Intravenous Anesthetics

Intravenous Anesthetics

Barbiturates

Barbiturates are hypnotically active drugs that are derivatives of barbituric acid, formed by the combination of malonic acid and urea. Barbiturates are classified according to duration of action; long acting: Phenobarbital, short acting: pentobarbital and ultra-short acting: thiopental, thiamylal, methohexital. The ultra short acting barbiturates are used in induction of anesthesia (Table 2:1).

Barbiturates depress the central nervous system reticular activating system, a complex polysynaptic (a place in the nervous system where many neurons with another neurons) network of neurons and regulatory centers located in the brain stem that controls several vital functions, including consciousness. They suppress transmission of excitatory neurotransmitters (e.g., acetylcholine) and enhance transmission of inhibitory neurotransmitters (e.g., Gamma Amino Butyric acid [GABA]).

Systemic and Side Effect

Barbiturates produce dose-dependent CNS depression ranging from sedation to general anesthesia when administered in induction doses. They do not have analgesic properties may even reduce pain threshold, and thus could be classified as an antianalgesic. Barbiturates are potent cerebral vasoconstrictors and produce predictable decreases in cerebral blood flow, cerebral blood volume, and intracranial pressure (ICP). As a result, they decrease cerebral metabolic rate for oxygen (CMRO2) in a dose-dependent manner. The ability of barbiturates to decrease ICP and CMRO2, make these drugs useful in the management of head injury. An exception to the generalization that barbiturates decrease electrical activity of CNS is methohexital, which activates epileptic foci.

Decrease in systemic blood pressure is principally due to peripheral vasodilation and reflects barbiturate-induced depression of the medullary vasomotor center and decreased sympathetic nervous system outflow from the CNS. Dilation of peripheral capacitance vessels leads to pooling of blood and decreased venous return, thus resulting in the potential for reduced cardiac output and systemic blood pressure. Patients with poorly controlled hypertension are particularly prone to wide swings in blood pressure during induction. A slow rate of injection and adequate preoperative hydration attenuate these changes in most patients.

Exaggerated decreases in systemic blood pressure are likely to follow the administration of barbiturates to patients with hypovolemia, because such patients are less able to compensate for the effects of peripheral vasodilation.

Barbiturate depression of the medullary ventilatory center decreases the ventilatory response to hypercapnia (excess carbon dioxide) and hypoxia. Anesthetic induction doses of thiopental and methohexital typically induce transient apnea, which will be more pronounced if other respiratory depressants are also administered. Barbiturate sedation typically leads to upper airway obstruction; apnea usually follows an induction dose. During awakening, tidal volume and respiratory rate are decreased. Barbiturates do not completely depress noxious airway reflexes, and bronchospasm in asthmatic patients or laryngospasm in lightly anesthetized patients may occur. Suppression of laryngeal reflexes and cough reflexes is not as profound as after propofol administration, which makes barbiturates an inferior choice for airway instrumentation in the absence of neuromuscular blocking drugs. Furthermore, stimulation of the upper airway or trachea (secretions, laryngeal mask airway, direct laryngoscopy, tracheal intubation) during inadequate depression of airway reflexes may result in laryngospasm or bronchospasm.

Barbiturates reduce renal blood flow and glomerular filtration rate in proportion to the fall in blood pressure.

Hepatic blood flow is decreased.

Contrast media, sulfonamides, and other drugs that occupy the same protein-binding sites as thiopental will increase the amount of free drug available and potentiate the organ system effects of a given dose. Ethanol, opioids, antihistamines, and other central nervous system depressants potentiate the sedative effects of barbiturates.

Thiopentone must be dissolved in isotonic sodium chloride or water to prepare solutions of 2.5% thiopental (If you have 500mg of thiopentone dilute with 20 ml of distilled water to make it 2.5%). When barbiturates are added to Ringer lactate or an acidic solution containing other water-soluble drugs, precipitation will occur and can occlude the IV catheter.

Local Side Effects (i.e. at the Site of Injection) of Thiopentone

If thiopentone is injected outside the vein certain complications can follow. The most serious is intra-arterial injection. When thiopentone enters an artery, there is spasm of the artery and also damage to the intima and crystal formation in the artery. This interferes with the flow of blood to the limb and if this ischemia is not corrected gangrene results.

Symptoms and signs of intra-arterial injection

• The patient will feel intense pain.
• The hand will be very pale or white.
• The hand will be cold (arterial spasm).
• The hand will be edematous.
• The pulse may be absent.

Treatment

• Leave the needle in the artery. Cancel surgery if possible.
• Flush with anticoagulant, e.g. heparin/saline (10 units/ml) 500 units.
• For relief of spasm inject procaine (10 ml of 1%) or lignocaine (10mls of 1%) into the artery.
• Sympathetic nerve blocks are recommended to dilate the collateral vessels and maintain the blood flow.
• Surgical exploration of the artery. Thrombectomy may be required.
• Full heparinisation may be required to prevent late arterial thrombosis.
• Occasionally amputation is needed.

Precautions

• Thiopentone must only be used in a concentration of 2.5% or less. This is prepared by diluting 0.5g of powder in 20 ml or 1g in 40 ml of water.
• During venepuncture the tourniquet must occlude only the vein and not the artery. The arterial pulsation will then be always palpable and reduce the chance of accidental entry into the artery.
• The medial side of the antecubital fossa is best avoided.
• It is wise to inject 2 ml of thiopentone and to inquire for any symptoms of pain. If the needle is not in the vein the patient will complain of an intense burning pain down the arm.

Relative contraindication: Hypotension or shock, severe cardiovascular disease, severe liver disease and myxedema.

Propofol

Mechanisms of Action and Clinical Use of Propofol

The mechanism by which propofol induces a state of general anesthesia may involve facilitation of inhibitory neurotransmission mediated by GABA (glycine and aminobutyric acid). GABA is the most important inhibitory neurotransmitter in the mammalian central nervous system. The function of GABAA receptors is modulated by a wide variety of pharmacological agents including convulsants, anticonvulsants, sedatives, anxiolytics, and anesthetics.

Site of clearance for propofol is hepatic.

Pain on injection is a common complaint and can be reduced by premedication with an opioid or co-administration with lidocaine, 50 to 100 mg intravenously.

Propofol (1 to 2.5 mg/kg IV) is most commonly administered for induction of general anesthesia. Increasing age, reduced cardiovascular reserve, or premedication with benzodiazepines or opioids reduces the required induction dose, whereas children need larger doses (2.5 to 3.5 mg/kg IV). Generally, titration of the induction dose (i.e., rather than an arbitrary bolus dose) helps prevent severe hemodynamic changes. Propofol is also often used for maintenance of anesthesia either as part of a balanced anesthesia regimen in combination with volatile anesthetics, sedative hypnotics, and opioids or as part of a total intravenous anesthetic technique, usually in combination with opioids. Therefore, a continuous infusion rate between 100 and 200 μg/kg/min is required for maintenance of anesthesia when combined with nitrous oxide or opioids.

It is insoluble in aqueous solutions and is therefore formulated as an emulsion containing 10% soybean oil, 2.25% glycerol, and 1.2% lecithin, the major component of the egg yolk phosphatide fraction. Because the available formulations support bacterial growth, good sterile technique is important. Solutions should be used as soon as possible or at least within 6 hours after opening the propofol vial. The solutions appear milky white and slightly viscous, their pH is approximately 7, and the propofol concentration is 1% (10 mg/mL). In some countries, a 2% formulation is available. Because the emulsion contains egg yolk lecithin, susceptible patients for egg allergy may experience allergic reactions.

Propofol is rapidly metabolized in the liver, and the resulting water-soluble compounds are presumed to be inactive and excreted through the kidneys. Plasma clearance is high and exceeds hepatic blood flow. The rapid plasma clearance of propofol explains the more complete recovery from propofol with less hangover than observed with thiopental. However, as with other intravenous drugs, transfer of propofol from the plasma (central) compartment and the associated termination of drug effect after a single bolus dose are mainly the result of redistribution from highly perfused (brain) to poorly perfused (skeletal muscles) compartments. Wake-up after an induction dose of propofol usually occurs within 8 to 10 minutes, as evident from the time course of the decline in plasma concentration after a single bolus dose

Systemic Effects of Propofol

In the central nervous system (CNS), propofol primarily acts as a hypnotic and does not have any analgesic properties. It produces a decrease in cerebral blood flow (CBF) and the cerebral metabolic rate for oxygen (CMRO2), which results in decreases in intracranial pressure (ICP) and intraocular pressure. It can be used for the administration for neuroprotection during neurosurgical procedures. Occasionally, excitatory effects such as twitching or spontaneous movement can be observed during induction of anesthesia with propofol. Although these effects may resemble seizure activity, propofol is actually an anticonvulsant and may be safely administered to patients with seizure disorders.

Propofol produces a larger decrease in systemic arterial blood pressure than any other drug used for induction of anesthesia. Propofol causes profound vasodilatation, whereas its direct myocardial depressant effect is not clear. The effect on systemic blood pressure is more pronounced in elderly patients, especially those with reduced intravascular fluid volume. Profound bradycardia and asystole after the administration of propofol can occur in healthy adults despite prophylactic anticholinergic.

Propofol is a respiratory depressant and often produces apnea following a dose used to induce anesthesia. A maintenance infusion will reduce minute ventilation through reductions in tidal volume and respiratory rate, with the effect on tidal volume being more pronounced. The ventilatory response to hypoxia and hypercapnia is also reduced. Propofol causes a greater reduction in upper airway reflexes than thiopental does, which makes it well suited for instrumentation of the airway, such as placement of a laryngeal mask airway. When compared with thiopental, propofol decreases the incidence of wheezing after induction of anesthesia and tracheal intubation in healthy and asthmatic patients.

Unlike many other anesthetics, propofol has antiemetic activity. Similar to thiopental and unlike volatile anesthetics, propofol probably does not enhance neuromuscular blockade from neuromuscular blocking drugs. Yet, propofol often provides excellent clinical conditions for endotracheal intubation without the use of neuromuscular blocking drugs.

Hypersensitivity for this drug

Ketamine

Ketamine induce analgesia, amnesia and unconsciousness. Like other intravenous induction drugs, the effect of a single bolus injection is terminated by redistribution to inactive tissue sites.

Ketamine has multiple effects throughout the central nervous system, including blocking polysynaptic reflexes in the spinal cord and inhibiting excitatory neurotransmitter effects in selected areas of the brain. In contrast to the depression of the reticular activating system induced by the barbiturates, ketamine functionally "dissociates" the thalamus (which relays sensory impulses from the reticular activating system to the cerebral cortex) from the limbic cortex (which is involved with the awareness of sensation). Although some brain neurons are inhibited, others are tonically excited. Clinically, this state of dissociative anesthesia causes the patient to appear conscious (e.g., eye opening, swallowing, muscle contracture) but unable to process or respond to sensory input.

The unpleasant emergence reactions after the administration of ketamine have restricted its use in the perioperative period. Nevertheless, ketamine's unique properties, including profound analgesia, stimulation of the sympathetic nervous system, bronchodilation, and minimal respiratory depression, make it an important alternative to the other intravenous anesthetics and a desirable adjunct in many cases. Moreover, ketamine can be administered by multiple routes (intravenous, intramuscular), thus making it a useful option for premedication in mentally challenged and uncooperative pediatric patients.

• Induction and maintenance of anesthesia: Induction of anesthesia can be achieved with ketamine, 1 to 2 mg/kg intravenously or 4 to 6 mg/kg intramuscularly. Though not commonly used for maintenance of anesthesia, the short context-sensitive half-time makes ketamine a consideration for this purpose.
• Analgesia: Small bolus doses of ketamine (0.2 to 0.8 mg/kg IV) may be useful during regional anesthesia when additional analgesia is needed (cesarean section under neuraxial anesthesia with an insufficient regional block). Ketamine provides effective analgesia without compromise of the airway.

Systemic Effects of Ketamine

Ketamine increases arterial blood pressure, heart rate, and cardiac output and beneficial to patients with acute hypovolemic shock. These indirect cardiovascular effects are due to central stimulation of the sympathetic nervous system and inhibition of the reuptake of norepinephrine. Ketamine should be avoided in patients with coronary artery disease, uncontrolled hypertension, congestive heart failure, and arterial aneurysms.

Rapid intravenous bolus administration or pretreatment with opioids occasionally produces apnea. Ketamine is a potent bronchodilator, making it a good induction agent for asthmatic patients. Although upper airway reflexes remain largely intact, patients at increased risk for aspiration pneumonia should be intubated. The increased salivation associated with ketamine can be attenuated by premedication with an anticholinergic (e.g., atropine) agent.

Consistent with its cardiovascular effects, ketamine increases cerebral oxygen consumption, cerebral blood flow, and intracranial pressure. These effects preclude its use in patients with head injury and space-occupying intracranial lesions. Undesirable psychomimetic side effects (e.g., illusions, disturbing dreams, and delirium) during emergence and recovery are less common in children and in patients premedicated with benzodiazepines.

The unpleasant emergence reactions after ketamine administration are the main factor limiting its use. Such reactions may include vivid colorful dreams, hallucinations, out-of-body experiences, and increased and distorted visual, tactile, and auditory sensitivity. These reactions can be associated with fear and confusion, but a euphoric state may also be induced, which explains the potential for abuse of the drug. Children usually have a lesser incidence of severe emergence reactions. Combination with a benzodiazepine may be indicated to limit the unpleasant emergence reactions and also increase amnesia.

The combination of theophylline and ketamine may predispose patients to seizures. Diazepam attenuates ketamine's cardio-stimulatory effects and prolongs its elimination half-life.

Ketamine is biotransformed in the liver to several metabolites, some of which (e.g., norketamine) retain anesthetic activity. Induction of hepatic enzymes may partially explain the development of tolerance in patients who receive multiple doses of ketamine. End products of biotransformation are excreted by the kidney.

Contraindication

• Increased ICP- they develop apnea because of increased CBF.
• Open eye injury - because ketamine increase ICP
• Ischemic heart disease- Ketamine increase myocardial o2 consumption.
• Ketamine contraindicated for psychiatric disease ( schizophrenia ).

Etomidate

Is an intravenous anesthetic with hypnotic but not analgesic properties and with minimal hemodynamic effects. Metabolism is primarily by ester hydrolysis to inactive metabolites, which are then excreted in urine (78%) and bile (22%).

Etomidate depresses the reticular activating system and mimics the inhibitory effects of GABA. This solution often causes pain on injection that can be lessened by a prior injection of lidocaine.

Etomidate is an alternative to propofol and barbiturates for the rapid intravenous induction of anesthesia, especially in patients with compromised myocardial contractility. After a standard induction dose (0.2 to 0.3 mg/kg IV), the onset of unconsciousness is comparable to that achieved by thiopental and propofol. Awakening after a single intravenous dose of etomidate is rapid. Etomidate does not produce analgesia, and postoperative nausea and vomiting may be more common than after the administration of thiopental.

Systemic Effects of Etomidate

Etomidate is a potent cerebral vasoconstrictor, as reflected by decreases in cerebral blood flow and intracranial pressure. These effects of etomidate are similar to those produced by comparable doses of thiopental. Similar to methohexital, etomidate may activate seizure foci. In addition, spontaneous movements characterized as myoclonus (twitching or spasm of muscle or a group of muscles) occur in more than 50% of patients receiving etomidate. Benzodiazepines or small sedative doses (0.03 to 0.05 mg/kg) prior to induction of anesthesia reduce the incidence.

A characteristic and desired feature of induction of anesthesia with etomidate is cardiovascular stability after bolus injection. The depressive effects of etomidate on myocardial contractility are minimal at concentrations used for induction of anesthesia.

The depressant effects of etomidate on ventilation are less pronounced than those of barbiturates, although apnea may occasionally follow rapid intravenous injection of the drug. Depression of ventilation may be exaggerated when etomidate is combined with inhaled anesthetics or opioids.

Etomidate causes adrenocortical suppression by producing a dose-dependent inhibition of an enzyme necessary for the conversion of cholesterol to cortisol. This suppression lasts 4 to 8 hours after an induction dose of etomidate.

Hypoadrenal shock