3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.1. Pharmacology principles
                      3.1.3.1.2. Pharmacodynamics
 3.1.3.1.2.2. Mechanism of drug actions 

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