Download General Anaesthetics

General anaesthetics
GAs are drugs which produce reversible:
 Loss of all sensation, especially pain
 Sleep (unconsciousness) and amnesia
 Immobility and muscle relaxation
 Abolition of somatic and autonomic reflexes.
STAGES OF ANAESTHESIA
 Stage of analgesia (from beginning of
anaesthetic administration to the loss of
consciousness)
 Stage of delirium (From loss of consciousness
to beginning of regular respiration). Apparent
excitement is seen—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.
 Surgical anaesthesia (from regular respiration
to cessation of spontaneous breathing).
Progressively— muscle tone decreases, BP falls, HR increases with weak pulse,
respiration decreases in depth and later in frequency also.
 Medullary paralysis (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.
Physiological changes during stages of general anaesthesia (with ether)
CLASSIFICATION
 Inhalational
 Gas
Nitrous oxide
 Volatile liquids
Ether
Halothane
Isoflurane
Desflurane
Sevoflurane
 Intravenous
 Fast acting drugs
Thiopentone sod.
Methohexitone sod.
Propofol
Etomidate
 Slower acting drugs
Benzodiazepines (Diazepam, Lorazepam)
Dissociative anaesthesia (Ketamine)
Opioid analgesia (Fentanyl)
INHALATION ANESTHETICS
 Inhaled gases are used primarily for maintenance of
anesthesia after administration of an IV agent.
 Depth of anesthesia can be rapidly altered by changing
the inhaled concentration.
•Inhalational agents have
very narrow therapeutic
indices, so the difference in
concentrations causing
surgical anesthesia and
severe cardiac and
respiratory depression is
small.
•No antagonists exist.
Volatile anesthetics delivered to the patient are
absorbed via the lungs into the systemic circulation
causing dose-dependent CNS depression
Nitrous oxide (N2O)
 It is a colourless, odourless, heavier than air, noninflammable gas
supplied under pressure in steel cylinders.
 It is nonirritating, but low potency anaesthetic.
 N2O is a good analgesic; even 20% produces analgesia equivalent to
that produced by morphine.
 Muscle relaxation is minimal.
Uses:
 N2O is generally used as a carrier and adjuvant to other anaesthetics.
A mixture of 70% N2O + 25–30% O2 + 0.2–2% another potent
anaesthetic is employed for most surgical procedures.
 N2O (50%)- for dental and obstetric analgesia.
ADR:
 Depression of bone marrow
 Peripheral neuropathy
 Pneumothorax
 Elevation of intracranial pressure
Ether (Diethyl ether)
First public
demonstration of
ether anesthesia on
October 16, 1846 at
the Ether Dome in
Boston
Ether (Diethyl ether)
 It is a highly volatile liquid, produces irritating vapours which
are inflammable and explosive.
 Ether is a potent anaesthetic, produces good analgesia and
marked muscle relaxation.
ADR:
 Induction is prolonged and unpleasant with struggling,
breathholding, salivation and marked respiratory secretions
(atropine must be given as premedication to prevent the patient
from drowning in his own secretions).
 Postanaesthetic nausea, vomiting and retching are marked.
 Ether is not used now in developed countries because of its
unpleasant ADR and inflammable properties.
 However, it is still used in developing countries, particularly in peripheral areas because it is—cheap,
can be given by open drop method (though congestion of eye, soreness of trachea and ether burns on
face can occur) without the need for any equipment, and is relatively safe even in inexperienced
hands.
Halothane
 It is a volatile liquid with sweet odour, nonirritant and
noninflammable.
 It is a potent anaesthetic.
 Poor analgesia and muscle relaxation.
 It is mainly used as a maintenance anaesthetic after i.v.
induction.
ADR:
 It tends to sensitize the heart to the arrhythmogenic
action of Adr. The electrophysiological effects are
conducive to reentry—tachyarrhythmias occur
occasionally.
 Malignant hyperthermia
 Hepatitis
Isoflurane
 Compared to halothane, it produces relatively rapid
induction and recovery.
 It is a good maintenance anaesthetic, but not preferred
for induction because of unpleasant odor which is not
liked by conscious patients, especially children.
Desflurane
 Desflurane is 5 times less potent than isoflurane.
 Irritates air passage and may induce coughing, breath-
holding and laryngospasm.
 A somewhat pungent odour makes it unsuitable for
induction.
 Potential arrhythmogenicity
Sevoflurane
 Potency are less than isoflurane but more
than desflurane.
 Absence of pungency makes it pleasant
and administrable through a face mask.
 No irritate air passage → selected for
induction as well as maintenance → good
even by pediatric patients.
 Its high cost and need for high-flow
open or semiclosed system makes it very
expensive to use.
INTRAVENOUS ANAESTHETICS
FAST ACTING DRUGS
 These are drugs which on i.v. injection produce loss of
consciousness in one arm-brain circulation time (~11 sec).
 They are generally used for induction because of rapidity
of onset of action. Then anaesthesia is usually maintained
by an inhalational agent.
 They also serve to reduce the amount of maintenance
anaesthetic.
Thiopentone sod.
 It is an ultrashort, highly soluble in water providing a very alkaline solution.
 Extravasation of the solution or involuntary intraarterial injection produces
intense pain; necrosis and gangrene can occur.
 Produces unconsciousness in 15–20 sec., t½ - 3 min.
 Poor analgesic. (Painful procedures should not be carried out under its influence unless an opioid or N2O has been
given; otherwise, the patient may struggle, shout and show reflex changes in BP and respiration)
 A weak muscle relaxant; does not irritate air passages.
Uses:
 For induction to general anaesthesia
 Sole anaesthetic for short operations that are not painful
 For rapid control of convulsions
 Euthanasia (Belgium and the Netherlands)
 Truth serum(to weaken the resolve of a subject and make them more compliant to pressure)
ADR (recovers rapidly):
 Respiratory depression, Laryngospasm
 Cardiovascular collapse
 Reflex tachycardia
Propofol
 It is an oily liquid (1% emulsion).
 Unconsciousness occurs in 15–45 sec and lasts 5–10
min. t½ -1 min.
Medical uses:
 For induction of anesthesia
 Procedural sedation
 Executions
ADR:
 Excitatory effects and involuntary movements
 “Milk of amnesia” (lack of memory for events)
 Fall in BP
 Respiratory depression
 Mild euphoria, hallucinations and disinhibition
SLOWER ACTING DRUGS
Benzodiazepines (BZDs)
 Uses:
For inducing, maintaining and supplementing




anaesthesia
For ‘conscious sedation’ for endoscopies, cardiac
catheterization, angiographies, during local/regional
anaesthesia, fracture setting, ECT, etc.
Produce sedation, amnesia and then unconsciousness
in 5–10 min.
BZDs are poor analgesics.
The anaesthetic action of BZDs can be rapidly reversed
by flumazenil
Ketamine
 ‘Dissociative anaesthesia’ characterized by
profound analgesia, immobility, amnesia
with light sleep. (The patient appears to be conscious
but is unable to process sensory stimuli and does not react to
them. Thus, the patient appears to be dissociated from his
body and surroundings).
 Produces effects within a 1 minute, but
patient remains amnesic for 1–2 hr.
ADR:
 Emergence delirium,
 Hallucinations
 Involuntary movements
 Clandestinely mixed in drinks, ketamine
is misused as rape drug.
Use for:
 for short operations without lose of
consciousness .
 in painful procedures (angiographies,cardiac
catheterization)
 trauma surgery
COMPLICATIONS OF GENERAL
ANAESTHESIA
During anaesthesia









Respiratory depression and hypercarbia.
Salivation, respiratory secretions.
Cardiac arrhythmias, asystole.
Fall in BP.
Aspiration of gastric contents: acid
pneumonitis.
Laryngospasm and asphyxia.
Awareness: dreadful perception and
recall of events during surgery. This may
occur due to use of light anaesthesia +
analgesics and muscle relaxants.
Delirium, convulsions and other
excitatory effects are generally seen with
i.v. anaesthetics.
Fire and explosion. This is rare now due
to use of non-inflammable anaesthetics.
After anaesthesia




Nausea and vomiting.
Persisting sedation
Pneumonia, atelectasis.
Organ toxicities: liver, kidney
damage.
 Nerve palsies—due to faulty
positioning.
 Emergence delirium.
 Cognitive defects: prolonged
excess cognitive decline has been
observed in some patients,
especially the elderly, who have
undergone general anaesthesia,
particularly of long duration.
PREANAESTHETIC MEDICATION
Preanaesthetic medication refers to the use of drugs
before anaesthesia to make it more pleasant and safe.
 Sedative-antianxiety drugs (BZD-Relief of anxiety
and apprehension preoperatively and to facilitate
smooth induction)
 Opioids (produce pre- and postoperative analgesia,
reduce the dose of anaesthetic required)
 Anticholinergics (to reduce salivary and bronchial
secretions, to prevent vagal bradycardia ,hypotension
and cardiac arrest)
Opioid Analgesics




Opium
Obtained from poppy (Papaver somniferum) capsule.
It contains two types of alkaloids:
Analgesic:
 Morphine
 Codeine
Nonanalgesic:
 Papaverine
 Noscapine
 Compounds that are derived from opium or are chemically
related to morphine are called ‘opiates’, while all those
having morphine-like action, irrespective of chemical
nature, are called ‘opioids’.
CLASSIFICATION OF OPIOIDS
Strong (full) agonists :
1) Natural opium alkaloids: Morphine, Codeine
2) Semisynthetic opiates: Diacetylmorphine (Heroin),
Ethylmorphine,Hydromorphone, Oxymorphone,
Hydrocodone, Oxycodone.
3) Synthetic opioids: Fentanyl, Methadone, Tramadol.
Agonist-antagonists and partial/weak agonists
 Nalorphine, Pentazocine, Butorphanol
 Buprenorphine
Pure antagonists
 Naloxone, Naltrexone
PHARMACOLOGICAL ACTIONS
CNS
 Analgesia
 Sedation
 Mood and subjective effects (a calming effect- there is loss of
apprehension, feeling of detachment, lack of initiative, limbs feel
heavy and body warm, mental clouding and inability to concentrate
occurs)
 Respiratory centre depression (Death in morphine
poisoning/overdose is due to respiratory failure).
 Cough centre depression
 Temperature centre depression → hypothermia
 Vasomotor centre depression → fall in BP.
 III nerve stimulation → Miosis
 Vagal centre stimulation → bradycardia
Characteristic pinpoint pupil
Neuro-endocrine
associated with morphine use
 ↓ FSH, LH, ACTH levels
 ↑ prolactin and GH levels
PHARMACOLOGICAL ACTIONS
CVS
 Vasodilatation
 Postural hypotension
 Heart rate decreases
 Cardiac work is reduced (anti-ischaemic property)
GIT
 Spasm of sphincters + decrease gut movements →
Constipation
Other smooth muscles
 Biliary tract -spasm of sphincter of Oddi → intrabiliary
pressure is increased → may cause biliary colic
 Urinary bladder- Tone of sphincter is increased → urinary
urgency and difficulty.
 Bronchi → bronchoconstriction
USES
 As analgesic opioids are indicated in severe pain of




any type
Preanaesthetic medication
Relief of anxiety and apprehension- especially in
myocardial infarction
Cough
Diarrhoea
A comparison of opioid agonist efficacy.
ADVERSE EFFECTS








Sedation, mental clouding, lethargy;
Euphoria / Dysphoria
Constipation
Respiratory depression,
Blurring of vision /Miosis
Urinary retention
Hypotension
Apnoea of the newborn (opioids are given to
the mother during labour).
 Tolerance and strong dependence
(psychological and physical)
 Bronchospasm
OPIOID RECEPTORS
The major effects of the opioids are mediated by three
receptor :
 μ (mu),
 κ (kappa),
 δ (delta).
Agonist-antagonists and
partial/weak agonists
Nalorphine, Pentazocine, Butorphanol, Buprenorphine
 Clinically, the agonist-antagonist (agonist at one opioid receptor, antagonist at
another) and partial/weak agonist (low intrinsic activity) opioids are analgesics of
limited efficacy equivalent to low doses of morphine.
 They cause low ceiling respiratory depression and have lower abuse potential.
 The effects of these drugs depend on previous exposure to opioids:
 In individuals who have not received opioids (naive patients), mixed agonist–
antagonists show agonist activity and are used to relieve pain.
 In the patient with opioid dependence, the agonist–antagonist drugs may show
primarily blocking effects (that is, produce withdrawal symptoms).
USES:
 Postoperative and moderately severe pain in burns, trauma, fracture, cancer, etc.
 short-lasting painful conditions (e.g. renal colic)
 treatment of morphine dependence
OPIOID ANTAGONISTS
Naloxone
 is the drug of choice for morphine poisoning
 Produce withdrawal syndrom in dependent subjects
 for reversing neonatal asphyxia due to opioid use during
labour
 to treat overdose with other opioids and agonistantagonists
Naltrexone
 differs from naloxone in having a long duration of action
(1–2 days) which makes it suitable for ‘opioid blockade’
therapy of postaddicts
Nonsteroidal Antiinflammatory
Drugs (NSAIDs)
In contrast to morphine NSAIDs:
do not depress CNS,
do not produce physical dependence,
have no abuse liability
are weaker analgesics (except for inflammatory pain).
 They are also called non-narcotic, non-opioid or aspirin-like
analgesics.
 They act primarily on peripheral pain mechanisms, but also
in the CNS to raise pain threshold.
CLASSIFICATION
Nonselective COX inhibitors (traditional NSAIDs)
Salicylates: Aspirin.
Propionic acid derivatives: Ibuprofen, Naproxen,
Ketoprofen.
Fenamate: Mephenamic acid.
Enolic acid derivatives: Piroxicam, Tenoxicam.
Acetic acid derivatives: Ketorolac, Indomethacin,
Nabumetone.
Pyrazolone derivatives: Phenylbutazone,
Oxyphenbutazone.
Preferential COX-2 inhibitors
Nimesulide, Diclofenac, Meloxicam, Etodolac.
Selective COX-2 inhibitors
Celecoxib, Etoricoxib, Parecoxib.
Mechanism
of action
NSAIDs
Beneficial actions due to
PG synthesis inhibition
 Analgesia: prevention of




pain nerve ending
sensitization
Antipyresis
Antiinflammatory
Antithrombotic (Aspirin)
Closure of ductus arteriosus
in newborn
Side effects due to PG
synthesis inhibition
 Gastric mucosal damage
(Ulcers)
 Bleeding: inhibition of
platelet function
 Asthma and anaphylactoid
reactions in susceptible
individuals
ADVERSE EFFECTS
 Peptic ulceration
 Profuse gastric bleeding
 Gastric discomfort / Gastric erosion
 Anaphylactoid reaction
For aspirin :
 Salicylism (dizziness, tinnitus (ringing in the ears),
excitement and mental confusion, hyperventilation and
electrolyte imbalance).
 Reye’s syndrome- hepatic encephalopathy in children
having viral (varicella, influenza) infection → aspirin is
absolutely contraindicated in children with temperature
 Aspirin-induced asthma
USES
 As analgesic - For headache, backache, myalgia, joint






pain, pulled muscle, toothache, neuralgias ,etc.
As antipyretic - in fever of any origin
Acute rheumatic fever
Rheumatoid arthritis
Osteoarthritis
Postmyocardial infarction and poststroke patients
(aspirin lowers the incidence of reinfarction)
Prevention of colon cancer- incidence of colon cancer
among regular aspirin users is much lower
SELECTIVE COX-2 INHIBITORS
(Coxibs)
 Because of the theoretical advantage of inhibiting COX-2
without affecting COX-1 function, some highly selective COX-2
inhibitors have been introduced:
Celecoxib, Etoricoxib, Parecoxib
 They cause less gastric mucosal damage; occurrence of peptic
ulcer and ulcer bleeds is clearly lower than with traditional
NSAIDs.
 They do not prolong bleeding time.
 BUT!!!! High risk of heart attack and stroke!!
 Should be used only in patients at high risk of peptic ulcer,
perforation or bleeds.
Antipyretic-Analgesics
Analgesic-antipyretics (with poor antiinflammatory action):
 Paraaminophenol derivative:
 Paracetamol (Acetaminophen).
 Pyrazolone derivatives:
 Metamizol (Dipyrone),
 Propiphenazone.
Paracetamol (Acetaminophen)
Trade names – Tylenol, Panadol
Actions:
 The central analgesic action
(inhibit COX-2 in brain)
 A good antipyretic action
 Antiinflammatory action
Used to treat:
 Pain (mild to moderate)- arthritis pain, low back pain, headaches,
postoperative pain,dental pain, etc.
The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment
of common pain conditions
 Fever
 The most commonly used ‘over-the-counter’ analgesic.
 Drug of choice to treat fever in children (no risk of Reye’s syndrome).
Adverse effects
Acute liver failure/ hepatotoxicity
 Risk for severe liver injury is related to
dose more than 325 mg of acetaminophen per 1 time (perfect
regiment – 325mg 4 times a day)
 Hepatotoxicity are multiplied when combined with alcoholic
drinks!!!
 A liver transplant is often required (due to severe liver damade)
 Antidote- acetylcysteine (acts as a precursor for glutathione,
helping the body regenerate enough to prevent or at least
decrease the damage to the liver)
 No gastric irritation, ulceration and bleeding → can be given to
ulcer patients
Choice of NSAIDs

Mild-to-moderate pain with little inflammation: paracetamol or low-dose ibuprofen.

Postoperative or similar acute but shortlasting pain: ketorolac, diclofenac or nimesulide.

Acute musculoskeletal, osteoarthritic, injury associated pain: paracetamol or diclofenac.

Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheumatic fever: naproxen,
piroxicam, indomethacin, high dose aspirin.

Gastric intolerance to traditional NSAIDs : a selective COX-2 inhibitor or paracetamol.
Arthritis patients who are dependent on NSAIDs and have developed peptic ulcer must receive concurrent
proton pump inhibitor as gastroprotective.

Patients with history of asthma or anaphylactoid reaction to aspirin/other NSAIDs: nimesulide, COX-2
inhibitor.

Patients with hypertension or other risk factor for heart attack/stroke: avoid selective COX-2 inhibitor; aspirin
may be used at the lowest dose.

Paediatric patients: only paracetamol, aspirin, ibuprofen and naproxen have been adequately evaluated in
children — should be preferred in them. Due to risk of Reye’s syndrome, aspirin should be avoided.

Fast acting drug is suitable for fever, headache and other short lasting pain, while longer acting drugs are
appropriate for chronic arthritic pain.

Pregnancy: paracetamol is the safest; low-dose aspirin is probably the second best.