1. Pharmacology of general anesthetics
بسم الله الرحمن الرحيم
Pharmacology of general anesthetics
Dr. Ashraf Arafat, MD
Assistant Professor
Department of Anesthesia, King Saud University

2. Intravenous Anesthetics

3. Benzodiazepines (BZ)
The 3 main drugs used in this category are diazepam, lorazepam and midazolam.
Primary uses:
Anti-anxiety agent pre-op for premedication.
Sedation
They are inadequate for use in surgical anesthesia “on their own”, and must therefore be used with another anesthetic agent (i.e. an inhalation anesthetic).

4. Advantages: Disadvantages: Relatively rapid onset Cause amnesia
Relatively little cardiovascular effect
Anti-convulsant
Disadvantages:
Not analgesic
Cause respiratory depression
Long-acting (diazepam or repeated inj. of midazolam)

5. b. midazolam (Dormicum)
a. diazepam (Valium) It is water-insoluble, so IV use requires a non-aqueous vehicle which can cause local irritation/pain
b. midazolam (Dormicum)
- water soluble, so drug of choice for IV administration
It has a more rapid onset and more rapid elimination than the other BZ’s.
The most potent amnestic
c. lorazepam (Ativan) water-insoluble, less potent amnestic than midazolam, but a more potent amnestic than diazepam.

6. Barbiturates
The 3 main drugs used in this category are thiopental, thiamylal, and methohexital.
Primary Use: Induction of anesthesia
Advantages:
Rapid onset ( sec)
Short duration (5 – 8 min) initial dose; redistributed from brain to muscle; prolonged on repeated injection

7. Disadvantages: Not analgesic Decrease blood pressure
Decrease respiratory rate and tidal volume or apnea.
Coughing, laryngospasm, bronchospasm.

8. Opioids The opioids most commonly used are fentanyl
Opioids produce moderate sedation and profound analgesia. They exert their effects by binding with opioid receptors in CNS ( 3 major opioid receptors μ (mu), κ (kappa), and δ (delta).
The opioids most commonly used are
fentanyl
sufentanil citrate (Sufenta)
alfentanil (Alfenta)
remifentanil (Ultiva)

9. Primary uses:
Analgesia
Advantages:
Profound analgesia
Relative cardiovascular stability
High potency, short duration (15-30 min.; Remifentanil; 5 min) except morphine
Reduces emergence phenomena
Reversible by opioid receptor antagonists
Disadvantages:
Nausea
Slow gastric emptying
Respiratory depression at high doses (assisted ventilation required).

10. Fentanyl
A potent synthetic opioid agonist with between times the analgesic potency of morphine.
Used to aid induction and maintenance of general anesthesia and to supplement regional and spinal anesthesia.
Ability to maintain cardiac stability.
Sufentanil citrate (Sufenta)
Rapid induction of analgesia (similar to Fentanyl)
Compared to fentanyl and sufentanil, alfentanil has a shorter duration of action because its high protein binding and relatively low lipid solubility .

11. Remifentanil (Ultiva)
Ultra short acting and rapidly cleared because it’s ester linkages are susceptible to hydrolysis by esterases in tissues and RBC’s.
Morphine
May produce hypotension and bronchoconstriction as a consequence of its histamine-releasing action.

12. Ketamine Primary uses: Advantages: Cardiovascular stimulant
A complete i.v. anesthetic -causes “dissociative anesthesia”
Primary uses:
Induction or anesthesia in at risk patients w/ cardiovascular problems
Sedation or general anesthesia in children
Advantages:
Cardiovascular stimulant
Bronchodilator
Profound analgesia and amnesia

13. Disadvantages:
Emergence reactions (not in children <15; adults >65)
Increases intracranial pressure
Suppresses respiration (less severe than other anesthetics)

14. Propofol (Diprivan) Primary uses: A sedative/hypnotic
Induction or maintenance of general anesthesia.
Sedating intubated, mechanically ventilated patients.
Advantages:
Rapid induction and recovery times even after repeated injections
Anti-emetic properties

15. Involuntary muscular movement Respiratory depression ,apnea
Disadvantages:
Pain on injection
Involuntary muscular movement
Respiratory depression ,apnea
bradycardia and hypotension.

16. Etomidate
Primary use: Induction in patients w/ cardiovascular problems
Advantages:
Rapid induction
Ultra-short acting (5 min)
No cardiovascular depression
Minimal respiratory depression
Disadvantages:
Pain on injection
Involuntary muscular movement
Nausea and vomiting
Hiccups
Not analgesic

17. Inhalational Anesthetics

18. Desflurane Advantages: Disadvantages:
Rapid onset and recovery of anesthesia (useful for outpatient procedures)
One of least metabolized to toxic byproducts
Disadvantages:
Low volatility, so requires a special vaporizer
Pungent and irritating to the airway (leading to more coughing, laryngospasm, so it is not as useful for extended surgical procedures)
High inspired gas concentrations lead to a significant increase in the patient’s BP & HR.

19. sevoflurane: Advantages:
Rapid onset and very rapid recovery of anesthesia (useful with children)
Not as pungent as desflurane (also useful with children)
Has good bronchodilating properties and is the agent of choice in patients with asthma, bronchitis, and COPD. It has little effect on the heart rate.

20. Disadvantages:
Carbon dioxide absorbents in anesthesia machines degrade sevoflurane to a fluorinated hydrocarbon, which is degraded by renal lyase enzymes to a thioacylhalide.
This compound has been observed to cause necrosis of the proximal tubule in rats.

21. Isoflurane: Advantages: Disadvantages:
It causes peripheral vasodilation and increased coronary blood flow (useful in patients with ischemic heart disease)
Disadvantages:
Moderate solubility, so recovery from anesthesia may be delayed
Isoflurane can make the heart “more sensitive” to circulating catecholamines (like epinephrine).

22. Halothane Used for induction in children (sweet pleasant odor);
Toxicity – cardiac arrhythmias,
“halothane hepatitis” (rare).

23. Nitrous Oxide
Not used alone (except where full anesthesia not necessary; e.g. dental procedures);
Causes more nausea/vomiting;
Contraindicated in patients with air filled cavities (e.g. air embolus, pneumothorax, etc) or vitamin B12 deficiency.

24. Neuromuscular blocking drugs

25. D. Neuromuscular blocking drugs
Used to perform tracheal intubation, facilitate ventilation and to provide optimal surgical operating conditions, for example during laparotomy.

26. Depolarizing(Succinycholine)
Structurally similar to acetylcholine and function as competitive inhibitors.
Very short duration of action
Metabolized very quickly by an enzyme called plasma cholinesterase.
A useful drug in situations where muscle relaxation is needed for only a short time such as to facilitate intubation.

27. Side effects : Fasciculations . Muscle pain Bradycardia.
Increases in ocular and gastric pressure,
Hyperkalemia .
Anaphylaxis.
Malignant hyperthermia: a dramatic increase in body temperature, acidosis, electrolyte imbalance and shock

28. Nondepolarizing blockers
They act by competitively blocking the binding of ACh to its receptors and inhibit muscular contraction.

29. Pancuronium bromide (Pavulon)
The first steroid NMBD in clinical use has a slow onset and long duration of action.
It does not cause histamine release
Weak sympathomimetic properties and causes tachycardia.
It is partly de-acylated in the liver to a metabolite with neuromuscular blocking properties, and partly excreted unchanged in the urine.
Its action is prolonged in renal and hepatic impairment.

30. Atracurium besylate (Tracrium)
Widely used and have an intermediate onset and duration of action .
It causes release of histamine but has no direct cardiovascular effects.
Metabolism is by Hofmann degradation and ester hydrolysis in the plasma, hence its duration of action is independent of renal and hepatic function.
A breakdown product of atracurium, laudanosine may accumulate due to very slow hepatic metabolism and upon crossing into the brain may cause seizures

31. Cisatracurium(Nimbex)
Isomer of atracurium
Less laudanosine formed .
Unlike atracurium it does not release histamine.
It is metabolised by Hofmann degradation and does not accumulate in renal failure.

32. Vecuronium bromide(Norcuron)
Vecuronium is structurally similar to pancuronium but has a slightly faster onset and shorter (intermediate) duration of action.
It does not release histamine or have any cardiovascular effects.
Metabolism in the liver occurs active metabolites before being excreted in the bile and urine.
Lack of dependence on good kidney function for elimination provide advantages over other neuromuscular blocking agents.

33. Rocuronium.
The most rapid onset of the clinically available non-depolarizing NMBDs. Intubating conditions can be achieved in seconds after an induction dose of 0.6 mg/Kg.
An intermediate duration of action .
Metabolised in the liver and excreted in the bile.
Minimal cardiovascular effects .
Does not release histamine,
Higher incidence of anaphylactic reactions

34. Anticholinesterases (Neostigmine)
(acetylcholinesterase inhibitors) are agents
that inhibit the action of the acetylcholinesterase enzyme at the neuromuscular
junction.
Clinical tests of adequate resolution of
neuromuscular block include the ability to lift the head from the bed for 5 seconds,
No role for anticholinesterases in reversing the effects of suxamethonium.

35. Side effects
Bradycardia, miosis, GI upset,
Nausea, bronchospasm, increased bronchial secretions, sweating and salivation.
For this reason an antimuscarinic such as glycopyrronium or atropine must be administered along with the anticholinesterase to minimise these effects.

36. Thank
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