Diazepam (Valium) was synthesized by Sternbachin 1959

Lorazepam a 2′ chloro-substitution product of oxazepam , was synthesized in 1971

Fryer and Walser's in 1976 synthesized midazolam

Midazolam was the first benzodiazepine that was produced primarily for use in anesthesia

Three benzodiazepine receptor agonists are commonly used in anesthesia are :-

short-lasting (midazolam),

intermediate-lasting (lorazepam),

long-lasting (diazepam)

relatively small and are lipid soluble at physiologic pH

Midazolam is the most lipid soluble of the three drugs

Binding of drug facilitates the actions of GABA ie principal inhibitory neurotransmitter in the CNS

Enhance the affinity of the receptors for GABA

enhanced opening of chloride gating channels leading to increased chloride conductance

hyperpolarization of the postsynaptic cell membrane, rendering postsynaptic neurons more resistant to excitation

Results into anxiolysis,sedation, anterograde amnesia, alcohol potentiation and anticonvulsant and skeletal muscle relaxant effects

Alpha-1 containing GABAA receptors are the most abundant receptor subtypes

Sedative effects of benzodiazepines reflect activation of alpha-1 subunits of GABAA

receptors

Anxiolytic activity is due to alpha-2 subunit activity

Midazolam is a water-soluble benzodiazepine with an imidazole ring in its structure that accounts for stability in aqueous solutions

Compared with diazepam, midazolam is two to three times more potent

has an affinity for the benzodiazepine receptor that is approximately twice that of diazepam

Compared with other benzodiazepines, the amnestic effects of midazolam are more potent than its sedative effects

Midazolam undergoes rapid absorption from the gastrointestinal tract and prompt passage across the blood-brain barrier

Only about 50% of an orally administered dose of midazolam reaches the systemic circulation, reflecting a substantial first-p ass hepatic effect

extensively bound to plasma proteins

elimination half-time of midazolam is 1 to 4 hours,

Short duration of action of a single dose of midazolam is due to its lipid solubility, leading to rapid redistribution from the brain to inactive tissue sites as well as rapid hepatic clearance

Midazolam is rapidly metabolized by hepatic and small intestine cytochrome P-450 (CYP3A4) enzymes

principal metabolite of midazolam, 1-hydroxym idazolam,has approximately half the activity of the parent compound

metabolite is rapidly conjugated to glucuronide and subsequently cleared by the kidneys

Metabolism of is slowed in the presence of drugs (cimetidine, erythromycin, calcium channel blockers,antifungal drugs) that inhibit cytochrome P-450 enzymes resulting in unexpected CNS depression

hepatic clearance rate of midazolam is five times greater than that of lorazepam and ten times greater than that of diazepam

Central Nervous System

Produces decreases in cerebral metabolic oxygen requirements(CMR0 2 ) and cerebral blood flow

Cerebral vasomotor responsiveness to carbon dioxide is preserved during midazolamanesthesia

show little or no change in intracranial pressure (ICP)

Midazolam is a potent anticonvulsant effective in the treatment of status epilepticus

produces dose-dependent decreases in ventilation

Transient apnea may occur after rapid injection of large doses of midazolam

depress the swallowing reflex and decrease upper airway activity

Cardiovascular System:-

decrease in systemic blood pressure and increase in heart rate

Cardiac output is not altered by midazolam

Induction

0.05-0.15 mg/kg

Maintenance 0.05 mg/kg

Sedation 0.5-1 mg repeated 0.07 mg/kg IM

1)Preoperative Medication:- most commonly used oral preoperative Midazolam 0.5 mg/kg administered orally 30

minutes before induction of anesthesia, provides reliable sedation and anxiolysis in children without producing delayed awakening

2) Intravenous Sedation:- Midazolam in doses of 1.0 to 2.5 mg i/v(onset within 30 to60 seconds) is effective for sedation duringregional anesthesia as well as for brief therapeutic procedures

Anesthesia can be induced by administration of midazolam,0.1 to 0.2 mg/kg N, over 30 to 60 seconds

Elderly patients require less midazolam for the i/v induction

4) Maintenance of Anesthesia:- may be administered to supplement opioids,

propofol, and/or inhaled anesthetics during maintenance of anesthesia

5)Postoperative Sedation:- loading dose 0.5 to 4 mg i/v and maintenance

dose 1 to 7 mg/hr IV) to produce sedation in intubated patients

6)Paradoxical Vocal Cord Motion:-

Paradoxical vocal cord motion is a cause of non organic upper airway obstruction and stridor that may manifest postoperatively. Midazoalm 0.5 to 1 mg IV may be an effective treatment for paradoxical vocal cord motion

7) Midazolam is a potent anticonvulsant effective in the treatment of status epilepticus

8) Nausea and Vomiting Prophylaxis:-midazolam, may play in the prevention of PONV

highly lipid-soluble benzodiazepine with a more prolonged duration of action compared with midazolam

dissolved in organic solvents (propylene glycol,sodium benzoate) because it is insoluble in water

Dilution with water or saline causes cloudiness but does not alter the potency of the drug

Injection by either the iM or IV route may be painful

Diazepam is well absorbed from the gastrointestinal tract, with peak plasma levels usually achieved in 1hr

relatively lipid soluble and readily penetrates the blood–brain barrier

highly protein binding limits the efficacy of hemodialysis in the treatment of diazepam overdose.

Diazepam rapidly crosses the placenta, achieving fetal concentrations equal to and sometimes greater than those present in the maternal circulation

metabolized by hepatic microsomal enzymes using an oxidative pathway of N demethylation

metabolites of diazepam are desmethyldiazepam and oxazepam, with a lesser amount metabolized to temazepam

removed as a conjugate of glucuronic acid Cimetidine inhibits P-450 hepatic microsomal

enzymes and thus prolongs the elimination half-time of both diazepam and desmethyldiazepam

elimination half-time of diazepam is prolonged, ranging from 21 to 37 hours in healthy volunteers

Central Nervous System - reduce the CMRO2

and CBF similar to midazolam CNS intoxication can be expected at

diazepam plasma concentrations of > 1,000 ng/mL.

Respiratory system-Diazepam produces minimal depressanteffects on ventilation

Combination of diazepam with other CNS depressants (opioids, alcohol) or in patients with COPD may result in exaggerated or prolonged depression of ventilation

produces minimal decreases in systemic blood pressure, cardiac output, and systemic vascular resistance

transient depression of baroreceptor-mediated heart rate

Skeletal Muscle:-

diminishes the tonic facilitatory influence on

spinal gamma neurons, and, thus, skeletal muscle tone is decreased

-Induction:-

0.3-0.5 mg/kg

-Maintenance:-

0.1 mg/kg

-Sedation:-

2 mg repeated until sedated

Preoperative medication of adults

management of delirium tremens

treatment of local anesthetic-induced seizures

Production of skeletal muscle relaxation by diazepam is often used in the management of lumbar disc disease and may be in the rare patient who develops tetany

Lorazepam is a more potent sedative and amnesic than midazolam and diazepam

Pharmacokinetics:-

conjugated with glucuronic acid in the liver to form pharmacologically inactive metabolites that are excreted by the kidneys

The elimination halftime is 10 to 20 hours

Lorazepam has a slower onset of action than midazolam or diazepam because of its lower lipid solubility and slower entrance into the CNS

metabolism of lorazepam is less likely than that of diazepam to be influenced by alterations in hepatic function, increasing age, or drugs that inhibit P-450 enzymes such as cimetidine

Induction-0.1 mg/kgMaintenance-0.02 mg/kgSedation-0.25 mg repeated until sedated

Clinical use:- (a)IV induction of anesthesia, (b) IV sedation during regional anesthesia (c) use as an anticonvulsant (d) effective in limiting the incidence of

emergence reactions after administration of ketamine

Fatigue and drowsiness are the most common side effects in patients treated chronically with benzodiazepines.

Decreased motor coordination and impairment of cognitive function may occur, especially when benzodiazepines are used in combination with other CNS depressant drugs

Acute administration of benzodiazepines

may produce transient anterograde amnesia

Benzodiazepines may inhibit platelet-activating factor induced aggregation resulting in drug-induced inhibition of platelet aggregation

Respiratory depression:-most commonly assosiated with midazolam

venous irritation and thrombophlebitis:-

-lorazepam and diazepam mainly

Dependence:- Even therapeutic doses of benzodiazepines may produce dependence as evidenced by the onset of physical or psychologic symptoms after the dosage is decreased or the drug is discontinued

Withdrawal symptoms (irritability,insomnia, tremulousness)

first benzodiazepine antagonist approved for clinical use

it is a competitive antagonist at the benzodiazepine receptor

Antagonism is reversible and surmountable

Uses and Doses of Flumazenil

Reversal of benzodiazepines 0.2 mg repeated up to 3 mg

Diagnosis in coma 0.5 mg repeated up to 1 mg

term opioid refers broadly to all compounds related to opium(Papaver somniferum )

In 1806, Sertürner reported the isolation of a pure substance in opium that he named morphine after Morpheus, the Greek god of dreams

i/v used opioids are mainly –

fentanyl,

alfentanil,

sufentanil,

remifentanil

Receptor Clinical Effect

μ Supraspinal analgesia (μ 1 )Respiratory depression (μ 2 )Physical dependenceMuscle rigidity

κ SedationSpinal analgesia

δ AnalgesiaBehavioralEpileptogenic

σ DysphoriaHallucinationsRespiratorystimulation

All opioid receptors couple to G proteins; binding of an agonist to an opioid receptor causes membrane hyperpolarization

Acute effects are mediated by inhibition of adenyl cyclase (reductions in intracellular cyclic adenosine monophosphateconcentrations) and activation of phospholipase C

Opioid receptor activation inhibits the presynaptic release and postsynaptic response to excitatory neurotransmitters (eg, acetylcholine, substance P) from nociceptiveneurons

Rapid and complete absorption

After intravenous administration, the distribution half-lives of all of the opioids are fairly rapid (5–20 min).

low molecular weight and high lipid solubility of fentanyl also favor transdermal absorption the transdermal fentanyl “patch”

increased lipid solubility of fentanyl and sufentanil, are associated with a faster onset and shorter duration of action when administered iv

alfentanil has a more rapid onset of action and shorter duration of action than fentanyl(Sufentanyl-most potent)

After smaller doses of the lipid- soluble drugs (eg, fentanyl or sufentanil), redistribution alone is the driver for reducing blood concentrations, whereas after larger doses biotransformation becomes an important driver in reducing plasma levels below those that have clinical effects.

time required for fentanyl or sufentanilconcentrations to decrease by half is context sensitive

all opioids depend primarily on the liver for biotransformation and are metabolized by the cytochrome P (CYP) system

Small V d of alfentanil contributes to a short elimination half-life (1.5 h)

End products of fentanyl, sufentanil, and alfentanil are inactive

Norfentanyl, the metabolite of fentanyl has greatest importance in diagnosing fentanylabuse.

ester structure of remifentanil makes it susceptible to hydrolysis (in a manner similar to esmolol) by nonspecific esterases in red blood cells and tissue

A. Cardiovascular:-

Larger doses of fentanyl, sufentanil, remifentanil,and alfentanil are associated with a vagus nerve–mediated bradycardia

sufentanil and fentanyl can be associated with reduced cardiac output

mild myocardial depression

Opioids depress ventilation, particularly respiratory rate

Sequestration by stomach and reabsorbed opoidsmay produce Biphasic resp. depression(FentanylMost commonly)

The apneic threshold—rises, and hypoxic drive is decreased

Rapid administration of larger doses of opioids(particularly fentanyl, sufentanil,remifentanil, and alfentanil) can induce chest wall rigidity(Wooden chest syndrome) severe enough to prevent adequate bag-and-mask ventilation effectively --treated with neuromuscular blocking agents

B. Respiratory:-

High dose

Sleep

Old age

Central nervous system depressant

Inhaled anesthetics

alcohol, barbiturates, benzodiazepines

Renal insufficiency

Hyperventilation,

Respiratory acidosis

opioids reduce cerebral oxygen consumption, cerebral blood flow,cerebral blood volume,

Stimulation of the medullary chemoreceptor

trigger zone is responsible for opioid-induced nausea and vomiting

Repeated dosing of opioids will reliably produce tolerance, a phenomenon in which larger doses are required to produce the same response

Prolonged dosing of opioids can also produce “opioid-induced hyperalgesia”

slow gastrointestinal motility by binding to opioid receptors in the gut and reducing peristalsis

Biliary colic may result from opioid-induced contraction of the sphincter of Oddi

Patients receiving long-term opioid therapy (eg, for cancer pain)doesn’t become tolerant to constipation,so it lead to recent development of the peripheral opioidantagonists like methylnaltrexone and alvimopan

neuroendocrine stress response to surgical stimulation is measured in terms of the secretion of specific hormones, including catecholamines, antidiuretic hormone, and cortisol

Large doses of opioids (typically fentanyl or sufentanil) block the release of these hormones in response to surgery

F.Dependence-both physical &psychological

G.Tolerance-mainly pharmacodynamic ,seen with all actions except constipation & miosis

Sufentanil- Intraoperative anesthesia

- 0.25–20 mcg/kg iv

Alfentanil- Intraoperative anesthesia

Loading dose- 8–100 mcg/kg iv

Maintenance infusion- 0.5–3 mcg/kg/min iv

Remifentanil- Intraoperative anesthesia

Loading dose- 1.0 mcg/kg iv

Maintenance infusion- 0.5–20 mcg/kg/min iv

Postoperative analgesia/sedation- 0.05–0.3 mcg/kg/min i/v

Fentanil-100 times more potent than morphine

Can be given iv,i/m,transmucosal,epidural,intrathecally

Cardiac stable Maximum biphasic respiratory depression Alfentanil-compared to fantanil quick onset

and short acting & assosiated with highest incidence of muscle rigidity

Sufentanil-most potent & opoid of choice for inhibiting cardiovascular response to laryngoscopy and intubations

Metabolized by non specific esterase(pseudo cholinesterase)

Shortest acting so agent of choice for day care surgery

Opoid of choice for renal patients

Causes significant hypotension

Contains glycine so cann’t be used through spinal/epidural because it can cause motor weakness

Most commonly, an opioid is combined with another drug more likely to provide hypnosis and amnesia

combination of alfentanil and propofol produces excellent TIVA, Alfentanil provides analgesia and hemodynamic stability while blunting responses to noxious stimuli, On the other hand, propofolprovides hypnosis and amnesia and is antiemetic

Profound synergism also exists when more than two agents, such as propofol-alfentanil-midazolam, are combined

TIVA techniques are especially useful when delivery of inhaled agents is compromised

Loading Dose (µg/kg)

Maintenance Infusion Rate

Additional Boluses

Alfentanil 25-100 0.5-2 µg/kg/min

5-10 µg/kg

Sufentanil 0.25-2 0.5-1.5 µg/kg/hr

2.5-10 µg

Fentanyl 4-20 2-10 µg/kg/hr 25-100 µg

Remifentanil 1-2 0.1-1.0 µg/kg/min

0.1-1.0 µg/kg

Premedication before alfentanil-propofolanesthesia can prolong postoperative recovery and should be avoided

Induction of anesthesia with alfentanil (25 to 50 µg/kg) and propofol (0.5 to 1.5 mg/kg), followed by infusions of alfentanil at 0.5 to 1.5 µg/kg/min and propofol at 80 to 120 µg/kg/min, will produce anesthesia in patients ventilated with air and O2 with or without N2O for a variety of procedures

Maintenance infusions vary according to patient condition and surgical stimuli

optimal propofol concentration decreases in the order of fentanyl > alfentanil > sufentanil≫ remifentanil

Drug infusions should be terminated 10 to 20 minutes before the end of anesthesia if N2O is used,Otherwise, propofol infusions should be terminated 5 to 10 minutes before anticipated patient awakening. Alfentanilinfusion rates do not need to be less than 0.25 to 0.5 µg/kg/min until surgery is terminated

In patients undergoing ear-nose-throat surgery

children at risk for malignant hyperthermia (in whom volatile agents are to be avoided)

Patients undergoing brief radiologic or painful procedures when rapid recovery is needed (e.g., mri, bone marrow aspiration)

Neurosurgical procedures to assist with control of intracranial pressure and for cerebral metabolic protection

Other minor surgical procedures

1959 De Castro and Mundeleer derived the concept of Neuroleptanalgesia, which involved the combination of a major tranquilizer (usually the butyrophenone droperidol) and a potent opioid analgesic (fentanyl) to produce a detached, pain-free state of immobilization and insensitivity to pain

characterized by analgesia, absence of clinically apparent motor activity, suppression of autonomic reflexes, maintenance of cardiovascular stability, and amnesia

addition of an inhaled agent, usually N2O, improves amnesia and has been called Neuroleptanesthesia

Butyrophenones cause sedation, tranquility, immobility, antiemesis, an extrapyramidalsyndrome with face and neck dyskinesia, oculogyric crises, torticollis, agitation, and hallucinations so now a days it is rare used

Neuroleptanalgesia or neuroleptanesthesia is absolutely contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs), in those who abuse drugs or alchohol, or in patients with Parkinson's disease.