General anesthetics

Dr. Hiwa K. Saaed, H.D, M.Sc, Ph.D

Department of Pharmacology & Toxicology

College of PharmacyUniversity of Sulaimani

Learning Objectives• Introduction and Properties of ideal general anesthetic• History of general anesthesia • Classification of General anesthetic agents

– Inhalation anesthetic agents, Potency; MAC– Intravenous anesthetic agents

• Mechanism of action of anesthesia• Depth of anesthesia (Guedel’s signs); Stages of Anesthesia• Surgical Period: pre, intra, post-operative

– Preoperative: • GA protocol• Patient factors in selection of GA• Preanesthetic medication

– Intraoperative: Induction, Maintenance and Recovery– Postoperative: Complications of General anesthesia

INTRODUCTION• General anaesthetics (GAs) are drugs which

produce reversible loss of all sensations and consciousness. It usually involves a loss of memory and awareness with insensitivity to painful stimuli, during a surgical procedure

General anesthesia

need for unconsciousness

‘Amnesia-hypnosis’

need for analgesia

‘Loss of sensory and autonomic reflexes’

need for muscle relaxation

PROPERTIES OF AN IDEAL ANAESTHETIC

• For the patient - It should be pleasant, non irritating, should not cause nausea or vomiting. Induction and recovery should be fast with no after effects.

• For the surgeon - It should provide adequate analgesia, immobility and muscle relaxation. It should be noninflammable and nonexplosive so that cautery may be used.

• For the anaesthetist - Its administration should be easy, controllable and versatile.

• Margin of safety should be wide - no fall in BP. Heart, liver and other organs should not be affected.

• It should be potent so that low concentrations are needed and oxygenation of the patient does not suffer.

• Rapid adjustments in depth of anaesthesia should be possible.

• It should be cheap, stable and easily stored.• It should not react with rubber tubing or soda

lime.

PROPERTIES OF AN IDEAL ANAESTHETIC

Balanced anesthesia - it is a term used to describe the multidrug approach to managing the patient needs. Balanced anesthesia takes advantage of drug’s beneficial effects while minimizing each agent’s adverse qualities.Intraoperatively, an ideal anesthetic drug:

1. would induce anesthesia smoothly, rapidly 2. and permit rapid recovery as soon as administration

ceased.

Since No single drug is capable of achieving these effects both rapidly and safely, a combination of drugs is used to take advantage of their best properties and minimize the undesirable side effects.

So a ‘balanced anesthesia’ is achieved by a combination of I.V and inhaled anesthesia and Preanesthetic medications

Balanced Anesthesia

HISTORY OF ANESTHESIA

• General anesthesia was absent until the mid-1800s.

• Ether synthesized in 1540 by cordus• Ether used as anesthetic in 1842 by dr. Crawford

W.Long• Ether publicized as anesthetic in 1846 by dr.

William morton. • Ether is no longer used in modern practice, yet

considered to be the first ‘ideal’ anesthetic• Chloroform used as anesthetic in 1853 by dr. John

snow• Endotracheal tube discovered in 1878• Thiopental first used in 1934• Curare first used in 1942 - opened the “Age of

anesthesia”

CLASSIFICATIONGeneral anesthesia

Inhalational

Gas

Nitrous oxideZenon

Volatile liquids

Etherhalothaneenfluraneisofluranedesflurane

Sevofluranemethoxyfluran

e

Intravenous

Slower acting

Dissociative anesthesia

ketamine

opiod analgesia

fentanyl

Benzodiazepines

diazepam

lorazepam

midazolam

Inducing agents

Thiopentone sod.

methohexitone sod.

propofol

Etomidate

droperidol

MECHANISM OF ACTION OF ANAESTHESIA

• No specific receptor has been identified. The focus is NOW on interactions of inhaled anesthetics with proteins comprising ion channels:

• GABAA receptors: Glycine receptors:• Nicotinic receptors: Blocks the excitatory postsynaptic current of

the nicotinic receptors. Anesthesia from physical interactions with lipophilic membrane

components• Anesthesia is produced by disturbance of the physical properties

of cell membranes• Anesthesia may be produced when anesthetics physically

dissolved into the cell membrane’s lipid biophase MEYERS OVERTON RULE.

• This theory fails to explain how the proposed disturbance of the lipid bilayer would result in a dysfunctional membrane protein

Anesthesia from selective interactions of anesthetics with cellular components

• GABAA Receptor (Ligand-gated ion channels) chloride channels gated by the inhibitory GABAA receptor

• GABAA receptor found throughout the CNS. Located in the post-synaptic membrane.

• GABAA Receptor mediates the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain

aN

bc

N g c

Na

cb

5 subunits arranged around a central pore:2 alpha, 2 beta, 1 gamma

Each subunit has N-terminal extracellular chain which contains the Ligand-binding site4 hydrophobic sections cross the membrane 4 times: one extracellular and two intracellular loops connecting these regions, plus an extracellular C-terminal chain

SIGNS & STAGES OF ANAESTHESIA (GUEDEL’S Signs) 

• Guedel (1920) described four stages with ether anaesthesia, dividing the III stage into 4 planes. The order of depression in the CNS is: Cortical centers→basal ganglia→spinal cord→medulla

 Stage of Analgesi

a

• analgesia and amnesia, the patient is conscious and conversational. Starts from beginning of anaesthetic inhalation and lasts upto the loss of consciousness

• Pain is progressively abolished • Reflexes and respiration remain normal• Use is limited to short procedures

Stage of Delirium

• From loss of consciousness to beginning of regular respiration• Patient may shout, struggle and hold his breath; muscle tone

increases, jaws are tightly closed, breathing is jerky; vomiting, involuntary micturition or defecation may occur

• . Heart rate and BP may rise and pupils dilate due to sympathetic stimulation

• No operative procedure carried out• Can be cut short by rapid induction, premedication

Surgical

anaesthesia

• Extends from onset of regular respiration to cessation of spontaneous breathing.

• This has been divided into 4 planes which may be distinguished as:• • Plane 1 roving eye balls. This plane ends when eyes become fixed.• • Plane 2 loss of corneal and laryngeal reflexes.• • Plane 3 pupil starts dilating and light reflex is lost.• • Plane 4 Intercostal paralysis, shallow abdominal respiration, dilated

pupil.

Medullary

paraly

sis

• Cessation of breathing to failure of circulation and death.• Pupil is widely dilated, muscles are totally flabby, pulse is

thready or imperceptible and BP is very low

Surgical period and GA Protocol

For the purpose of safe surgery we can categorize the surgical period as: preoperative, Intraoperative and postoperative.

Use preanesthetic medication↓

Induce by I.V thiopental or suitable alternative↓

Use muscle relaxant↓

Intubate↓

Use, usually a mixture of N2O and a halogenated hydrocarbon→maintain and monitor.

↓Withdraw the drugs → recover

I. Preoperative period-Selection of anesthetic agent

Patient factors in selection of anesthesia: safe and efficient anesthetic regimen based on: 1. the nature of the surgical or diagnostic

procedure, 2. status of health of organ systems: patient’s

physiologic, psychologic, pathologic, and pharmacologic state e.g., IHD, HTN, hypovolemic shock, bronchial asthma.

Liver and kidney: the release of fluoride, bromide, and other metabolic products of the halogenated hydrocarbons can affect these organs, especially with repeated anesthetic administration over a short period of time.

Patient factors in selection of anesthesia: status of organ systems

• Respiratory system: All inhaled anesthetics depress the respiratory system. Interestingly, they are bronchodilators.

• Cardiovascular system: whereas the hypotensive effect of most anesthetics is sometimes desirable, ischemic injury of tissues could follow reduced perfusion pressure.

• Nervous system: 1.the existence of neurologic disorders (e.g., epilepsy or

myasthenia gravis) 2. A patient history of a genetically determined

sensitivity to halogenated hydrocarbon-induced malignant hyperthermia

Malignant hyperthermia:• is an autosomal dominant genetic disorder of

skeletal muscle that occurs in susceptible individuals undergoing general anesthesia with volatile agents and muscle relaxants (eg, succinylcholine).

• The malignant hyperthermia syndrome consists of the rapid onset of tachycardia and hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, and acid-base imbalance.

• Rx Dantroline

Patient factors in selection of anesthesia:

• Pregnancy: 1.nitrous oxide can cause aplastic anemia in

the unborn child. Oral clefts have occurred in the fetuses of women who have received benzodiazepines.

2.Diazepam should not be used routinely during labor, because it results in temporary hypotonia and altered thermoregulation in the newborn.

AMERICAN SOCIETY OF ANESTHELOGISTS CLASSIFICATION

• Healthy individuals having no organic, physiological, biochemical or psychological disturbance ;pathology is localised and non systemic

ASA I

• Mild to moderate systemic disturbance, e.g. Epileptic children on medicationASA II

• Severe systemic disturbance or disease, even though it may not be possible to define the degree of disability with finality e.g. Children with congenital heart disease

ASA III

• Severe systemic disorder that are already life threatingASA IV

• The moribund(dying) patient who is unlikely to survive without planned procedures

ASA V

Preanesthetic medications:• serve to

– calm the patient, relieve pain, – protect against undesirable effects of the subsequently

administered anesthetics or the surgical procedure.– facilitate smooth induction of anesthesia, – lowered the dose of anesthetic required

Preanesthetic Medicine: • Benzodiazepines; midazolam or diazepam:

Anxiolysis & amnesia.• barbiturates; pentobarbital: sedation• Diphenhydramine: Prevention of allergic reactions:

antihistamines• H2 receptor blocker- ranitidine: Reduce gastric

acidity.

Preanesthetic medications:

• Antiemetics- ondansetron: Prevents aspiration of stomach contents and post surgical vomiting:

• opioids-fentanyl: Analgesia:• Anticholinergics: scopolamine:

– Amnesia– Reduce bronchial and salivary secretion:

irritant inhaled anesthetic cause excessive salivation and secretion.

– Reduce any tendency to bronchospasm– Prevent bradycardia and hypotension:

manipulation of visceral organs stimulates vagus leading to bradycardia.

II. Intraoperative periodInduction, maintenance, recovery from anesthesia Induction: the period of time from the onset of administration of the anesthetic to the development of effective surgical anesthesia in the patient. It depends on how fast effective concentrations of the anesthetic drug reach the brain. During induction it is essential to avoid the dangerous excitatory phase (stage II delirium) that was observes with the slow onset of action of some earlier anesthetics. Thus GA is normally induced with an I.V thiopental, which produces unconsciousness within 25 seconds after injection. At that time, additional inhalation or IV drugs comprising the selected anesthetic combination (skeletal M. relaxants) may be given to produce the desired depth of surgical stage III anesthesia.Inhalation induction: For children without IV access, non pungent agents, such as halothane or sevoflurane, are used to induce GA.

II. Intraoperative period -Maintenance:

• Maintenance: Anesthesia is usually maintained by the administration of volatile anesthetics, because these agents offer good minute-to-minute control over the depth of anesthesia.

• Opioids such as fentanyl are often used for pain along with inhalation agents, because the later are not good analgesics.

• -Usually: N2O + volatile agent (halothane, isoflurane)

• -Less often N2O + I.V Opioid analgesic (fentanyl, morphine, pethidine + N.M blocking agents

II. Intraoperative period -Recovery:

• the time from discontinuation of administration of the anesthesia until consciousness and protective physiologic reflexes are regained.

• It depends on how fast the anesthetic drug diffuses from the brain.

• For most anesthetic agents, recovery is the reverse of induction; that is, redistribution from the site of action (rather than metabolism) underlies recovery.

III. Postoperative period

• N.M blocking agents and Opioids induced respiratory depression have either worn off or have been adequately reversed by antagonists.

• Regained consciousness and protective reflex restored

• Relief of pain: NSAIDs• Postoperative vomiting: metoclopramide,

prochlorperazine

Inhalation anesthetics• Common features of inhaled anesthetics

– Modern inhalation anesthetics are nonflammable, nonexplosive agents.

– Decrease cerebrovascular resistance, resulting in increased perfusion of the brain

– Cause bronchodilation, and decrease both minute ventilation and hypoxic pulmonary vasoconstriction

• MAC (potency): The alveolar concentration of an anesthetic gas needed to eliminate movement among 50% of patients challenged by a standardized painful stimulus (skin incision). – MAC is the ED50 of the anesthetic. – the inverse of MAC is an index of potency of the anesthetic.

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uptake and distribution of inhalation anesthetics

• The movement of these agents from the lungs to the different body compartments depends upon their solubility in blood and tissues as well as on blood flow.

• Because gases move from one compartment to another within the body according to partial pressure gradients, a steady state (SS) is achieved when the partial pressure in each of these compartments is equivalent to that in the inspired mixture.

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Factors Determine the time course for attaining SS:

1. Anesthetic concentration in the inspired air (Alveolar wash-in): replacement of the normal lung gases with the inspired anesthetic mixture.

The time required for this process is – directly proportional to the functional residual

capacity of the lung, – inversely proportional to the ventilatory rate; it is

independent of the physical properties of the gas.

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2. Anesthetic uptake: is the product of gas solubility in the blood, cardiac output, and the alveolar to venous partial pressure gradient of the anesthetic.

Solubility in the blood: called the blood/gas partition coefficient.

The solubility in blood is ranked in the following order: halothane>enflurane>isoflurane>sevoflurane>desflurane>N2O.

An inhalational anesthetic agent with low solubility in blood shows fast induction and also recovery time (e.g., N2O), and an agent with relatively high solubility in blood shows slower induction and recovery time (e.g., halothane).

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Factors Determine the time course for attaining SS:

Four major tissue compartments determine the time course of anesthetic uptake:

Brain, heart, liver, kidney, and endocrine glands: these highly perfused tissues rapidly attain a steady-state with the PP of anesthetic in the blood.

– Cardiac output: low COP will result in slow delivery of the anesthetic. An increase in COP leads to an increase in pulmonary blood flow, thus blood capacity increases and tension rises slowly. Therefore in circulatory shock, decreased pulmonary blood flow and increased ventilation may speed up the induction of anesthesia with some anesthetics particularly those with high blood solubility.

– Alveolar to venous partial pressure gradient of the anesthetic: this is driving force of delivery

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Factors Determine the time course for attaining SS:

• Effect of different tissue types on anesthetic uptake: the time required for a particular tissue to achieve a steady-state with PP of an anesthetic gas in the inspired mixture is

– inversely proportional to the blood flow to that tissue. – directly proportional to the tissues volume and the

tissue/blood solubility coefficient of the anesthetic molecules.

• Skeletal muscles: poorly perfused, and have a large volume, prolong the time required to achieve steady-state.

• Fat: poorly perfused. However, potent GA are very lipid soluble. Therefore, fat has a large capacity to store anesthetic. This combination of slow delivery to a high capacity compartment prolongs the time required to achieve steady-state.

• Bone, ligaments, and cartilage: these are poorly perfused and have a relatively low capacity to store anesthetic.

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Factors Determine the time course for attaining SS:

• Wash out: when the administration of anesthetics discontinued, the body now becomes the “source” that derives the anesthetic into the alveolar space. The same factors that influence attainment of steady-state with an inspired anesthetic determine the time course of clearance of the drug from the body. Thus N2O exits the body faster than halothane.

Factors Determine the time course for attaining SS:

Halothane (Prototype)

Advantages:• Potent anesthetic, rapid induction & recovery• Neither flammable nor explosive, sweet

smell, non irritant • Does not augment bronchial and salivary

secretions.• Low incidence of post operative nausea and

vomiting.• Relaxes both skeletal and uterine muscle,

and can be used in obstetrics when uterine relaxation is indicated.

• Not hepatotoxic in pediatric patient, and combined with its pleasant odor, this makes it suitable in children for inhalation induction. 04/11/2023 33

Halothane :Disadvantages: • Weak analgesic (thus is usually coadministerd

with N2O, opioids)• Is a strong respiratory depressant• Is a strong cardiovascular depressant; halothane

is vagomimetic and cause atropine-sensitive bradycardia.

• Cardiac arrhythmias: serious if hypercapnia develops due to hypoventilation and an increase in the plasma concentration of catecholamines)

• Hypotensive effect (phenylephrine recommended)

• Hepatotoxic: is oxidatively metabolized in the liver to tissue-toxic hydrocarbons (e.g., trifluroethanol and bromide ion).

• Malignant hyperthermia

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Enflurane

Advantages:• Less potent than halothane, but produces rapid

induction and recovery• ~2% metabolized to fluoride ion, which is

excreted by the kidney• Has some analgesic activity• Differences from halothane: Fewer arrhythmias,

less sensitization of the heart to catecholamines, and greater potentiation of muscle relaxant due to more potent “curare-like” effect.

Disadvantages: CNS excitation at twice the MAC, Can induce seizure

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Isoflurane:

Advantages:• A very stable molecule that undergoes little

metabolism• Not tissue toxic• Does not induce cardiac arrhythmias• Does not sensitize the heart to the action of

catecholamines• Produces concentration-dependent hypotension

due to peripheral vasodilation• It also dilates the coronary vasculature,

increasing coronary blood flow and oxygen consumption by the myocardium, this property may make it beneficial in patients with IHD.

Desflurane: – Rapidity of induction and recovery: outpatient surgery– Less volatility (must be delivered using a special

vaporizer) – Like isoflurane, it decreases vascular resistance and

perfuses all major tissues very well.– Irritating cause apnea, laryngospasm, coughing, and

excessive secretions

Sevoflurane:– Has low pungency, not irritating the airway during

induction; making it suitable for induction in children– Rapid onset and recovery: – Metabolized by liver, releasing fluoride ions; thus, like

enflurane, it may prove to be nephrotoxic.

Methoxyflurane– The most potent and the best analgesic anesthetic

available for clinical use. Nephrotoxic and thus seldom used.

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Nitrous oxide (N2O) “laughing gas”

• It is a potent analgesic but a weak general anesthetic.

• Rapid onset and recovery: • Does not depress respiration, and no muscle

relaxation. • No effect on CVS or on increasing cerebral blood

flow• Clinical use: dental surgery, obstetrics,

postoperative physiotherapy, refractory pain in terminal illness, and maintenance of anesthesia.

• The least hepatotoxic, Teratogenic, bone marrow depression.

• Second gas effect: N2O can concentrate the halogenated anesthetics in the alveoli when they are concomitantly administered because of its fast uptake from the alveolar gas.

• Diffusion hypoxia: speed of N2O movement allows it to retard oxygen uptake during recovery.

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Intravenous anestheticsBarbiturates (thiopental, methohexital)• Potent anesthetic but a weak analgesic• High lipid solubility; quickly enter the CNS and

depress function, often in less than one minute, and redistribution occur very rapidly as well to other body tissues, including skeletal muscle and ultimately adipose tissue (serve as a reservoir).

• Thiopental has minor effects on the CVS but it may cause sever hypotension in hypovolemic or shock patient

• All barbiturates can cause apnea, coughing, chest wall spasm, laryngospasm, and bronchospasm

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Intravenous anesthetics/Propofol

Phenol derivativeIt is an IV sedative-hypnotic used in the induction and or maintenance of anesthesia. Onset is smooth and rapid (40 seconds)It is occasionally accompanied by excitatory phenomena, such as muscle twitching, spontaneous movement, or hiccups.

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Intravenous anesthetics/Propofol

Decrease BP without depressing the myocardium, it also reduce intracranial pressure.

It is widely used and has replaced thiopental as the first choice for anesthesia induction and sedation, because it produces a euphoric feeling in the patient and does not cause post anesthetic nausea and vomiting.

Poor analgesia.

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Intravenous anesthetics/Etomidate • Is used to induce anesthesia, it is a hypnotic

agent but lacks analgesic activity.• Induction is rapid, short acting• It is only used for patients with coronary artery

disease or cardiovascular dysfunction, • No effect on heart and circulation• Adverse effects: a decrease in plasma cortisol

and aldosterone levels which can persist for up to eight hours. This is due to inhibition of 11-B-hydroxylase

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Intravenous anesthetics/ ketamine

• Ketamine (phencyclidine derivative) • A short acting anesthetic (up to 15 min) induces

a dissociated state in which the patient is unconscious but appear to be awake and does not fell pain.

• Profound analgesia, less vomiting• Provides sedation, amnesia, and immobility• Interacts with NMDA receptor,

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Intravenous anesthetics/ ketamine • Sympathomimetic effect: stimulates the central

sympathetic outflow, causes stimulation of the heart and increased BP and COP.

This property is especially beneficial 1. in patients with either hypovolemic or

cardiogenic shock, 2. as well as in patients with asthma. Ketamine is

therefore used when circulatory depression is undesirable. BP is often increased.

• It increases cerebral blood flow and induces postoperative hallucinations “nightmares” particularly in adults,

• No M. relaxation

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Adjuvants/Opioids (fentanyl, sufentanil)

Benzodiazepine (midazolam, lorazepam and diazepam)• Are used in conjunction with anesthetics to

sedate the patient.Opioids: • Analgesic, not good amnesic, used together with

anesthetics.• They are administered either I.V, epidurally, or

intrathecally• All cause hypotension, respiratory depression and

muscle rigidity as well as post anesthetic nausea and vomiting, antagonized by naloxone.

Neuroleptanesthesia: Is a state of analgesia and amnesia produced when fentanyl is used with droperidol and N2O, Is suitable for burn dressing, endoscopic examination

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46

Properties of Intravenous Anesthetic AgentsDrug Induction and

RecoveryMain Unwanted

EffectsNotes

thiopental Fast onset (accumulation occurs, giving slow recovery) Hangover

Cardiovascular and respiratory depression

Used as induction agent declining. ↓ CBF and O2 consumptionInjection pain

etomidate Fast onset, fairly fast recovery

Excitatory effects during induction Adrenocortical suppression

Less cvs and resp depression than with thiopental, Injection site pain

propofol Fast onset, very fast recovery

cvs and resp depression Pain at injection site.

Most common induction agent. Rapidly metabolized; possible to use as continuous infusion. Injection pain. Antiemetic

ketamine Slow onset, after-effects common during recovery

Psychotomimetic effects following recovery, Postop nausea, vomiting ， salivation

Produces good analgesia and amnesia. No injection site pain

midazolam Slower onset than other agents

Minimal CV and resp effects.

Little resp or cvs depression. No pain. Good amnesia.

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Non-barbiturate induction drugs effects on BP and HR

Drug Systemic BP Heart Rate

propofol ↓ ↓

etomidate No change or slight ↓

No change

ketamine ↑ ↑