General anesthetic agents Lecture 4

Midazolam MOA

- A benzodiazepide drug; - Slower anaesthesia onset and offset than with drugs mentioned previously; - Also used as a pre-operative sedative (anxiolytic) or used during procedures such as endoscopy, where full, general anaesthesia is not required; - In an event of an overdose, its effects can be reversed with a drug called flumazenil.

Timeline of General anesthesia Induction?

- Induction by using standard procedure - with an IV administration of a general anaesthetic - e.g. propofol, followed by an IV administration of an analgesic (for pain relief) drug - e.g. fentanyl; OR - Induction by using inhalation anaesthetic - either by a) oxygen (O2)/air with an inhalation anaesthetic e.g. sevoflurane, or b) oxygen (O2)/nitrous oxide (N2O) with an inhalation anaesthetic e.g. sevoflurane;

Where are muscarinic M2 ACh receptors expressed at?

•cardiomyocytes (the cardiac muscle cells); Agonist: muscarine, ACh Antagonist: atropine

What is balanced anesthesia?

Balanced anaesthesia requires different pharmacological agents, depending on the duration of the surgical/invasive procedure. A simple, short surgical procedure would require a single anaesthetic agent.

Explain Benzodiazepines?

Benzodiazepines, which have powerful sedative, anxiolytic and anticonvulsant effects, selectively potentiate the effects of GABA at GABAA receptors, depending on the subunit composition of the receptor. They bind with high affinity to GABAA receptors in such a way that the binding of GABA is facilitated and its agonist effect is enhanced.

For what are IV anesthetics used?

Intravenous anaesthetics are normally used for the Induction phase of the general anaesthesia because they produce unconsciousness in approx. 20 seconds (as soon as the drug reaches the brain, following an IV administration). They are usually not used for maintaining anaesthesia, because their elimination from the body is slow, compared with that of inhalation agents.

What are inotropic glutamate receptors?

Ionotropic glutamate receptors are NMDA, AMPA and kainate receptors (named originally according to their specific agonists).

How can its action be blocked?

Its action may be blocked by blocking postsynaptic receptors, or by persistent/continued postsynaptic depolarisation. Many of these individual steps serve as valuable drug targets.

Biosynthesis of GABA

Out of Glutamine becomes Glutamate via the Glutaminase in neurons and glial cells. Out of Glutamate gamma-aminobutyric acid is made via the enzyme Glutamic acid decarboxylase.

How is Neurotransmission at the NMJ performed?

an action potential arrives down the motor neuron; voltage-gated Ca2+ channels open and the Ca2+ ions enter the presynaptic nerve terminal; ACh-filled vesicles release ACh via exocytosis; ACh diffuses accross a synaptic cleft; ACh acts on postsynaptic nicotinic ACh receptors, which are ligand-gated ion channels which open to allow Na2+ ions entry and K+ ions exit; a postsynaptic membrane becomes depolarised (there is an ↑ in + charge inside it) and a threshold is reached for an action potential to fire; an action potential propagates along the sarcolemma (the cell membrane surrounding a skeletal muscle fiber) of the skeletal muscle to allow a contraction to take place; ACh is removed from the synaptic cleft by an action of the acetylcholinesterase enzyme, which breaks-down/metabolises ACh.

All drugs that are used clinically as NMJ-blocking drugs are non- depolarising agents, acting as competitive antagonists at the postsynaptic nicotinic, ACh receptors, as follows:

suxamethonium pancuronium, vecuronium, atracurium, doxacurium, cisatracurium, rocuronium.

What is Dantrolene?

Dantrolene, a muscle relaxant drug, blocks these Ca2+ channels and overturns malignant hyperthermia.

Effect of Desflurane on respiration?

Desflurane, an inhalation anaesthetic, is pungent (smelly) and, thus, is able to cause coughing, laryngospasm and bronchospasm. Therefore, desflurane is not used for Induction of anaesthesia, only for Maintenance.

Where do the general anaesthetics exert their effect?

General anaesthetics are administered into the systemic circulation and they exert their main effects on the central nervous system (CNS).

What is the role of glutamate?

Glutamate is widely and fairly uniformly distributed in the CNS, where its concentration is much higher than in other tissues. Glutamate source in the CNS comes mainly from either glucose, via the Krebs cycle, or glutamine, which is synthesised by glial cells and taken up by the neurons (very little comes from the periphery). Glutamate acts via both ionotropic (ligand-gated ion channels) and metabotropic (G protein- coupled) receptors. Only ionotropic glutamate receptors are known to be involved in mediating the action of some general anaesthetic agents.

What are the side effects of Chloroform?

However, it was hepatotoxic and it caused a severe cardiovascular depression (inhibition), leading to intra-operative and post-operative deaths.

What is the timeline of general anaesthesia?

Induction: a transition between the awake to the anaesthetised, the unconscious state Maintenance: keeping the patient unconscious and paralyzed during surgery/invasive procedures Emergence: a reversal of unconsciousness and paralysis Recovery: monitoring of vital signs (airway function, speaking, eating, drinking), pain and other potential complications.

Timeline of General anesthesia Maintenance and Emergence?

- Maintenance - by either a) oxygen (O2)/air with an inhalation anaesthetic e.g. sevoflurane, or b) intravenous anaesthetic e.g. propofol with an intravenous administration of an analgesic e.g.fentanyl; use of an NMJ-blocking drug e.g. rocuronium. - Emergence - stopping of a general anaesthetic drug, stopping of an NMJ-blocking drug; administration of an anticholinesterase drug e.g. neostigmine (if an NMJ-blocking drug was used); administration of an muscarinic, ACh, M2 receptor antagonist drug e.g. atropine (if neostigmine was used); administration of an analgesic (for pain relief) drug e.g. an NSAID, and antiemetic (prevention of nausea/vomiting) drug.

Propofol, fospropofol MOA

- Rapid anaesthesia onset, within approx. 30 seconds following IV route of administration; - Rapid rate of redistribution (t1/2= 2-4 minutes ® short-acting agent); - Rapid recovery - less "hangover" or "after-effect" (e.g. including drowsiness) and less nausea and vomiting than with inhalation anaesthetics - therefore, useful as a day-case surgery; - Cardiovascular depressant (inhibitor) effect of propofol may lead to hypotension and bradycardia; - Respiratory depression (inhibition) may occur; - Contraindicated for use in children and ill patients for prolonged maintenance of sedation because of appearance of a so-called propofol infusion syndrome or PRIS (characterised by severe metabolic acidosis, skeletal muscle necrosis, hyperkalaemia, hepatomegaly, lipaemia - accumulation of lipoproteins, renal failure, arrythmia and cardiovascular collapse which occurs in 1:300 patients).

Etiomidate MOA

- Rapid anaesthesia onset; - Short duration of action; - Similar agent to thiopental, but favoured over thiopental, because of the larger difference between the anaesthetic dose and the dose needed to produce cardiovascular depression (inhibition) ® safer than thiopental; - More rapidly metabolised than thiopental and, thus, less likely to cause a prolonged after-effect; - It causes less hypotension than propofol or thiopental; - Problems with its use are involuntary movements during the Induction phase of anaesthesia, post- operative nausea and vomiting and pain at the injection site; - It should be avoided in patients at risk of having adrenal insufficiency, as etomidate suppresses the production of adrenal steroids; - It is preferable to thiopental in patients at risk of circulatory failure.

Ketamine MOA

- Slower anaesthesia onset, within approx. 1 to 2 minutes following IV route of administration; - Causes "dissociative anaesthesia", a marked sensory loss, analgesia and amnesia, without complete loss of consciusness; - Involuntary movements and peculiar sensory experiences (hallucinations) often occur during Induction and Recovery phases; - Blood pressure and heart rate usually increase following its administration, while respiration is unaffected by the effective anaesthetic doses of the agent - this makes it safer to use ketamine than other anaesthetic agents in low-technology healthcare systems or in Accident & Emergency (A&E), Emergency Room (ER) departments where it can also be injected via an IM route of administration; - Disadvantage - it can cause an increase in intracranial pressure (the pressure inside the skull - the brain tissues), hallucinations and, sometimes, delirium and irrational behaviour during the Recovery phase of general anaesthesia.

Thiopental MOA

- Used only as a general anaesthesia Induction agent because the drug accumulates in the body (in the body fat) and its metabolism reaches a saturation point; - Rapid anaesthesia onset (due to its high lipid solubility) is achieved, within approx. 20 seconds, following an IV route of administration; - Short duration of action, approx. 5 to 10 minutes ® short-acting agent (because of the redistribution of the drug to well-perfused tissues e.g. liver, kidneys); - Caution - respiratory depression (inhibition) can occur with low doses of the drug (even those that do not abolish reflex responses to painful stimuli); - It is highly bound to plasma albumin. - Its slowly declining plasma concentration, following large or repeated IV doses, means that it has a long after-effect.

What does a complex surgery require, which drugs?

- a pre-operative sedative/anxiolytic drug - e.g. diazepam; - a general anaesthesia-inducing drug administered by an IV route of administration - e.g. propofol, followed by an analgesic drug - e.g. fentanyl; - an inhalation anaesthetic to maintain anaesthesia - e.g. sevoflurane; - a neuromuscular junction-blocking drug, to induce skeletal muscle paralysis - e.g. rocuronium; - an anticholinesterase agent, to reverse skeletal muscle paralysis - e.g. neostigmine - towards the end of the surgical procedure; - a muscarinic, ACh receptor (mAChR) M2 antagonist, to prevent bradycardia - e.g. atropine.

Effect of halothane?

- halothane, a general inhalation anaesthetic, causes sensitisation to adrenaline, with no harm coming to a patient. Exception represents an occurance of an neuroendocrine tumour, a phaeochromocytoma, that secretes catecholamines (including adrenaline and noradrenaline) into the circulation, in which case there is a risk of ventricular fibrillation.

Effect of isofluorane?

- isofluorane, a general inhalation anaesthetic, inhibits sympathetic outflow, that is, secretions of adrenaline, noradrenaline, reduces arterial and venous tone and, thus, decreases arterial and venous pressure;

Effect of nitrous oxide?

- nitrous oxide (N2O) and ketamine increase sympathetic outflow, increase heart rate and maintain blood pressure;

Which features do inotropic glutamate receptors have?

- they are highly permeable to Ca2+ ions, therefore, activation of NMDA receptors is particularly effective in promoting the entry of Ca2+ ions resulting in neuronal excitation - ketamine blocks the Ca2+ channel pore, thereby, blocks the conductance of ions going through it, resulting in a block of excitation that would otherwise take place; - they are readily blocked by Mg2+ ions; - their activation requires glutamate and glycine binding (both glutamate-binding site and glycine- binding site must be occupied for the channel to open and for glutamate-induced excitation to take place) - xenon competes with glycine for the glycine binding site, thus inhibiting the activation of the NMDA receptor.

How is ACh synthesized?

ACh is synthesised from a precursor molecule, it is stored within vesicles, its release occurs upon arrival of an action potential, its inactivation takes place via an enzyme or re-uptake mechanism, or via transporters that take it back to the pre-synaptic terminal.

How is neostigmine administered?

Administration of neostigmine is followed by administration of atropine which is necessary to prevent unwanted effect of large amount of ACh (caused by inhibiting the break-down/metabolism of ACh) acting at the muscarinic M2 ACh receptors expressed in the cardiomyocytes - causing the heart to slow-down/stop, i.e. causing bradycardia. [Muscarinic M2 ACh receptors are G protein-coupled receptors which are inhibitory receptors - when ACh binds to them, cardiomyocytes become hyperpolarized, that is, inhibited. Because of that, the cardiac contraction is reduced/slowed-down.]

What do agonists of GABA a receptors cause?

Agonists at GABAA receptors may cause hallucinations. Muscimol is derived from a hallucinogenic mushroom (mostly its cap) Amanita muscaria.

Describe inhalation anesthetics?

All inhalation anaesthetics are small, lipid-soluble molecules that readily cross alveolar membranes to enter the bloodstream. From the blood, inhaled anaesthetics enter the brain (as the BBB is freely permeable to inhalation anaesthetics) and cause loss of consciousness. Therefore, it is the rate of delivery of the drug to and from lungs, via the inhaled air and, then, the bloodstream, which determines the overall pharmacological effect of an inhaled anaesthetic.

What is the definition of the word anaesthesia?

Anaesthesia - Greek word meaning "loss of sensation". Definition: it is a drug-induced, reversible loss of consciusness which allows surgery or invasive procedures to be performed in a patient.

What do antagonists of GABAa receptors cause?

Antagonist at GABAA receptor which induces seizures/convulsions isbicuculline. Bicuculline has been isolated from plants such as Dicentra cucullaria, Adlumia fungosa and several Corydalis species. It is only used as an experimental drug/tool. Another antagonist at GABAA receptor which also induces seizures/convulsions is picrotoxin (cocculin), another plant product. It acts by blocking the GABAA receptor channel. It is also only used as an experimental drug/tool.

Biosynthesis of ACh

Choline, a precursor molecule of ACh - via Choline acetyltransferase enzyme (CAT) - degraded by Acetylcholinesterase enzyme (AChE) x e.g. neostigmine - to ACh breakdown

What are other drugs that enhance the action of GABA?

Drugs that also enhance the action of GABA, but whose mechanism of action is less well defined than that of benzodiazepines, include other CNS depressants, such as barbiturates, neurosteroids (metabolites of progesterone and androgens or a synthetic neurosteroid called alphaxalone), general anaesthetic agents.

What are NMJ-blocking drugs?

Drugs that block neurotransmitter transmission at the neuromuscular junction (NMJ) are called neuromuscular junction (NMJ)-blocking drugs.

Until when was ether in use, and what are the dissadvantages of it?

Ether was in use in clinical anaesthesia until 1950s. Dissadvantages of ether: it is a very volatile substance (easily evaporates) with high flammability.

Which drug is the exception, which can be used for induction and maintenance of general anesthesia?

Exception represents a drug called propofol which can be used as a continuous IV infusion agent for the Maintenance of general anaesthesia because of its rapid metabolism; ketamine can be used on its own to produce general anaesthesia for short procedures, without the need for an inhalation agent.

What are inhalation agents? Name the two most important?

Inhalation anaesthetics - ether and chloroform are agents that are still used in animal research. In human clinical practice, new inhalation agents are being used - isoflurane, desflurane, sevoflurane. Also, xenon and nitrous oxide (N2O) are still in use. Halothane is used only occasionally. Nitrous oxide (N2O) - rapidly induces general anaesthesia. Also, it is an effective analgesic drug in concentrations too low to cause unconsciusness. It is always used as a mixture with oxygen (O2) and never on its own as a general anaesthetic, but as an adjunct to other volatile/inhaled general anaesthetics to speed up the Induction phase of anaesthesia. Xenon - an inert gas that was shown many years ago (in 1951) to have anaesthetic properties. It lacks toxicity, but its relatively low potency and high cost are its disadvantages.[It may also be neuroprotective in neonatal hypoxia.]

Where does GABA bind on the GABA a receptor?

GABA binds at the interface between the a and the b subunits. Volatile or inhaled anaesthetics also bind at the interface between the a and the b subunits.Intravenous anaesthetics may bind only to the b subunit. Therefore, drugs (general anaesthetics, benzodiazepines, barbiturates, neurosteroids, alcohol) may act at different sites at GABAA receptors, as follows: - the GABA-binding site, or- several modulatory sites (e.g. benzodiazepines), or - the ion channel.

Degradation and removal of GABA?

GABA is degraded via GABA transaminase enzyme in astrocytes.

What are GABA a receptors?

GABAA receptors are ligand-gated ion (Cl-) channels. GABA as an agonist at GABAA receptors increases Cl- ion permeability, which hyperpolarises a neuronal cell (increases the amount of -ve charge), as Cl- ions enter (influx) the cell, thereby reducing the cell's excitability. GABAA receptors are primarily located/expressed postsynaptically and the actions of GABA achieves the postsynaptic inhibition.

What is malignant hyperthermia?

Malignant hyperthermia is a side effect triggered by inhaled anaesthetics and depolarising neuromuscular junction blocking drug such as suxamethonium ("suxa") in genetically susceptible patients (individuals who carry mutations in the gene encoding a ryanodine receptor (RyR), which controls the release of Ca2+ ions from the sarcoplasmic reticulum, a Ca2+ ion store, resulting in heat production in skeletal muscle and a dramatic rise in body temperature that can be fatal).

What is the mechanism of action of general anesthetic agents?

Mechanism of action - various - because anaesthetic agents do not belong to one recognisable chemical class. Almost all anaesthetic agents (exceptions are ketamine and xenon) potentiate the action of γ- aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, at GABAA receptors.

Effect of general anesthetics on respiration?

Most general anaesthetics [with exceptions of nitrous oxide (N2O), xenon and ketamine] depress (inhibit) respiration markedly.

What effect do general anesthetics have on the heart?

Most general anaesthetics decrease cardiac contractility, but their effects on cardiac output and blood pressure vary because of simultaneous actions on the sympathetic nervous system and vascular smooth muscle (via neurotransmitters adrenaline, noradrenaline)

Why are NMDA receptors important general anesthetics?

NMDA receptors are an important site of action of general anaesthetics such as nitrous oxide (N2O), xenon and ketamine which act, in different ways, to reduce NMDA receptor-mediated excitation. NMDA receptors mediate the effects of glutamate, which is the major excitatory neurotransmitter in the CNS. Xenon, an inert gas, inhibits the NMDA receptors by competing with glycine (an allosteric modulator at the NMDA receptor) for its regulatory site on the NMDA receptor. Ketamine blocks the pore of the NMDA receptor channel.

What is neostigmine?

Neostigmine is administered to reverse the action of non-depolarising NMJ-blocking drugs, in order to achieve rapid postoperative recovery of skeletal muscle strength (for breathing-diaphragm and walking).

What is a neuromuscular block?

Neuromuscular block is an important adjunct (a supplementary part) to general anaesthesia for a complex surgery, when artificial ventilation is available. (As the diaphragm is inhibited/paralysed.) NMJ is a chemical synapse between a motor neuron and a skeletal muscle fibre. NMJ relays nerve impulses or action potentials that travel from the brain or spinal cord down a motor neuron to axon terminals, then to a so-called end-plate on a skeletal muscle fibre before triggering a contraction of the skeletal muscle.

Nicotine is an agonist for what?

Nicotine is an agonist for nicotinic, ACh receptors which is extracted from tobacco plants. Acetylcholine (ACh) is a physiological agonist for nicotinic, ACh receptors.

Where are nicotinic ACh receptors expressed and what are its agonist and antagonist?

Nicotinic ACh receptors (nAChRs) are expressed in• skeletal muscle (at skeletal neuromuscular junction); AGONIST: e.g. nicotine, ACh; ANTAGONIST: e.g. curare or tubocurarine.

Effect of nitrous oxide on respiration?

Nitrous oxide (N2O), an inhalation agent, has less of an effect than other general anaesthetics, because its low potency prevents very deep anaesthesia from being produced by this agent.

How can you reverse NMJ blockage?

Reversal of NMJ blockade can also be carried out by administration of acetylcholinesterase (AChE) inhibitors or anticholinesterases (e.g. neostigmine).

How is the reversal of NMJ blockage induced?

Reversal of NMJ blockade induced by drugs such as • rocuronium • vecuronium is carried out by using of a synthetic cyclodextrin - sugammadex, a chelating agent that selectively binds NMJ-blocking drugs, forms an inactive complex with them in the plasma, which is then being excreted unchanged in urine.

What kind of receptors are RYRs and IP3Rs?

Ryanodine receptors (RYRs) and inositol-1,4,5-trisphosphate receptors (IP3Rs) are ligand- gated ion channels.

What are ryanodine receptors (RyR)?

Ryanodine receptors (RYRs) and inositol-1,4,5-trisphosphate receptors (IP3Rs) regulate a release of Ca2+ ions from intracellular Ca2+ ion stores, sarcoplasmic reticulum and endoplasmic reticulum. Ryanodine receptors (RYRs) and inositol-1,4,5-trisphosphate receptors (IP3Rs) are also called Ca2+ release channels. Ryanodine is a plant insecticide which was isolated from a South American plant Ryania speciosa.

What is skeletal muscle contraction dependent on?

Skeletal muscle contraction is dependent on the neurotransmitter acetylcholine (ACh). Chemical transmission which is performed by ACh is called cholinergic transmission. For the skeletal muscle contraction, ACh signalling involvesnicotinic ACh receptors (nAChR).

What is the MOA of sugammadex?

Sugammadex reduces pharmacologically free plasma drug concentration of rocuronium or vecuronium. Sugammadex interacts with progesterone with high affinity and may interfere with hormonal contraceptive effectiveness. A dose of 4mg/kg of sugammadex has been predicted to decrease progesterone exposure by 34%, similar to a decrease that occurs when a daily dose of an oral contraceptive is taken 12 hours too late. This might lead to a reduction in the effectiveness of any hormonal contraceptives and an increase the risk of unwanted pregnancy.

What as the first anaesthetic agent?

The first anaesthetic agent was ether used in 1846 at the Massachusetts General Hospital (in the Ether Dome, a surgical operating amphitheater) in Boston, USA.

By which route do inhalation agents enter and leave the body?

The lungs are the only important route by which an inhalation anaesthetic enters and leaves the body.

What is the most sensitive region of the brain for general anesthetics to bind to?

The most sensitive regions of the brain to general anaesthetic agents are the midbrain reticular formation, thalamic sensory relay nuclei and, to a lesser extent, parts of the cortex. Inhibition of these regions results in unconsciousness and analgesia. However, as the concentration of a general anaesthetic is increased, all brain functions are progressively affected including motor control, reflex activity, respiration and autonomic regulation. High concentrations of any general anaesthetic affect all parts of the CNS, causing profound inhibition which, in the absence of artificial respiration, leads to death from respiratory failure.

What other anaesthetic agents were used?

The second anaesthetic agent was nitrous oxide (N2O or "laughing gas") used for the first time in 1847. Chloroform was used soon after - it had more pleasant odour than ether and was/is non-flammable.

NMDA, AMPA and kainate receptors are tetrameric ligand-gated channels, from what subunits are they formed?

They are all tetrameric ligand-gated ion channels formed by the following subunits:- NMDA receptors are formed from seven types of GluN subunits (GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B); - AMPA receptors are formed from four types of GluA subunits (GluA1-4); - kainate receptors are formed from five types of GluK subunits (GluK1-5). [AMPA is an artificial glutamate analogue. Naturally occurring agonist at AMPA receptors is quisqualic acid found within the flower petals of some plants, e.g. Pelargonium x hortorum.]

By which genes are RYRs expressed?

Three genes encode ryanodine receptors (RYRs) which are expressed in humans: RYR1, RYR2, and RYR3. RYR1 gene is mainly associated with ryanodine receptors RyR1 expressed in skeletal muscle. RYR2 gene is mainly associated with ryanodine receptors RyR2 expressed in cardiac muscle. RYR3 gene is mainly associated with ryanodine receptors RyR3 expressed in brain tissue.

How do drugs, that block NMJ act postsynaptically?

by blocking the postsynaptic nicotinic, ACh receptors (non-depolarising agents), or by persistently activating the postsynaptic, nicotinic ACh receptors (depolarising agents, e.g. suxamethonium).

What are the goals of General anesthesia?

hypnosis (unconsciusness,deepsleep)-by using general anaesthetic agents; • muscleparalysis-by using neuromuscularjunction blocking drugs; • analgesia(painrelief)-by using analgesic drugs.