Basic principles of pharmacology

Stereochemistry

[Ref: SH4:p3]

Stereochemistry is the study of molecule structure in 3D.

Terminology

Chiral

Chiral describes a molecule that has a centre or centres of 3D asymetry.

Enantiomer

Enantiomer is a pair of molecules that exist in 2 forms that are mirror images of one another, but cannot be superimposed.

Effects on polarised light

When dissolved in solutions, they rotate polarised light

• Clockwise
  = dextrorotatory
  = d
  = [+]
  = (???) Rectus
• Anticlockwise
  = levorotatory
  = l
  = [-]
  = (???) Sinister

Properties of enantiomers

• Enantiomers have the same physical and chemical properties
• Biological effects are not the same
  --> Can even antagonise each other

Racemic mixture

Racemic mixtures are solutions where the two enantiomers are present in equal proportions
--> Actions cancel out
--> Does NOT rotate polarised light

Examples

Examples of racemic mixture

Common drugs administered as racemic mixture

• Thiopentone
• Methohexital
• Ketamine

Examples of enantiomers

Ketamine

S(+) enantiomer of ketamine is

• More potent
• Less likely to cause emergence delirium

Ropivacaine

...is S(-) enantiomer of a bupivacaine homolog

• Has less cardiac toxicity than the R(+) enantiomer

(???) (Is ropivacaine administered as a racemic mixture or not?) I think it is administered as S(-) --> Ref???

Levobupivacine

... is S(-) enantiomer of bupivacaine

• Has less cardiotoxicity than the R(+) enantiomer

Cisatracurium

... is one of the ten isomers of atracurium

• Less histamine-releasing potential

Inhalational agents

• Most inhalational agents are chiral (except for SEVO)
• Enantiomer-selective effects for inhalational agents are not as strong as it is for IV anaesthetics

Others

Dextrose - dextrorotatory

Describing drug response

[Ref: SH4:p5]

Special terms

Hyperreactivity

Hyperreactivity describes unusually low dose produce the expected pharmacological reponse

Hypersensitivity

Hypersenstivity is usually used to describe allergic reactions

Hyporeactive

Hyporeactive describes situation where an exceptionally large dose is required to produced the desired/expected pharamcologic effect

Tolerance

Tolerance is when hyporeactivity is acquired from chronic exposure to a drug

Tachyphylaxis

Tachyphylaxis is where tolerance develops within a few doses of a drug

e.g. nitrate, suxamethonium, ephedrine

Idiosyncrasy

... where unusual effect of a drug occurs in a small percentage of population (regardless of the dose of drug administered)

 

Mechanism of tolerance

1. Development of cellular tolerance

aka neuronal adaptation

• Most important of all mechanisms
• Responsible for tolerance to:
  * opoids
  * barbituates
  * alcohol

2. Enzyme induction

3. Depletion of neurotransmitter

• ... where there has been sustained stimulation

4. Formation of antibodies to the drug

• Immunity is involved