GENERAL ANAESTHETIC AGENTS

OUTLINE

DEFINATION INTRODUCTION CLASSIFICATION MECHANISM OF ACTION INDUCTION STAGES OF GA GENERAL PRECAUTIONS DURING USE OF GA PRE-MEDICANTS

Definition

An anesthetic is a drug or agent that produces a complete or partial loss of feeling. There are three kinds of anesthetics:

GENERAL, REGIONAL LOCAL

Regional anaesthetic or nerve block. For example, a woman giving birth by caesarean section may have an epidural. This is an injection into the spine that numbs the body from the waist down.

Local anaesthetic anaesthetic is injected into the immediate area to be operated on. For example, your dentist may inject local anaesthetic into your gum before removing a tooth.

When a patient undergoes a general anesthetic, they lose sensation and become unconscious. General anaesthetic may be given as an injection or as a gas. An anaesthetist will administer a general anaesthetic.

BEFORE ANAESTHESIA

The following is critical Medical history, including any pre-existing conditions, such as diabetes or heart problems Surgical history Allergies, for example, to drugs or foods Drugs you may be taking, including cigarettes and alcohol.

INTRODUCTION

General anaesthetics are used to make patients unaware or unresponsive to painful stimulation They are given systemically and main effect is on the CNS Modern medicine would not be possible without these agents

HISTORY

Inhalational anaesthetics(I.A) were discovered in 1846 Before operations done on struggling patients and done at lightening speed Most operations were amputations Nitrous oxide(laughing gas) used in 1800,tested on the PM Then ether, given in parties to cause euphoria, then chloroform

Types

Old ,obsolete Chloroform Ether Xenon Trichloroethylene cyclopropane

Intravenous agents

Ketamine Propofol Thiopental Etomidate midazolam

inhalational

Nitrous oxide Isoflurane Desflurane Sevoflurane Halothane Enflurane Ether Methoxyflurane

Several different types of drug are given together during general anaesthesia Anaesthesia is induced by volatile drug given by inhalation, with an intravenously administered drug anesthesia is maintained with an intravenous or inhalational anesthetic.

G. A characteristics
They induce analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, Skeletal muscle relaxation.

The extent to which an individual drug can exert these effects varies with the drug, route of administration clinical situations.

Properties of an ideal anesthetic agent

Result in rapid loss of consciousness, which eliminates awareness, memory of pain, anxiety, and stress throughout the surgical period; Provide a level of analgesia sufficient to abolish the reex reactions to pain, such as muscular movement and cardiovascular stimulation;

Have minimal and reversible inuence on vital physiological functions, such as those performed by the cardiovascular and respiratory systems; Lead relaxation of skeletal muscle to facilitate endotracheal intubation, provide the surgeon ready access to the operative eld, and reduce the dose of anesthetic required to produce immobility;

Lack operating room safety hazards, such as ammability and explosiveness Prompt patient recovery to psychomotor competence, facilitating the clinicians assessment of the patient and the patients ability to become physiologically selfsupporting.

MECHANISMS OF ANAESTHETIC ACTION

Anaesthetic agents were originally thought to act by interacting physically rather than chemically with lipophilic membrane components to cause neuronal depression. However this theory implies that all anaesthetics interact in a common way (unitary theory of anaesthesia)

This is being challenged by more recent studies which demonstrate that specific anaesthetics exhibit selective and distinct interactions with neuronal processes These interactions are not easily explained by a common physical association with membrane components.

THEORIES OF ANAESTHETIC ACTION

Anaesthesia from Physical Interaction With Lipophilic Membrane Components The importance of physical interaction in anaesthesia is supported by the observation that noble gases such as xenon, which do not chemically interact with tissues, produce unconsciousness.

Theory 1

Membrane conformational changes are observed on exposure to anesthetics, further supporting the importance of physical interactions that lead to disruption of membrane macromolecules.

For example, exposure of membranes to clinically relevant concentrations of anesthetics causes membranes to expand beyond a critical volume (critical volume hypothesis) associated with normal cellular function.

Theory 2

Additionally, membrane structure becomes disorganized, so that the insertion of anesthetic molecules into the lipid membrane causes an increase in the mobility of the fatty acid chains in the phospholipid bilayer (membrane uidization theory)

Theory 3

prevent the interconversion of membrane lipids from a gel to a liquid form, a process that is assumed necessary for normal neuronal function (lateral phase separation hypothesis).

Theory 4

Anaesthesia from Selective Interactions of Anaesthetics With Specific Cellular Components Various anesthetics interact specically with different components of the GABAA- receptor chloride ionophore and enhance chloride conductance, some directly and others by enhancing the action of GABA.

Inhalational agents directly activate the chloride channel as well as facilitate the action of GABA. Barbiturates, propofol, benzodiazepines, and etomidate primarily enhance the action of GABA by interacting with specic receptor sites.

Also, anesthetics enhance other processes known to inhibit neuronal function, such as the glycine receptorgated chloride channel. A smaller number of anesthetics, including ketamine, N2O, and xenon, produce neuronal inhibition by antagonizing excitatory neuronal transmission mediated via the N-methyl-Daspartic acid (NMDA) receptor.

Some inhalational drugs activate K channels and so contribute to hyperpolarization and reduced neuronal excitability. These agents also inhibit the function of the protein complex involved in neurotransmitter release.

Many compounds produce anaesthesia,including inert gas like xenon Potency is related to lipid solubility not with chemical structure

Summary of M.O.A..

Earlier theories suggested interaction with lipid bylayer,recent evidence favours interation with membrane ion channels Most enhance activity of GABA receptors Others effects include activation of pottassium channels and inhibition of excitatory NMDA receptors

STAGES OF ANESTHESIA

The traditional description of the stages of anesthesia (the so-called Guedel's signs) were derived from observations of the effects of diethyl ether, which has a slow onset of central action owing to its high solubility in blood. Using these signs, anesthetic drug effects can be divided into four stages of increasing depth of central nervous system depression:

STAGE 1- Stage of analgesia

The patient initially experiences analgesia without amnesia. Later in Stage I, both analgesia and amnesia are produced.

STAGE 2- Stage of excitement

: During this stage, the patient often appears to be delirious and may vocalize but is definitely amnesic. Respiration is irregular both in volume and rate vomiting may occur if the patient is stimulated. Therefore efforts are made to limit the duration and severity of this stage, which ends with the re-establishment of regular breathing.

STAGE 3- Stage of surgical anesthesia

This stage begins with the recurrence of regular respiration and extends to complete cessation of spontaneous respiration (apnea). Four planes of stage III have been described in terms of changes in ocular movements eye reflexes, and pupil size, which under specified conditions may represent signs of increasing depth of anesthesia.

STAGE 4- Stage of medullary

depression

This deep stage of anesthesia includes severe depression of the vasomotor center in the medulla, as well as the respiratory center. Without circulatory and respiratory support, death rapidly ensues.

NOTE-ONE

In current anesthetic practice, the distinctive signs of each of the four stages described above are usually obscured because of the more rapid onset of action of modern intravenous and inhaled anesthetics (compared with ether),

NOTE 2

Ventilation is often controlled mechanically.

NOTE 3

In addition, the practice of administering other pharmacologic agents preoperatively (eg, preanesthetic medication) or intraoperatively (eg, opioid analgesics, cardiovascular drugs) can also alter the clinical signs of anesthesia.

The most reliable indication that stage III (surgical anesthesia) has been achieved is loss of responsiveness to noxious stimuli and reestablishment of a regular respiratory pattern.

The adequacy of the depth of anesthesia for a specific surgical stimulus is assessed by monitoring changes in respiratory cardiovascular responses to the surgical stimulation.

Surgery and Long-term Medication

The risk of losing disease control on stopping long term medication before surgery is often greater than the risk posed by continuing it during surgery. It is vital that the anesthetist knows about all drugs that a patient is (or has been) taking.

Patients with adrenal atrophy resulting from long-term corticosteroid use may suffer a precipitous fall in blood pressure unless corticosteroid cover is provided during anesthesia and in the immediate postoperative period Anesthetists must therefore know whether a patient is, or has been, receiving corticosteroids (including high-dose inhaled corticosteroids).

DRUGS THAT MUST BE STOPPED

Antiepileptics, Antiparkinsonian antipsychotics Cardiovascular Anxiolytics bronchodilators

glaucoma drugs immunosuppressant's, drugs of dependence thyroid or antithyroid drugs

Patients taking Antiplatelets medication or an oral anticoagulant present an increased risk of surgery. Heparin therapy should be considered

others

combined oral contraceptives If antidepressants need to be stopped, they should be withdrawn gradually to avoid withdrawal symptoms. In view of their hazardous interactions MAOIs should normally be stopped 2 weeks before surgery

Tricyclic antidepressants need not be stopped, but there may be an increased risk of arrhythmias and hypotension (and dangerous interactions with vasopressor drugs); therefore the anaesthetist should be informed if they are not stopped.

Lithium should be stopped 24 hours before major surgery Normal dose can be continued for minor surgery monitor fluids and electrolytes

Anaesthesia and driving

Patients given sedatives and analgesics during minor outpatient procedures should be very carefully warned about the risk of driving afterwards. For intravenous benzodiazepines and for a short general anaesthetic the risk extends to at least 24 hours after administration Alcohol should be avoided

Potassium-sparing diuretics may need to be withheld on the morning of surgery because hyperkalaemia may develop if renal perfusion is impaired or if there is tissue damage Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonist can be associated with severe hypotension after induction of anesthesia; these drugs may need to be discontinued 24 hours before surgery.

Prophylaxis of acid aspiration

Regurgitation and aspiration of gastric contents (Mendelsons syndrome) is an important complication of general anesthesia,

worse in obstetrics and during emergency surgery, and requires prophylaxis against acid aspiration. Prophylaxis is also needed in those with gastro-oesophageal reflux disease prophylaxis needed where gastric emptying may be delayed.

An H2-receptor antagonist or a proton pump inhibitor such as Omeprazole may be used before surgery to increase the pH and reduce the volume of gastric fluid. They do not affect the pH of fluid already in the stomach and this limits their value in emergency procedures; oral H2-receptor antagonists can be given 1-2 hours before the procedure but Omeprazole must be given at least 12 hours earlier

Antacids are frequently used to neutralize the acidity of the fluid already in the stomach; clear (non-particulate) antacids such as sodium citrate are preferred. Sodium citrate 300 mmol/litre (88.2 mg/mL) oral solution is normally used

Pre-medication

PRE-ANAESTHETIC MEDICATION (ANAESTHETIC ADJUNCTS) A general anesthetic is usually given with adjuncts that augment specific components of anesthesia thus permitting lower doses of general anesthetics and resulting in fewer side effects.

Premedication:

These drugs are given to allay fear and anxiety in the pre-operative period (including the night before an operation), to relieve pain and discomfort when present, and to augment the action of subsequent anesthetic agents..

A number of the drugs used also provide some degree of pre-operative amnesia. The choice will vary with I. the individual patient II. the nature of the operative procedure III. the anesthetic to be used

other prevailing circumstances such as Outpatient obstetrics and recovery facilities. The choice also varies between elective and emergency operations

Classes of premeds
Antimuscarinic-hyoscine Benzodiazepines-diazepam lorazepam,temazepam,midazolam Analgesics-Nsaids. opioids 2-adrenoceptor agonists-clonidine Neuromuscular blocking drugs

Antimuscarinic Drugs

Antimuscarinic drugs are used (less commonly nowadays) as premedicants to dry bronchial and salivary secretions They are also used before or with Neostigmine to prevent bradycardia, excessive salivation, and other Muscarinic actions of Neostigmine. They also prevent bradycardia and hypotension associated with drugs such as halothane, Propofol, and suxamethonium.

Atropine sulphate

Rarely used for premedication Has an emergency role in the treatment of vagotonic side-effects

Dose Premedications, by intravenous injection, 300 600 mcgs immediately before induction of anaesthesia; CHILD 20 mcgs/kg (max 600 mcgs) By subcutaneous or intramuscular injection, 300 600 mcgs 30 60 minutes before induction; CHILD 20 mcgs/kg (max. 600 mcgs)

Hyoscine hydrobromide

reduces secretions and also provides a degree of amnesia, sedation and anti-emesis. Unlike atropine it may produce bradycardia rather than tachycardia. In some patients, especially the elderly, hyoscine may cause the central ant cholinergic syndrome (excitement, ataxia, hallucinations, behavioral abnormalities and drowsiness).

Glycopyrronium bromide

reduces salivary secretions. When given intravenously it produces less tachycardia than atropine. It is widely used with Neostigmine for reversal of non-depolarising neuromuscular blocking drugs. Phenothiazines do not effectively reduce secretions when used alone.

Benzodiazepines

Benzodiazepines possess useful properties for premedication including relief of anxiety, sedation, and amnesia.

Short-acting benzodiazepines taken by mouth are the most common premedicants. They have no analgesic effect so an opioid analgesic is required for pain

Benzodiazepines can alleviate anxiety at does that do not necessarily cause excessive sedation They are of particular value during short procedures or during operations under local anesthesia

Amnesia reduces the likelihood of any unpleasant memories of the procedure Benzodiazepines are also used in intensive care units for sedation, particularly in those receiving assisted ventilation

Benzodiazepines may occasionally cause marked respiratory depression and facilities for its treatment are essential flumazenil is used to antagonize the effects of benzodiazepines. They are best avoided in myasthenia gravis especially pre-operatively.

diazepam

Diazepam is used to produce mild sedation with amnesia. It is a long-acting drug with active metabolites and a second period of drowsiness can occur several hours after its administration. Peri-operative use of diazepam in children is not generally recommended; its effect and timing of response are unreliable and paradoxical effects may occur.

Diazepam is relatively insoluble in water and preparations formulated in organic solvents are painful on intravenous injection a high incidence of venous thrombosis is reported (which may not be noticed for several days after the injection). Intramuscular injection of diazepam is painful and absorption is erratic

An emulsion formulated for intravenous injection is less irritant and reduces the risk of venous thrombosis it is not suitable for intramuscular injection. Diazepam is also available as a rectal solution but this preparation is not used for premedication or sedation.

temazepam

Temazepam is given by mouth and has a shorter duration of action and a more rapid onset than diazepam given by mouth It has been used as a premedicants in inpatient and day-case surgery; anxiolytic and sedative effects last about 90 minutes although there may be residual drowsiness.

lorazepam

Lorazepam produces more prolonged sedation than temazepam and it has marked amnesic effects. It is used as a premedicants the night before major surgery a further, smaller dose may be required the following morning if any delay in starting surgery is anticipated. Alternatively the first dose may be given early in the morning on the day of operation.

midazolam

Midazolam is a water-soluble benzodiazepine that is often used in preference to intravenous diazepam; recovery is faster than from diazepam, but may be significantly longer in the elderly

Midazolam is associated with profound sedation when high doses are given intravenously or when used with certain other drugs.

overdosage

There have been reports of overdosage when high strength midazolam has been used for conscious sedation. The use of high-strength midazolam (5 mg/mL in 2 mL and 10 mL ampoules, or 2mg/mL in 5 mL ampoules) should be restricted to general anaesthesia,

It is advised that flumazenil is available when midazolam is used, to reverse the effects .

Benzodiazepines Benzodiazepines can produce anesthesia similar to that of barbiturates, but are more commonly used for sedation rather than anesthesia because prolonged amnesia and sedation may result from anesthetizing doses.

As adjuncts, benzodiazepines are used for anxiolysis, amnesia, and sedation prior to induction of anesthesia or for sedation during procedures not requiring general anesthesia. The benzodiazepine most frequently used in the perioperative period is midazolam followed distantly by diazepam and lorazepam.

Midazolam has several advantages over both diazepam and lorazepam.

It is water soluble and typically is administered intravenously but also can be given orally, intramuscularly, or rectally. Oral midazolam is particularly useful for sedation of young children.

Midazolam produces minimal venous irritation as opposed to diazepam and lorazepam, which are formulated in propylene glycol and are painful on injection, sometimes producing thrombophlebitis.

Midazolam has the pharmacokinetic advantage, particularly over lorazepam, of more rapid onset and shorter duration of effect. Sedative doses of midazolam (0.010.07 mg/kg intravenously) reach peak effect in about 2 minutes and provide sedation for about 30 minutes

Elderly patients tend to be more sensitive to and have a slower recovery from benzodiazepines thus, titration to the desired effect of smaller doses in this age group is prudent.

For either prolonged sedation or general anesthetic maintenance, midazolam is more suitable for infusion than other benzodiazepines, although its duration of action does significantly increase with prolonged infusions

Analgesics

With the exception of Ketamine and nitrous oxide, neither parenteral nor currently available inhalational anesthetics are effective analgesics. Thus, analgesics typically are administered with general anesthetics to reduce anesthetic requirement and minimize hemodynamic changes produced by painful stimuli.

Nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, or acetaminophen may provide adequate analgesia for minor surgical procedures. Because they produce rapid and profound analgesia, opioids are the primary analgesics used during the perioperative period.

Fentanyl , sufentanil , alfentanil , remifentanil , meperidine , and morphine are the major parenteral opioids used in the perioperative period. The primary analgesic activity of each of these drugs is produced by agonist activity at opioid receptors.

Their order of potency (relative to morphine) is: sufentanil (1000x) > remifentanil (300x) > fentanyl (100x) > alfentanil (15x) > morphine (1x) > meperidine (0.1x). The choice of a perioperative opioid is based primarily on duration of action, given that at appropriate doses, all produce similar analgesia and side effects.

During the perioperative period, opioids often are given at induction to prevent responses to predictable painful stimuli (e.g., endotracheal intubation and surgical incision). Subsequent doses either by bolus or infusion are titrated to the surgical stimulus and the patients hemodynamic response

Marked decreases in respiratory rate and heart rate with much smaller reductions in blood pressure are seen to varying degrees with all opioids. Muscle rigidity that can impair ventilation sometimes accompanies larger doses of opioids

. The incidence of sphincter of Oddi spasm is increased with all opioids, although morphine appears to be more potent in this regard. The frequency and severity of nausea, vomiting, and pruritus after emergence from anesthesia are increased by all opioids to about the same degree. A useful side effect of meperidine is its capacity to reduce shivering, a common problem during emergence from anesthesia.

2-adrenoceptor agonists

These agents have been found to produce sedation and analgesia. The sedative properties may be related to their action on 2-receptors in the locus cereleus while analgesia likely occurs via 2-receptors in the spinal cord

Agents used for sedation include clonidine and IV dexmedetomidine.

A solution of clonidine is available for epidural anesthesia. Cardiovascular side effects such as bradycardia and hypotension limit the doses that can be used. As adjunctive drugs they reduce the dose requirement for opioids and anaesthetics during surgery.

Neuromuscular Blocking Agents

Depolarizing (e.g., succinylcholine) and nondepolarizing muscle relaxants (e.g., pancuronium) often are administered during the induction of anesthesia to relax muscles of the jaw, neck, and airway and thereby facilitate laryngoscopy and endotracheal intubation

. Following induction, continued muscle relaxation is desirable for many procedures to aid surgical exposure and to provide additional immobility.

The action of nondepolarizing muscle relaxants usually is antagonized, once muscle paralysis is no longer desired, with an acetylcholinesterase inhibitor such as neostigmine or edrophonium combined with a muscarinic receptor antagonist e.g.atropine to offset the muscarinic activation resulting from esterase inhibition.

Other than histamine release by some agents, nondepolarizing muscle relaxants used in this manner have few side effects.

succinylcholine has multiple serious side effects e.g. bradycardia, hyperkalaemia, severe myalgia induction of malignant hyperthermia in susceptible individuals.