General Anesthesia• General Anesthesia is the loss of response &

perception of all external stimuli. • Ideal of anesthesia :1. Induce a smooth and rapid loss of consciousness 2. Allowing for a prompt recovery after administration

is discontinued 3. The drug would also possess a wide margin of safety

with less adverse effects 4. The modern practice of anesthesiology most

commonly use of combinations of intravenous and inhaled drugs . (so called balanced anesthesia technique ) which take advantage of the favorable properties of each agent while minimize their adverse reaction .

Components of General Anesthesia: • Unconsciousness

• Analgesia (most GA’s are poor analgesics)

• Attenuation of autonomic responses to painful stimuli

• Amnesia

• Immobility (neuromuscular relaxation)

Hypnosis

Analgesia Muscle relaxation

Phases of Anesthesia●Induction: putting the patient to sleep●Maintenance: keeping the patient asleep●Recovery: waking the patient up.

●Preanesthetic medication:1.It is the use of drugs prior to anesthesia to make it more safe and pleasant.2.To relieve anxiety – benzodiazepines.3.To prevent allergic reactions – antihistaminics.4.To prevent nausea and vomiting – antiemetics.5.To provide analgesia – opioids.6.To prevent Bradycardia and secretion – atropine.

Balance anesthesia • Modern anesthesia involves a combination of I.V (eg for

induction of anesthesia) and inhaled (eg maintenance of anesthesia)

• Muscle relaxant are ● Commonly used to facilitate ● Tracheal intubation .• Potent opioid analgesic ,• and cardiovascular drugs ● (eg β-blocker , α 2 agonist, ● calcium channel blockers) ● and used to control● transient autonomic● responses , to noxious ● (painful) surgical stimuli .

Classic Stages of Anesthesia● Stage 1: Analgesia : decreased awareness of pain, amnesia ● Stage 2 delirium & excitation ● enhanced reflexes, irregular respiration , vomiting may occur if

the patient is stimulated , for this reason to limit the duration and severity of this stage by rapidly increasing the concentration of the agent .

● Stage 3: Surgical Anesthesia ◦ unconscious, no pain reflexes, regular respiration, BP is

maintained, change in ocular movement , eye reflex , and pupil size..

● Stage 4: Medullary Depression ◦ respiratory & CV depression requiring ventilation &

pharmacologic support. . Not all stages are observed with modern GAs. all stages are Seen

mainly with Ether

Amnesia

sedation

Hypnosis

Coma

Death

Awake

Hypnosis

Gas Volatile liquids* Barbiturates

Opioids

Benzodiazepines

(nitrous oxide) (halothane isoflurane,desflurane, sevoflurane)

Enflurane

(thiopental)

(midazolam)

(fentanyl)

(etomidate, propofol)

General Anesthetics

Inhalational Parenteral

ketamine

Inhaled Anesthetics

• Easily vaporized liquid halogenated hydrocarbons Administered as gases

• Depth of anesthesia is dependent upon the concentration of anesthetic in the central nervous system.

The speed of induction of anesthesia depends on:

1-anesthetic concentration in the inspired air: increases in the inspired anesthetic concentration

increasing the rate of transfer into the blood . • 2- GA solubility (less soluble GAs equilibrate

more quickly with blood & into tissues such as the brain).

• The (blood \ gas partition) coefficient is a useful index of solubility and define the relative affinity of an anesthetic for the blood compared with that of inspired gas.

• The partition coefficient for nitrous oxide are extremely low (relatively insoluble in blood) therefore diffuse from the lung into the arterial blood , thus few molecule are required to rise its partial pressure and therefore the arterial tension rise rapidly ,

• conversely, for anesthetic with moderate to high solubility ( the arterial tension of the gas increase less rapidly).

• Thus inverse relationship between the blood solubility of an anesthetic and the rate of its rise arterial tension

BLOOD GAS PARTITION CO-EFFICIENT

BLOOD GAS PARTITION COEFFICIENT

Agents with low solubility in blood quickly saturate the

blood. The additional anesthetic molecules are

then readily transferred to the brain.

Anesthesiology● Blood : gas partition co-efficient: ● It is a measure of solubility in the blood. ● It determines the rate of induction and

recovery of Inhalational anesthetics.● Lower the blood \ gas co-efficient – faster the

induction and recovery – Nitrous oxide.● Higher the blood \ gas co-efficient – slower

induction and recovery – Halothane.

● 3. Ventilation rate ◦Hyperventilation increase the speed of

induction of anesthesia with inhaled anesthetic that would normally have a slow onset ◦ 4. the pulmonary blood flow ◦ Increased pulmonary blood flow, exposure

a large volume of blood to the anesthetic agent in the alveoli , thereby increasing the blood carrying capacity and decreasing the rate of rise in the anesthetic tension in the blood and brain.

Minimum Alveolar Concentration(MAC)● The minimum alveolar anesthetic concentration

required to eliminate the response to a painful stimulus in 50% of patients (is the median effective dose(ED50)of the anesthetic )

● MAC is a measure of GA potency. ● When several GAs are mixed, their MAC values

are additive (e.g. nitrous oxide is commonly mixed with other anesthetics).

MAC % Nitrous Oxide >100 Halothane 0.75Methoxyflurane 0.16

Pharmacodynamic (Mechanism of action )

● 1- old theory : the anesthetic agent with lipid matrix of the nerve membrane , this lead to secondary changes in ion flux and interaction with membrane of the ligand – gated ion channel

2- Effect via facilitation GABA receptor function. 3- Antagonism the action of the excitatory

neurotransmitter glutamic acid on the N-methyl-aspartate (NMDA) channel receptor

4- membrane hyper polarization by their activation of potassium channel

5- anesthetic decease the duration of opening nicotinic receptor – activated cation channel – an action that decrease the excitatory effect of acetylcholine synapse .

Pathway for General Anesthetics

• Inhalational anesthesia refers to the delivery of gases or vapors from the respiratory system to produce anesthesia

Properties of Inhaled anesthetics

● Nitrous Oxide (N2O) laughing gas• Colorless, odorless, tasteless, and does not burn • MAC > 100% : Incomplete anesthetic• Good analgesia• Weak anesthesia• Low soluble in blood• Sedative and analgesic (used for induction only)• Used in 30% conc with oxygen in dentistry• Less effect on respiratory and cardiovascular system.• Rapid onset & recover• Used along with other anesthetic; fast induction &

recovery.● * fewer side effects also seen in children

● Halothane• The first halogenated inhalational anesthetic• Potent anesthesia ,weak analgesia• Low MAC.(0.77)• Used as maintenance Anesthesia• Medium rate of onset & recovery• Although inexpensive, its use has declined• Sensitizes the heart to epi-induced arrhythmias

● It inhibits uterine contractions.●Halothane hepatitis and malignant hyperthermia can

occur .

Enflurane ◦ Rapid induction and recovery ◦ good muscle relaxation ◦Metabolize into fluoride ion ◦ NO cause hepatitis

●Seizures occurs at deeper levels –contraindicated in epileptics.●Caution in renal failure due to fluoride.●decreases systemic vascular

resistance-- lowers blood pressure (decrease blood pressure).

Isoflurane:- It is commonly used with oxygen or nitrous oxide. -Rapid recovery - Isoflurane Used for maintenance of anesthesia

- good muscle relaxation -Stable (no tissue toxicity)

• Depresses respiratory -- less than enflurane • Myocardial depressant-- less than enflurane • Not Sensitizes myocardium to catecholamines . • Excellent muscle relaxant-- potentiates effects of

neuromuscular blockers. • Bronchoirritating, laryngospasm as aside effect.

●

Parenteral AnestheticsParenteral anesthetics (IV): (advantage )

1. 1.Parenteral Anesthetics unlike inhaled anesthetic , intravenous agent do not require specialized vaporizer equipment .

● 2. Intravenous anesthetic have onset of anesthetic ● action faster than the most rapid inhaled agent ● (desflurane , sevoflurane ) therefore IV agent are ● commonly used for induction of general ● anesthesia . ● 3. Recovery is mainly by redistribution. ● 4. Also reduce the amount of inhalation anesthetic ● for maintenance.

●

Parenteral Anesthetics (IV)● Most commonly used drugs to induce

anesthesia: ◦ Barbiturates (Thiopental) ◦ Benzodiazepines (Midazolam) ◦ Opioids (Morphine & Fentanyl) ◦ Propofol ◦ Etomidate ◦ Ketamine

Barbiturate

• Weak analgesia • It also has anti seizure activity . • Reduce hepatic blood flow and glomerular filtration rate . • It is an ultra short acting barbiturates. • Diffusion out of the brain rapidly because of redistribution

of the drug to other tissues. ● Consciousness regained within 10-20 mins by

redistribution to skeletal muscle. ● It is eliminated slowly from the body by metabolism . • Side effect :Tissue necrosis—gangrene , cough,

laryngospasm (contraindicated in asthmatic patient)

CN

S Ef

fect

s

Increasing dose

Coma Barbiturates

Benzodiazepines

Hypnosis

Sedation, disinhibition, anxiolysis

Possible selective anticonvulsant &

muscle-relaxing activity

Dose Response Relationships

Anesthesia

Medullary depression

Thiopental• Redistribution

Etomidate (Amidate ®)●Rapid induction (~ 1 min)●Used as a supplement with nitrous oxide for short

surgical procedures ●Short duration of action (3-5 minutes )●Hypnotic, but not analgesic and coadministration of

opioid is require ●Rapid recovery( <10 minute ).●It suppress the production of steroids from the

adrenal gland . ●CVS stability is the main advantage over

anesthetics.

● Adverse effect 1. Pain at the site of injection ,2. myoclonic activity ,3. post operative nausea and vomiting ,4. adrenocortical suppression via effects on

steroidogenesis ,5. prolong infusion may result in hypotension

and electrolyte imbalance and oliguria because of its adrenal suppressive effects

Propofol (Diprivan ®)● Propofol ● Produces anesthesia as rapidly as i.v. barb’s but

recovery is more rapid than with barb’s. ● Unconsciousness in ~ 45 seconds and lasts ~15

minutes. • Patients subjectively feel better in the immediate

postoperative period because of the reduction in postoperative nausea and vomiting and sense of well-being .

• Sedative\hypnotic drug • Can cause marked hypotension (>barb)

• Commonly used for maintenance of anesthesia following induction of anesthesia.

• Produce euphoric feeling• Myocardial depression and peripheral

vasodilation may occur-- • Not water soluble-- painful (50%) • Adverse effect • Pain at the site of injection , • muscle movement and tremor ,

Benzodiazepines• Produce sedation and amnesia (Sedative doses

achieved within 2 min). • Potentiate GABA receptors • Slower onset and (short duration) within 30 min

therefore Used for short procedure. • The Benzodiazepines antagonist (flumazenil) can

be used to accelerate recovery when excessive doses of IV administration.

• Used to produce amnesia & sedation prior to induction of GA with another agent.

• Lorazepam • Slower onset of action (10-20 minutes)--

not used for induction • Used as adjunct for anxiolytic and

sedative properties ● Midazolam• More potent than diazepam or lorazepam • Induction slow, recovery prolonged • May depress respirations when used with

narcotics • Minimal cardiac effects • Water soluble

Narcotic agonists (opioids)

• Used for analgesic action. • Mechanism of action is receptor

mediated

Opioids (Morphine, Fentanyl *)● GAs do not produce effective analgesia (except for

ketamine). ● Opioids Given before surgery to minimize hemodynamic

changes produced by painful stimuli. This reduces GA requirements.

• Minimal cardiac effects-- no myocardial depression ● High doses can cause hypotension and respiratory

depression. ● Fentanyl induce analgesia rapid than morphine ● Used for post-operative analgesia • Opioid effects can be antagonize by naloxone . that

reverses analgesia and respiratory depression. ● Meperidine, morphine, fentanyl, are commonly used

Ketamine • Is a Dissociative anesthesia that Stimulates central

sympathetic pathways • Is the only IV anesthetic that possesses both

anesthetic and analgesic properties as well as the ability to produce dose- related cardiovascular stimulation

● Ketamine produce : profound analgesia, cataleptic state, immobility, amnesia with light sleep. eyes open, involuntary limb movement, unresponsive to pain .

● Heart rate and BP are elevated due to sympathetic stimulation. ● Respiration is not depressed and reflexes are not abolished.

Ketamine● Mechanism of action • blockade of the membrane effect of the excitatory

neurotransmitter glutamic acid at NMDA receptor (NMDA receptor antagonist )

• Rapid onset and last for 5-10 min.(short acting) • Increases heart rate & blood pressure (opposite of other

GAs). Dangerous for hypertensive • Can be used in shock states (hypotensive) or patients at

risk for bronchospasm. • contra indicated in hypertensive patient . • topical use in some types of arthritis • It is useful for burn dressing and trauma surgery. ●

● Side Effect ● Emergence delirium, hallucinations and

involuntary movements occurs in 50% cases during recovery.

salivation, hallucinations with postoperative disorientation● unpleasant dreams (15%) (adult) therefore

give diazepam before administration ketamine to reduce the incidence of these adverse effect.

NMJ Blockers (Muscle Relaxants)● (Succinylcholine , tubocurarine)● Used to: • Relax skeletal muscle • facilitate intubation• insure immobility

• Reversed by neostigmine during post-op period• Neuromuscular Junction

● Nondepolarizing Muscle Relaxants • Competitively inhibit end plate nicotinic cholinergic

receptor eg: pancuronium, tubocurarine. • side effects muscarinic stimulation. • Reversal of NMB by anticholinesterase-- inhibit

acetylcholinesterase such as neostigmine, pyridostigmine, edrophonium.

• Atropine : blocks side effects of Neostigmine.● Depolarizing Muscle Relaxants• Depolarize the end-plate nicotinic receptor • Succinylcholine used clinically

• short duration due to plasma cholinesterase • side effects-- fasiculations, myalgias. • bradycardia-- muscarinic receptor • malignant hyperthermia