General Anaesthetics Dr Ibanda H This document discusses general anaesthetics including: 1. The uses of premedication such as sedation, pain reduction and muscle relaxation. 2. Factors to consider when selecting anaesthetics including the procedure, side effects, pharmacokinetics and patient factors. 3. The goals of anaesthesia including surgical anaesthesia while minimizing adverse effects and maintaining homeostasis. 4. The stages of anaesthesia and examples of inhalation, intravenous and other anaesthetics along with their characteristics, uses and considerations.

1. General Anaesthetics
Dr Ibanda H

2. What is the use of premedication in Anaesthesia
• To Control sedation
• To Reduce postoperative pain
• Muscle relaxation
• To Provide amnesia
• To decrease anxiety
• To get appropriate/desirable CVS and autonomic nervous system effect response to anaesthesia (e.g. reduce
GIT secretion)
• To reduce the dosage of anaesthetic used. E.g. if we use muscle relaxants.
Some of the drugs used as premedication
• Benzodiazepine
• Atropine
• Skeletal muscle relaxants

3. Factors to consider when selecting an
anaesthetic
• The procedure to be done (e.g., duration of the surgery)
• Side effects of the drugs
• Pharmacokinetics of the drug
• Patient’s age and other associated medical condition
• Any other drugs the patient is using.
• Availability of other pre-medications (e.g. muscle relaxants, sedatives)

4. What are the goals of anaesthesia
• To achieve surgical anaesthesia.
• Minimizing the adverse effects of anaesthetic drugs and the
procedure of anaesthesia
Procedures in anaesthesia may include intubation, IV catheter insertion, and Spinal needle insertion
all these are associated with risks which should be reduced
• Sustaining physiologic homeostasis during surgical procedures that
may involve major blood loss, tissue ischemia, reperfusion of ischemic
tissue, fluid shifts, exposure to a cold environment, and impaired
coagulation.
• Improving post operative outcomes

5. Stages of Anaesthesia
• Stage I: Stage of analgesia
• Stage II: stage of delirium
• Stage III: surgical anaesthesia
• Stage IV: medullary paralysis

6. Inhalation Anaesthetics

7. Volatile anaesthetics: These are in
a liquid form at room temperature
• Ether
• Halothane
• Enflurane
• Isoflurane
• Desflurane
• Sevoflurane
• Gaseous Anaesthetics: these are
gases at room temperature.
Example include:
• Nitrous oxide
• Xenon

8. Factors that facilitate uptake of gaseous anaesthetics
• Partial pressure of the anaesthetic gas in the inspired mixture of gases
• Pulmonary ventilation
• Alveolar exchange
• Solubility of the anaesthetic in blood
• Solubility of the anaesthetic in tissue
• Cardiac output
Elimination of inhalational Anaesthetics: when the patient is disconnected from the
supply of gaseous anaesthetics, gradients are reversed to enable exhalation of the
inspired gases. The factors that govern induction also govern recovery. A gas with quick
onset of action will also wear off quickly. Most GA are eliminated unchanged.
Metabolism is significantly for Halothane (20%).
There is a likelihood that more lipid soluble gases will wear off very slowly if they have
partitioned in fat and muscles.

9. • How do we measure potency a gaseous anaesthetic
Minimum alveolar concentration (MAC) : this minimum alveolar
concentration of a gas that will lead to nonresponse to a surgical
incision (surgical anaesthesia).

10. What are the characteristics of an ideal inhalation anaesthetic
To the patient
• It should be pleasant
• It should not cause nausea or vomiting
• Induction and recovery should be fast
• Should have few/no after effect
To the surgeon
• It should provide adequate analgesia
• It should provide immobility
• It should provide muscle relaxation
• It should not be flammable and non-explosive to allow use of cautery.
To anaesthetists/anaesthesiologists.
• It should have a wide margin of safety to enable titration
• It doesn’t affect liver, heart and lungs
• It’s very potent so that little of it is needed to achieve anaesthetic goals
• It should not affect oxygen delivery during induction, maintenance & recovery
• Should be cheap, stable and easy to store
• It should enable rapid adjustment of the depth of anaesthesia
• It should not react with the rubber tubing (for delivery) or the soda lime (used to remove H20
vapour from the gas)

11. Intravenous Anaesthetics
Ketamine, Propofol, Etomidate, Thiopental, Methohexital,
Dexmedetomidine

12. Etomidate
Mechanism of action:
At low concentrations, (R)-etomidate is a modulator at GABAA receptors
containing β2 and β3 subunits.
Whereas at higher concentrations, etomidate can elicit currents in the
absence of GABA and behaves as an allosteric agonist. Its binding
site is located in the transmembrane section of this receptor between
the alpha and beta subunits (α−β+). β3-containing GABAA receptors
are involved in the anaesthetic actions of etomidate, while the β2-
containing receptors are involved in some of the sedative and other
actions

13. Clinical uses of etomidate
• Rapid sequence induction/intubation to induce anaesthesia
• Conscious sedation
• Induction of anaesthesia
Advantages of using etomidate
• Less suppression of cardiorespiratory function
• No histamine release in response to etomidate
• It has an easy dosing profile
• Protection from myocardial and cerebral ischaemia.
• It’s the only anaesthetic that can reduce intracranial pressure and,
maintain arterial pressure, making it suitable in patient with traumatic
brain injury.

14. Read about: etomidate speech and memory test (eSAM).
Disadvantages of using etomidate
• Adrenal suppression
• Seizure activity

15. ketamine
Chemistry: Ketamine is a phencyclidine derivative. It’s highly lipid-soluble
and partially water-soluble.
M/A: it is thought to inhibit NMDA receptors. Unlike most IV anaesthetics,
ketamine causes analgesia
PK: Ketamine has a rapid onset of action and has low protein binding.
After single IV bolus, its effect is terminated by redistribution to inactive
tissue sites. Metabolism of ketamine occurs in the liver. Cytp450 catalyses N-
demethylation of ketamine to an active metabolite, Norketamine. Excretion
of conjugated metabolites is via urine.

16. System effects of Ketamine
CNS:
 Dissociative anaesthesia.
 Ketamine increases cerebral blood flow due to cerebral vasodilation. That is why we don’t use Ketamine
when intracranial pressure is raised or when there is cerebral pathology
 Emergency reactions: Hallucination; out of body experience; vivid colourful dreams; and increased, and
distorted tactile, visual & auditory sensitivity. Fear and confusion too happen. Euphoria is the reason this
drug has been used for recreation (abuse).
NB: Emergency reactions are less prevalent and less severe in Children. Co-administration of a BZD reduces the
incidence and severity of the reaction and facilitates amnesia.
CVS: Ketamine is direct myocardial depressant but it causes a transient increase in systolic BP, HR, & CO. The
increase in CO, HR, & BP is due stimulation of the sympathetic nervous system. The increase HR, CO and BP
increases myocardial workload and oxygen demand, which may not be desired in some patients (e.g.
Hypertensive, and IHD). The increase in myocardial oxygen demand can be blunted by co-administering
ketamine with opioids, BZDs or Inhaled anaesthetics.
Respiratory system: ketamine doesn’t produce serious depression of respiration. After a single IV bolus, RS
response to hypercapnia remains normal, and blood gases remain stable. Increased salivation may affect
airway patency.
Ketamine causes bronchodilation, making it useful in patients with reactive airway disease &
Bronchoconstriction.

17. Clinical use of Ketamine
Advantages of using ketamine
 Analgesia
 Stimulation of sympathetic nervous system, its useful especially in patients
whose blood pressures are very low.
 Bronchodilation
 Minimal depression of respiratory system
 Ketamine can be given by multiple routes, e.g. oral, IV, IM, rectal and
epidural, making it very good in some emergency procedures.
Disadvantages of ketamine
 Increased secretions
 Psychotomimetic symptoms
 Increased cerebral blood flow may be undesired.

18. Use of ketamine
• Induction of anaesthesia
• Maintenance of anaesthesia
• Analgesia

19. Propofol
• Mechanism of action: the presumed M/A is through potentiation of
the chloride current mediated through the GABA receptor complex.
• PK:
Very lipid soluble, hence quick onset of action.
Metabolised in the liver to inactive, water soluble metabolites that are excreted in the
urine.
The drug has a significant extrahepatic metabolism(about 30%).
Recovery from Propofol is more complete, and likely all anaesthetics, redistribution from
the CNS to other tissues is key in recovery from anaesthesia. Awakening occurs in 8-10 min.
(read about kinetics of Propofol after IV bolus, 3 compartment model.

20. System effects of Propofol
CNS:
• it is hypnotic & not analgesic
• Involuntary movements, e.g. twitching, at induction
• Reduces cerebral blood flow and CMRO2 and reduces ICP
• It’s neuroprotective like thiopental
CVS
• vasodilation (arterial & venous) causes decrease in blood pressure especially in the old,
hypovolaemic, & after rapid injection
• No baroreflex response to reduce pressure: just increase in HR
• Can cause bradycardia and asystole even in healthy adults
Respiratory:
• Can cause apnoea
• Reduce tidal volume and Respiratory rate
• Reduced respiratory system response to hypoxia and hypercapnia
• Reduces upper airway reflexes (more than thiopental does)

21. Other effects of Propofol
• Better intubation conditions even if the drug is not neuromuscular blocker
• Metabolic acidosis
• Propofol infusion syndrome
The clinical features of Propofol infusion syndrome (PRIS) are acute refractory bradycardia
leading to asystole, in the presence of one or more of the following: metabolic acidosis
(base deficit > 10mmol/l, rhabdomyolysis, hyperlipidaemia, and enlarged or fatty liver(Kam
& Cardone 2007). This occurs if Propofol is used for more than 48hr at doses higher than
4mg/kg/hr.
Risk factors for PRIS include: young age, exogenous catecholamine use, CNS disease,
Respiratory system illness, glucocorticoid administration, inadequate Carbohydrate intake &
mitochondrial disease.
PRIS is rare, and it’s presumed to be a result of direct effect of Propofol on mitochondrial
respiratory chain, or effect of Propofol on fatty acid metabolism.
Treatment of PRIS is: Haemodialysis, and cardiorespiratory support.
• Propofol has an antiemetic activity; this is desirable.
• Pain at administration of Propofol: this can be managed by administering Propofol
with an opioid.
NB The effects of Propofol can be reduced by titration of the induction dose

22. Uses of Propofol
• Induction of anaesthesia
• Maintenance of anaesthesia
• Conscious sedation
• Sedation in ICU
• Short duration general anaesthesia, e.g. in emergency departments,
radiology departments e.t.c
• Treatment of postoperative nausea and vomiting (we use sub-
anaesthetic doses)

23. Dexmedetomidine
Mechanism of action:
Dexmedetomidine is a highly selective agonist at α2 receptors.
Activation of α2 receptors in the CNS is responsible for the effects of
dexmedetomidine. Dexmedetomidine activates α2 in spinal cord to give
analgesia and in sleep pathways (locus caeruleus) to cause hypnosis.
The sleep induced by dexmedetomidine is similar to physiological
sleep.
System effects
CNS: activates α2 receptor in endogenous sleep pathway. It reduces cerebral
blood flow without affecting ICP. There is potential for tolerance & dependence

24. Clinical use of dexmedetomidine
• Dexmedetomidine is used for short-term sedation of intubated and
ventilated patients in an ICU setting.
• It can also be used as an adjunct to general anaesthesia. Use of
dexmedetomidine as an adjunct in general anaesthesia reduces the dose
requirements for inhaled and injected anaesthetics
• It can be used for sedation in procedures like fiberoptic tracheal intubation
or regional anaesthesia
• Sedation and analgesia in the postoperative period: these are beneficial
effects of using dexmedetomidine as an adjunct to injected or inhaled
anaesthetics. We achieve analgesia and sedation without getting
respiratory depression (as is the case with opioids).

25. Barbiturates used in general anaesthesia
Methohexital, thiopental

26. METHOHEXITAL
Methohexital is Ultra-short-acting highly lipophilic barbiturate; it has a
faster onset of action and recovery time compared to thiopental, and
it’s twice as potent.
Mechanism of action: it’s a barbiturate. It binds to GABA receptors,
enhancing the inhibitory effects of GABA by prolonging duration of
opening of chloride channels.
PK: quick onset of action, 73% protein bound. Metabolism occurs in the
liver through demethylation and oxidation. Side-chain oxidation is the
most important biotransformation involved in termination of biologic
activity. Excretion occurs via the kidneys through glomerular filtration

27. Uses of Methohexital
• Induction of anaesthesia
• Induction of deep sedation
• Can be used as an adjunct to regional anaesthesia
• During Electroconvulsive therapy: this is because Methohexital lowers the
seizure threshold.
Adverse effects
The manifestations of an ultrashort-acting barbiturate in overdose include
central nervous system depression, respiratory depression, hypotension, loss
of peripheral vascular resistance, and muscular hyperactivity ranging from
twitching to convulsive-like movements. Other findings may include
convulsions and allergic reactions. Following massive exposure to any
barbiturate, pulmonary edema, circulatory collapse with loss of peripheral
vascular tone, and cardiac arrest may occur.
Its should used with caution in patients with respiratory diseases e.g. COPD,
pneumonia.

28. Benzodiazepines
Midazolam, Lorazepam

29. Mode of Action: Benzodiazepines bind to GABA receptors & increase
the inhibitory effect of GABA at GABA receptors by increasing the
frequency of opening of chloride channels. BZD effect can be reversed
by use the antidote Flumazenil.
PK: They are very lipid soluble, so, they enter CNS rapidly and act
rapidly before being redistributed to inactive tissues and subsequent
termination of drug effect. BZD have active metabolites.
System effects:
• CNS: Decrease CMRO2, cerebral blood flow. No effect on ICP. Anti-seizure.
• CVS: midazolam reduces BP more than diazepam. This reduction is more
pronounced in hypovolemic patients.
• Respiratory system: minimal suppression of respiration. RS response to co2.
but if given with opioid, respiratory suppression can be severe.
• Other effects: pain at injection, phlebitis,

30. Clinical uses of Benzodiazepines
• Part of preoperative medication
We get muscle relaxation, amnesia, reduction of emergency phenomenon due to
ketamine, sedation and anxiolysis if we use Benzodiazepines as part of premedication.
• Intravenous sedation
• To Suppress seizure activity
• To induce anaesthesia (rarely used)
N.B: Benzodiazepines have a synergistic effects with other drugs like opioids and Propofol. The
synergy can also translate into increased side effects e.g. respiratory depression if these drugs are
combined.

31. Opioid analgesics
Fentanyl, methadone, Morphine, meperidine

32. Uses opioid Analgesics
• Analgesia
• Combined with BZD to achieve general anaesthesia in patient with low
circulatory reserves
• Their effect can be reversed by use of antagonists like Naloxone, Naltrexone &
Nalmefene.
Adverse effect (disadvantages of opioid analgesics)
• Respiratory depression
• There is no amnesia even if high doses are used.
• Risk of addiction
• Chest wall and laryngeal rigidity which hampers mechanical ventilation
• Tolerance
(Students to look up PK, PD and examples of opioid analgesics).

33. References
Kam, P. C & Cardone, D. (2007). Propofol infusion syndrome.
Anaesthesia, 62(7), pp. 690-701.
Brunton, L., Parker, K. Blumenthal, D., & Buxton, I. (2008). Goodman &
Gilman’s manual of pharmacology and therapeutics. New York.
McGraw Hill.
Katzung, G. B., Masters, B. S, & Trevor, A. J. (2011). Basic & clinical
pharmacology. New York. McGraw Hill.