Induction Agents, Opiates and Anxiolytics

Propofol

Metabolism and excretion

• Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver. ⁽¹⁾
• The half life of elimination of propofol has been estimated at between 2 and 24 hours.
• Its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues.
• When used for IV sedation, a single dose of propofol typically wears off within minutes. ⁽²⁾
• It has a rapid onset and recovery along with anti amnestic effects.

Effect on circulation

• Cardiovascular depression
• Bradycardia. 
• Propofol anesthesia reduces parasympathetic tone to a lesser degree than sympathetic tone. This predisposes the patient to developing bradycardia in response to parasympathetic stimuli. ⁽³⁾
• Hypotension
• Low cardiac output
• Propofol decrease the mean arterial pressure and cardiac index, increase the heart rate and may occasionally leads to myocardial ischemia in patients with coronary artery disease. ⁽⁴⁾

Effect on respiration

• Respiratory depression, Transient apnea occur on induction with propofol anesthesia. ⁽⁵⁾
• Hypoventilation, Dyspnea
• Respiratory acidosis during weaning
• Bronchospasm
• Propofol acts at the airway level decreasing respiratory system and lung impedances as a result of central airway dilation. ⁽⁶⁾
• Propofol provides protection against tracheal intubation induced bronchoconstriction. ⁽⁷⁾

Effect on other organs

• Decrease intra ocular pressure
• Safe to use in porphyria
• Does not trigger malignant hyperthermia
• Propofol has short ;asting analgesic properties during its administration, wheras the solvent like formulation 10% Intralipid had no effect on pain perception. ⁽⁸⁾
• Propofol anesthesia did not significantly afeect whole body protein synthesis and oxidation but caused a small decrease in whole body protein breakdown, possibly mediated through the suppression of plasma cortisol concentration. ⁽⁹⁾

Drug interactions

• Diazepam, lorazepam
• Ciprofloxacin
• Warfarin
• Rosuvastatin
• Duloxetine
• Metronidazole
• Furosemide
• Pregabalin
• Pentoprazole, esmoprazole
• Acetaminophen
• Cholecalciferol
• Ondansetron

Adverse effects

• Rash and pruritis
• Lactic acidosis due to lipid base impairing hepatic lactate metabolism
• Profound sedation with small doses
• Depression of swallowing reflex
• Renal side effect include green colour of urine
• Rare side effect is dystonia
• Mild myoclonic movements are common
• Reported priapsim in some individuals
• Acute pancreatitis has also been reported

Etomidate

Metabolism and excretion

• Etomidate is metabolized by ester hydrolysis (hepatic & tissue) as well as N-dealkylation. 
• Metabolites are inactive and excreted by renal and biliary routes.
• Etomidate administration results in rapid onset, follow by an initial redistribution phase which is also rapid (initial redistribution halftime = 2.7 minutes). ⁽¹⁾
• Etomidate clearance ranges from 18-25 ml/kg/min. ⁽²⁾
• Rapid onset following IV administration is described as “one arm-brain circulation time”. 
• Methoxycarbonyl etomidate is an etomidate analogue that retains etomidate’s important favorable pharmacological properties. It is rapidly metabolized, ultra short acting and does not produce prolonged adrenocortical suppression after bolus administration. ⁽³⁾
• Etomidate induced inhibition of hepatic drug metabolism can prolong the elimination of drugs with low hepatic clearance rates (eg. antipyrine). Etomidate does not alter the rate of elimination of high clearance anesthetics and analgesic drugs (eg. ketamine, fentanyl). ⁽⁴⁾

Effect on circulation

• Very minimal cardiovascular effects
• Blood flow to heart and oxygen consumption are reduced during induction with etomidate
• In human myocardium, etomidate exerts a dose dependent negative ionotropic effect which is reversible with beta adrenergic stimulation. The concentrations required to produce the ionotropic effects are in excess of those reached during clinical use. ⁽⁵⁾
• Etomidate is particularly beneficial in managing elderly patients with compromised cardiovascular status
• Etomidate is a safe intravenous agent particularly in patients with minimal cardiac reserve requiring high inspired oxygen tension. ⁽⁶⁾

Effect on respiration

• Respiratory depression
• Ventilation is depressed less with etomidate in comparison to barbiturates
• Apnea may follow from rapid iv etomidate administration
• The effects of etomidate on respiration are less than those of other iv induction agents, but involuntary muscle movement during induction remains a problem. ⁽⁷⁾

Effect on other organs

• Cerebral metabolism is reduced
• Cerebral blood flow is reduced
• Intra cranial pressure is reduced
• Etomidate is cerebroprotective, with the ability to decrease intracranial pressure and maintain cerebral perfusion, making it ideal agent for patients with head injuries. ⁽⁸⁾

Drug interactions

• Adrenaline
• Spironolactone
• Lorazepam
• Diphenhydramine
• Diltiazem
• Methyl prednisolone
• Haloperidol
• Furosemide
• Naloxone
• Vecuronium
• Promethazine
• Clopidogrel
• Ketorolac
• Acetaminophen
• Ondansetron

Adverse effects

• Transient adrenal suppression is noted after induction dose of etomidate. ⁽⁸⁾
• Opsoclonus
• Skeletal muscle movements, mainly myoclonic
• Transient injection site pain
• Hiccups
• Rare side effects are apnea, hypoventilation/ hyperventilation, hypotension, laryngospasm, nausea and vomiting, oxygen desaturation, snoring

ketamine

Metabolism and excretion

• The liver microsomal enzyme system metabolizes ketamine (Ketalar) involving hydroxylation and demethylation. 
• Ketamine undergoes extensive hepatic metabolism, primarily via N-demethylation to norketamine. At ketamine concentrations typically achieved during anesthesia (5 microM), the rate of S(+) ketamine demethylation was 20% greater than that of R(-) ketamine and 10% greater than that of the racemate. ⁽¹⁾
• Norketamine is subsequently metabolized by multiple hydroxylation steps.
• The high lipid solubility of ketamine results in a rapid onset of action.
• Similarly, recovery from the anesthetic effects is probably due to redistribution from the brain to other compartments.
• Time to onset following IV bolus (dosage = 2 mg/kg) is about 30-60 seconds with effect lasting between 10-15 minutes.  Complete recovery occurs soon thereafter.
• Clearance is mediated by the liver microsomal enzyme system; therefore, factors that decrease hepatic blood flow will retard clearance and prolong ketamine effect.  E.g. halothane’s ability to reduce liver blood flow, thereby and principal prolonging ketamine action.
• Pharmacokinetic variables of ketamine in intensive care patients are greater than in healthy volunteers and in surgical patients. The increase in the volume of distribution is greater than the increase in clearance, resulting in a longer estimated half-life of ketamine. ⁽²⁾

Effect on circulation

• Ketamine administration increases heart rate, cardiac output, and blood pressure.   These effects may be relatively contraindicated in patients sensitive to the expectable increase in myocardial oxygen consumption.  
• Ketamine exhibits potential negative cardiovascular effects in patients with catecholamine dependent heart failure. It should not be considereda first line drug for long term sedation of patients with impaired left ventricular function. ⁽³⁾
• The failing myocardium exposed to ketamine has reduced ability to increase contractility even in the presence of increased beta adrenergic stimulation. ⁽⁴⁾
• The hemodynamic alterations after ketamine administration in children undergoing cardiac catheterization are small and does not alter the clinical status of the patient. ⁽⁵⁾

Effect on respiration

• Pulmonary effects are very limited. 
• Limited pulmonary effects apply when ketamine is used as the only agent; however, respiratory depression would occur in ketamine is combined with other drugs which are classified as CNS depressants.
• Ketamine (Ketalar) tends to relax bronchial smooth muscle
• Salivation following ketamine administration  may trigger laryngospasm.
• Furthermore, despite retention of reflexes, aspiration may still occur.
• Ketamine administration causes prolongation of inspiratory period of respiration, due to disinhibition of inspiratory neurons. ⁽⁶⁾
• Ketamine administration improves ventilation, oxygenation, hemodynamics and oxygen delivery in isoflurame anesthetized dogs in a dose dependent manner. ⁽⁷⁾
• The coadministration of small dose of ketamine attenuates propofol induced hypoventilation, produces positive mood effects without perceptual changes after surgery, and may provide earlier recovery of recognition. ⁽⁸⁾

Effect on other organs

• Ketamine induces a unique anesthetic state referred to as dissociative anesthesia in which the patient may appear “awake” or as is frequently described “cataleptic”. 
• Eyes remain open with cough, swallow, and corneal reflexes present; Amnestic properties are present.
• Regarding psychological effects of ketamine, it produce a range of perceptual distortions and not hallucination. Mild referential ideas, affective flattening and alogia are also seen. Ketamine does not reproduce the full picture of schizophrenia. ⁽⁹⁾
• Anesthesia induction characteristics are
• • increased limb muscle tone
  • salivation, lacrimation, nystagmus, pupillary dilatation
• It increases intra cranial pressure, cerebral blood flow and cerebal metabolism
• Increased electroencephalographic activity
• Emergence syndrome: There is a significant likelihood (10%-30%) that the patient will experience unusual psychological reactions to ketamine anesthesia.  These reactions include illusions/hallucinations and “out of body” experiences– collectively termed emergence syndromes which may last 1-3 hours.

Drug interactions

• Zolpidem
• Lorazepam, alprazolam, diazepam
• Diphenhydramine
• Hydromorphone
• Clonazepam
• Eszopiclone
• Pregabalin, gabapentin
• Esmoprazole
• Acetaminophen
• Oxycodone
• Promethazine
• Topiramate
• Ketorolac
• Cholecalciferol

Adverse effects

• Emergence syndrome
• Tachycardia
• Increased cardiac output
• Increased intracranial pressure
• Tonic clonic movements
• Visual hallucination
• Vivid dreams
• Diplopia
• Increased intraocular pressure
• Injection site pain
• Nystagmus
• Anaphylaxis cardiac arrhythmias
• Cough reflex depressed
• Fasciculations
• Hypersalivation
• Hypertonia
• Laryngospasm
• Respiratory depression or apnea with large doses or rapid infusion

Midazolam

Metabolism and excretion

• Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam.
• Age related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite.
• However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam.
• Midazolam is poorly absorbed orally with only 50 percent of the drug reaching the bloodstream.
• Midazolam is primarily metabolized in the liver and gut by human cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite, (alpha)-hydroxymidazolam (also known as 1-hydroxy-midazolam), and 4-hydroxymidazolam (makes up 5% or less of the biotransformation products). ⁽¹⁾
• The small intestine contributes to first pass oxidative metabolism of midazolam by mucosal CYP3A4. ⁽²⁾
• 1-hydroxy-midazolam is at least as potent as the parent compound and may contribute to the overall activity of midazolam. ⁽¹⁾
• The therapeutic as well as adverse effects of midazolam are due to its effects on the GABA_Areceptors; midazolam does not activate GABA_A receptors directly but it enhances the effect of the neurotransmitter GABA on the GABA_A receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition.

Effect on circulation

• Bigeminy
• Premature ventricular contraction
• Vasovagal episode
• Bradycardia/ tachycardia
• Nodal rhythm
• MIdazolam used for induction of anesthesia results i a transient depression of baroreflex function and a sustained decrease of symoathetic tone. DEpression of arterial baroreflex heart rate responses under midazolam anesthesia are less pronounced than the depression of baroreflex responses. ⁽³⁾
• Midazolam induces a predominant sympathetic activity, leading to increased heart rate and decreased blood pressure. This should be considered during conscious sedation, especially in patients at risk of cardiovascular complications.  ⁽⁴⁾
• Flumazenil does not antagonize the cardiac effects of midazolam. It has no effect on the peripheral type benzodiazepine receptor of the myocardum. ⁽⁵⁾

Effect on respiration

• Laryngospasm, bronchospasm
• Dyspnea
• Hyperventilation
• Wheezing
• Shallow respiration
• Airway obstruction
• Midazolam causes a direct depression of central respiratory drive. ⁽⁶⁾
• Even though midazolam produce a significant sedation effect, which is reversed by flumazenil, the drug has no effect on ventilation at rest and ventilatory responses to hypoxia and hypercapnia. ⁽⁷⁾

Effect on other organs

•  Retrograde amnesia
•  
• The hypnotic effects of midazolam may result from inhibition of brain structures involved in arousal and sensory processing, its sedative effects may result from inhibition of subcortical motor and limbic regions. ⁽⁸⁾
• Euphoria
• Hallucination
• Confusion
• Nervousness and anxiety
• Emergence delirium or agitation
• MIdazolam causes dose related changes in regional cerebral blood flow in brain regions associated with the normal functioning of arousal, attention and memory. ⁽⁹⁾
• Sleep disturbance, insomnia, nightmares
• Athetoid movements, seizure-like activity
• Ataxia, dizziness
• dysphoria, slurred speech, dysphonia
• Activation of GABA_A receptors which include the specific binding subunits for midazolam plays a role in the inhibition of neuronal death induced by brain ischemia. ⁽¹⁰⁾

Drug interactions

• Amprenavir, atazanavir, Boceprevir
• Carbamazepine
• Cimetidine
• Clarithromycin, erythromycin
• Clobazam
• Diltiazem
• Docetaxel
• Efavirenz
• Fluconazole
• Phenytoin, Fosphenytoin
• Indinavir, ritonavir
• Ketoconazole
• Omeprazole
• Verapimil

Adverse effects

• Nausea and vomiting
• Coughing
• Oversedation
• Headache
• Drowsiness
• Local side effects on iv injection include:

         Tenderness

         Pain during injection

         Redness

         Induration

         Phlebitis

Remifentanil

Metabolism and excretion

• Remifentanil is unique in its metabolism as it is not hepatically metabolized .
• remifentanil has an ester linkage which undergoes rapid hydrolysis by non-specific tissue and plasma esterases.
• This means that accumulation does not occur with remifentanil and its context sensitive half life remains at 4 minutes after a 4 hour infusion.
• Despite long infusion, the drug concentration decline by 50% within about 4 minutes of stopping the infusion. ⁽¹⁾
• Remifentanil produces physiological changes consist with potent γ- eceptor agonist activity, including analgesia and sedation. Termination of the therapeutic effect of remifentanil mostly depends on metabolic clearance rather than redistribution. ⁽²⁾
• Remifentanil is also rapid acting drug in terms of its onset of effect. The drug has short latency to peak effect after the administration of bolus.
• Because of short duration of action, an excessively rapid decline in analgesia can occur if the drug is not administered carefully.

Effect on circulation

• Remifentanil causes bradycardia either by parasympathetic activation or by other negative chronotropic effects. It causes RR interval lengthening. ⁽³⁾
• Decrease in arterial pressure
• The infusion of 0.25-0.5 µg/kg/min remifentanil combined with 0.2 mg/kg/minpropofol produced little effect on arterial blood pressure an dled to good recovery. The analgesia produced was sufficient to control the nociceptive response applied by electrical stimulation, suggesting that it may be appropriate for performing surgery. ⁽⁴⁾
• The addition of remifentanil to propofol affects bispectral index (BIS) onlywhen painful stimulus is applied. Remifentanil attenuated or abolished increases in BIS and mean arterial pressure (MAP) after tracheal intubation in a comparable dose dependent fashion. ⁽⁵⁾
• Remifentanil does not produce significant direct effects on intrinsic cardiac automaticity. ⁽⁶⁾

Effect on respiration

• Respiratory depression
• Decrease in respiratory rate and tidal volume
• There is decrease in rapid eye movement sleep. Obstructive sleep apnea is worsened by remifentanil infusion due to marked increase in the number of sleep apneas. ⁽⁷⁾
• Careful monitoring of respiratory function is essential when administering remifentanil as respiratory depression can occur even at low doses. ⁽⁸⁾

Effect on other organ system

• Reduction in sympathetic nervous system tone
• Remifentanil crosses the placenta but appears to be rapidly metabolized, redistributed or both. Maternal sedation and respiratory changes occur, but without adverse neonatal or maternal effects. ⁽⁹⁾
• Remifentanil can be used for on top analgesia in head trauma patients without adverse effects on cerebrovascular hemodynamics, cerebral perfusion pressure or intracranial pressure. ⁽¹⁰⁾

Drug interactions

• MAO inhibitors (furazolidine, linezolid, moclobemide, phenelzine, procarbazine, selegiline)
• Sedatives
• Tranquilizers
• Anti anxiety drugs like diazepam
• Narcotic pain relievers like codeine
• Psychiatric medicines (phenothiazines, tricyclic antidepressants)
• Anti epileptic (carbamazepine)
• Muscle relaxants
• Antihistamines (Diphenhydramine)
•  

Adverse effects

• Most common side effects are sense of dizziness, intense itching (pruritis)

More coomon side effects are

• Blurred vision
• Chest pain or discomfort
• Confusion
• Difficult or troubled breathing
• Lightheadedness, dizziness or fainting
• Muscle stiffness or tightness
• Pale or blue lips, fingernails or skin
• Shortness of breath
• Slow or irregular heartbeat
• Sweating
• Unusual tiredness or weakness

Less common side effects

• Bluish lips or skin
• Chills
• Decrease in cardiac output
• Fast, pounding, or irregular heart beat or pulse
• Feeling of warmth
• Fever
• Headache
• Nausea or vomiting
• Nervousness
• Pain after surgery
• Pain in the shloulder, arms, jaw and neck
• Pounding in the ears
• Problem in bleeding or clotting
• Shivering

Rare side effects

• Abdominal or stomach pain
• Black, tarry stools
• Bleeding gums
• Blood in urine or stool
• Bodyaches or pain
• Burning, crawling, itching, numbness
• Congestion
• Cough or hoarseness
• Cough producing mucus
• Difficulty in swallowing
• Disorientation
• Dry mouth
• Dysphoria or ear pain
• Hiccups
• Increased menstrual flow or vaginal bleeding
• Increased sweating, thirst and urination
• Loss of apetite
• Muscle cramps
• Weight gain

Precaution

• Head injury
• Pre existing lung disease (asthma, emphysema)
• Patients allergic to fentanyl, codeine
• Patients on alcohol
• Pregenancy and lactation

Contraindications

• Sloe heart rate
• Patients with abnormally low blood pressure
• Significant decrease in lung function

Thiopental

Metabolism and excretion

• Thiopental rapidly and easily crosses the blood brain barrier as it is a lipophilic molecule.
• It has short duration of action
• It get redistributed away from central circulation towards muscle and fat tissue, due to its very high fat: water partition coefficient (approximately 10), leading to sequestration in fat tissue.
• Once redistributed, the free fraction in the blood is metabolised in the liver.
• Sodium thiopental is mainly metabolized to pentobarbital 5-ethyl-5-(1-methyl-3-hydroxybutyl)-2-thiobarbituric acid, and 5-ethyl-5-(1-methyl-3-carboxypropyl)-2-thiobarbituric acid. ^{(1), (2)}
• Thiopentone is almost completely metabolised before excretion, less than 1% of unchanged drug is present in urine.
• Primary site of metabolism is liver; small extent in other tissues, especially the  kidneys and brain.
• Clearance: 3.4 ml/kg/minutes
• The concentration dependent or non linear protein binding of thiopental after a single iv bolus administration doe not enhance thiopental anesthetic effect. ⁽³⁾

Effect on circulation

• It causes circulatory depression
• Decrease in heart rate, hypotension
• After thiopental administration, heart rate, mean arterial pressure, mean pulmonary arterial pressure, pulmonary vascular resistance and mixed oxygen tension increased wheras oxygen utilization ratio and arteriala and mixed venous pH decreased. However, after 60 min, all the measurements returned to values similar to those obtained prior to thiopental administration. ⁽⁴⁾
• Thiopental reduce the sympathetic tone and cause change in heart rate variability. ⁽⁵⁾
• In vivo, thiopentone administered at a relatively slow rate causes large reduction in myocardial contractility and cardiac reserve, in absence of significant changes in myocardial blood flow or oxygen consumption. ⁽⁶⁾
• Thiopental a decrease in baroreflex sensitivity, associated with tachycardia. ⁽⁷⁾

Effect on respiration

• It causes respiratory depression
• Causes apnea and airway obstruction
• Laryngeal reflexes and cough reflexes are not depressed until large doses are given.
• Thiopental produce a selective depression of the upper airway motor activities, with stronger effects on the hypoglossal nerve. ⁽⁸⁾

Effect on other organ system

• Dose dependent depression of cerebral cortex, ascending reticular activating system and medullary centre resulting in sedation, hypnosis, anaesthesia, respiratory depression.
• Decrease in Cerebral metabolic oxygen consumption, Cerebral blood flow and ICP
• Anticonvulsant effect
• Stimulates CTZ, so nausea and vomiting
• Cerebral mateabolic effects of thiopental are secondary to functional effects. Thiopental provide no cerebral protection during hypoxia and does not couple oxidative phosphorylation in vivo. ⁽⁹⁾
• Thiopental decrease the regional cerebral blood flow primarily in the cerebellar and posterior brain regions. ⁽¹⁰⁾
• Thiopental act in the spinal cors to suppress movement occuring with noxious stimulation. Halothane appears to be less potent in the brain. ⁽¹¹⁾
• It has no analgesic property
• Pupil first dilate and then constrict
• Decrease in peristalsis

Drug interactions

• Alcohol or other CNS depressant
• Antihypertensives, especially diazoxide or ganglionic blockers such as

guanadrel, guanethidine, mecamylamine, or trimethaphan or Diuretics or

Hypotension-producing medications

• Concurrent use of antihypertensives with CNS depressant effects, such as

clonidine, guanabenz, methyldopa, metyrosine, pargyline, and rauwolfia

alkaloids

• Hypothermia-producing medications
• Ketamine
• Magnesium sulfate, parenteral
• Phenobarbital or Phenytoin
• Phenothiazines, especially promethazine

Adverse effects

• Headache
• Prolonged somnolence
• Nausea
• Agitated emergence
• Altered odor or taste sensation similar to rotting onions or garlic

Contraindications

Absolute contraindications

• Acute intermittent porphyria (thiopentone induces mitochondrial enzyme D- aminolevulinic acid synthetase. As a result, production of heme is accelerated, and  acute intermittent porphyria may be precipitated in susceptible patients)
• Barbiturate allergy
• H/O paradoxic excitation
• Status asthmaticus: In severe asthma it is thought that thiopentone may occasionally cause bronchospasm.

Relative contraindications

• Patients with a low circulating blood volume, such as after haemorrhage, are prone to severe hypotension with thiopentone. (barbiturate anaesthetics produce cardiovascular  depressant effects; condition may be exacerbated)
• Patients with cardiac disease (particularly those with stenotic heart valve lesions) are at risk from the cardiovascular depressant effects of thiopentone. The drug must be  carefully titrated against effect.
• Patients with partial airway obstruction, acute inflammation of mouth/ upper airway  should not be given an intravenous anaesthetic agent as total airway obstruction  develops.
• Hepatic dysfunction
• Uraemia/ renal insufficiency (hypnotic effect may be prolonged or potentiated)
• Uncontrolled Diabetes/ Adrenal cortical insufficiency/ mexoedema
• Hypokalemic familial periodic paralysis
• Dystrophia myotonica, Myaesthenia Gravis, Huntington’s chorea (respiratory depression may be prolonged; dosage should be carefully titrated)
• Thermally injured children (hypotension, require large dose 7—8 mg/kg
• Children less than 1 year of age: respiratory centre easily depressed, relatively large dose required.
• Alcoholic patient taking disulfiram

Precaution

• Liver disease
• Addison’s disease
• Myxedema
• Severe heart disease
• Severe hypotension
• Severe lung disease
• Family history of porphyria

Methohexital

Metabolism and excretion

• Metabolism of methohexital is primarily hepatic (i.e., taking place in the liver) via demethylation and oxidation.
• Side-chain oxidation is the primary means of metabolism involved in the termination of the drug’s biological activity.
• Protein binding is approximately 73% for methohexital.
• The terminal elimination half-life of the drug is relatively short (70-125 min), which is a result of a high metabolic clearance rate (657-999 ml plasma/min). ⁽¹⁾
• In addition to the initial redistribution of an anaesthetic dose of methohexitone, the quick recovery of patients is a result of rapid metabolism of the drug. ⁽¹⁾
• Methohexital protect the brain against thge ischemic damage. ⁽²⁾
• Ischemia and anoxia accelerated the gylocolysis rate which was inhibited by mthohexital. The energy metabolism was more rapidly normalized after ischemia or anoxia when methohexital was added to the perfusion medium. The spontaneous electrical activity of the isolated brain was maintained in ishemia or anoxia for a longer period and appeared again more rapidly in the recovery periods when methohexitol was present. ⁽³⁾

Effect on circulation

• Circulatory depression
• Thrombophlebitis
• Hypotension
• Tachycardia
• Peripheral vascular collapse
• Propofol is a useful alternative to methohexital for induction and maintenance of outpatient anesthesia. Methohexital and propofol both causes cardiovascular and respiratory depression on induction. Propofol is associated with fewer side effects (hiccoughing, nausea and vomiting) intra and postoperatively. Recovery times for awakening, orientation and ambulation are shorter with propofol. ⁽⁴⁾
• Methohexital reduces the left ventricular performance. ⁽⁵⁾
• Methohexitone inhibit the efferent cardiac vagal drive by their central action independently of baroreflex function. This central vagolysis is the cause of their positive chronotropic effects. ⁽⁶⁾
• Neutrophill leukocyte oxidative burst is depressed more by propofol than methohexital 24 hours after induction of anesthesia. ⁽⁷⁾

Effect on respiration

• Methohexital sedation causes respiratory depression. ⁽⁸⁾
• Laryngospasm
• Bronchospasm
• Hiccups
• Dyspnea
• Methohexital and etomidate depress the medullary centres that modify ventilatory drive in response to changing CO2 tensions. Ventilation at any given CO2 tension is greater after etomidate than after methohexital. ⁽⁹⁾

Effect on other organ system

• Causes skeletal muscle hyperactivity (twitching)
• Seizures
• Emergence delirium
• Suppression of brain metabolism occurs with methohexital during cerebral ischemia. ⁽¹⁰⁾
• Excitatory effects on EEG are seen in 12.5% patients after methohexital induction. ⁽¹¹⁾

Drug interactions

• Barbiturates
• Warfarin
• Halothane
• Corticosteroids (prednisolone)
• Sedatives
• Tranquilizers
• Anti anxiety drugs like diazepam
• Psychiatric drugs
• Anti epileptic drugs
• Muscle relaxants
• Antihistamines (diphenhydramine)

Adverse effects

• Pain and redness at injection site
• Drowsiness
• Nausea and vomiting
• Shivering

Serious and rare side effects include:

• Burning sensation at the site of injection
• Changes in skin appearance
• Mental/ mood changes
• Severe pain or redness in the legs
• Hiccups
• Cough
• Skeletal muscle twitching
• Seizures
• Low blood pressure
• Fast/slow/ irregular heart beat

Contraindications

• Patient with hypersensitivity to barbiturates
• Patients with latent or manifest porphyria

Precaution

• Patient with allergy especially to barbiturates (phenobarbital)
• Blood problems (porphyria, anemia)
• Asthma or other lung diseases (COPD)
• Heart problems (congestive heart failure)
• Kidney disease
• Liver disease
• Hypothyroidism
• Alcohol use
• Low or high blood pressure
• Seizures
• Neuromuscular disease (myasthenia gravis)
• Pregnancy and lactation