Mechanism of drug actions

[SH4:p19; RD5:Chp3]

 

TIER CCCC

 

Transport protein

Ion channels

Enzymes

Receptors

Chemical

Chelating

Colligative

Counterfeit

 

 

Pathways of drug actions

[RD5:p22]

Drugs invoke cellular changes by acting on proteins such as:

• Receptors
  * Transmembrane protein receptors --> ligand-gated, G-protein-coupled, kinase-linked
  * Cytoplasmic (intracellular) receptors
  * See [Receptors]
• Ion channels
• Enzyme system (stimulation or inhibition)
• Carrier/Transport proteins

 

Drugs also act by their other properties:

• Physicochemical
  * Chelation
  * pH changes
  * Colligative properties
• Pro-drug

Ion channels

[RD5:p23,p46]

• 4 main types of ion channels
  * Voltage-gated channels
  * Ligand-gated channels (See [Receptors])
  * Calcium release channels (IP3 and ryanodine receptors on the endoplasmic or sarcoplasmic reticulum)
  * Store-operated calcium channels
• Examples of drugs acting on ion channels
  * e.g. Local anaesthetics and phenytoin block voltage-gated Na+ channel
  * e.g. Dihydropyridines block voltage-gated Ca2+ channel (L type)
  * e.g. Sulfonylureas --> Act on ATP-sensitive K+ channel in pancreatic B-cells --> Increase insulin secretion

Enzyme systems

Examples include:

• Neostigmine inhibits acetylcholinesterase reversibly
• Aspirin inhibits cyclooxygenase irreversibly
• ACE inhibitors inhibits angiotensin-converting enzyme
• Immunosuppressive drugs (such as ciclosporin) binds to cytosolic proteins, immunophilins
  --> Immunophilins is an isomerase that catalyses cis-trans isomerisation of proline residues in proteins
  --> Inhibition of immunophilin leads to immunosuppression
• Fluorouracil act as "false substrates"
  --> Replaces uracil as an intermediate in purine biosynthesis
  --> But cannot be converted into thymidylate
  --> Blocking DNA synthesis and preventing cell division

NB:

• False substrates are drugs undergo chemical transformation to form an abnormal product that subverts the normal metabolic pathway
  * e.g. fluorouracil, amphetamine

Carriers

Examples include:

• Cardiac glycosides (such as digoxin) inhibits Na-K pump
• Loop diuretics inhibits Na/K/Cl co-transporter in loop of Henle
• Cocaine inhibits noradrenaline re-uptake
• Probenecid inhibits weak acid carriers in renal tubules

Other action pathways

Physicochemical

• Formation of strong bonds with metallic cations (chelating drugs)
  * e.g. activated charcoal
  * e.g. Dicobalt edetate chelates cyanide ions [???]
• Direct neutralisation of gastric acid
  * e.g. antacids

Colligative properties

[Colligative properties]

• Colligative properties are properties which depend on the osmolarity of a solution
• e.g. Mannitol

 

Prodrugs

• Levodopa --> Dopamine
• Parecoxib --> Valdecoxib