SALINE into the artery to dilute the drug

4. Administer Local Anaesthetic to relieve pain. e.g. lignocaine 50mg ( 5ml 1%); procaine 50-100mg (10-20 ml 0.5%)

5. Administer Vasodilator to reduce vasospasm. e.g. papaverine 40-80mg (10-20 ml 0.4%)

6. Consider Stellate ganglion or brachial plexus block to encourage vasodilation hence improve circulation & tissue oxygenation

7. Start IV HEPARIN to reduce subsequent thrombosis

8. Consider intra-arterial injection of HYDROCORTISONE.

9. Urokinase infusion.

10. Postpone surgery.

Dosage should be reduced and the medication administered slowly if barbiturate anaesthetics are used in the presence of the following medical problems.

1. Addison's disease, severe anaemia, Hepatic function impairment, Myxedema

2. Renal function impairment (hypnotic effect may be prolonged or potentiated)

3. Severe Cardiovascular disease, Congestive heart failure, hypotension or shock (barbiturate anesthetics produce cardiovascular depressant effects; condition may be exacerbated)

4. Myasthenia gravis and other neuromuscular disorders, other, such as muscular dystrophies and myotonias (respiratory depression may be prolonged; dosage should be carefully titrated)

5. Respiratory disease involving dyspnea or obstruction, particularly status asthmaticus

6. Sensitivity to barbiturates

Absolute contraindication – Acute intermittent porphyria or or variegate porphyria.