Untitled Quiz

Pharmacokinetic (ADME) Properties

• The study of how the body affects a drug.
• It's essential for medicinal chemists to analyze a drug's absorption, distribution, metabolism, and excretion at an early stage.

Pharmacodynamic Properties

• The study of how a drug affects the body.
• Focuses on the physiological response, mechanism of drug action, and dose-response curve.

Physicochemical Properties and Drug Action

• Minor modifications in chemical structure can cause significant changes in activity.
• This is influenced by physical factors, such as:
  • Partition coefficient (log P)
  • Dissociation constant (PKa)
  • Steric factor
  • Solubility
  • Polymorphism

Physicochemical Properties and ADME

• The physicochemical properties of a drug impact its pharmacokinetic profile by affecting its ADME.

Routes of Administration

• Parentral route: IV, IA, intraspinal (direct access to blood, no absorption barrier)
  • IM, SC, IP: (Drugs need to pass through membranes)
• GIT route:
  • Drug dissolution in GIT fluids is crucial for absorption, and the dissolution rate is affected by:
    • Particle size: Smaller particles have larger surface areas, leading to faster dissolution (example: Spironolactone in micronized form).
    • pH of the medium: Weakly acidic drugs dissolve better in basic regions of the GIT, and vice versa.
      • Stomach pH (1- 3.5), duodenum (6 - 7), ileum (8)

Absorption

• Active transport or carrier-mediated:
  • Requires energy
  • Moves against concentration gradient
  • Requires similarity between the drug and the natural substrate.
• Passive diffusion:
  • Does not require energy
  • Moves according to concentration gradient
  • No specific substrate requirement.
• Convective absorption:
  • Small molecules (molecular radius < 4A°) pass through water-filled pores
  • Does not require energy

Passive Diffusion

• Rate of diffusion is proportional to the drug concentration on the other side of the membrane.
  • -dC / dt: rate of diffusion
  • C1: concentration of drug at the site of absorption
  • K: proportionality constant (depends on the membrane)

Rate of Passive Diffusion

• Depends on:
  • Area of the membrane
  • Thickness of the membrane
  • Partition coefficient of the drug

Dissociation Constant (pKa)

• Most drugs are either weak acids or bases.
• Henderson-Hasselbach Equation:
  • Weak acids:
    • pH = pKa + log ([salt] / [acid])
  • Weak bases:
    • pH = pKw - pKb + log ([base] / [salt])

Partition Coefficient (log P)

• The logarithmic ratio between the concentration of a compound in the organic phase and its concentration in the aqueous phase at equilibrium.
  • log P = log (CO / CW)
  • Example: Barbital (pKa = 7.8, log P = 0.7) and secobarbital (pKa = 7.9, log P = 23.3) - secobarbital has better absorption due to its higher log P value.

Sites of Loss

• Protein binding:
  • Drug-protein complex: Large, inactive form
  • Protein + free drug: Active form
  • Advantages:
    • Storage site: Slow release of free drug
    • Contributes to long duration of action (ME)
• Metabolism:
• Excretion:
• Storage sites:

Neutral Fat

• Partition into neutral fats depends on:
  • Log P
  • pKa

Excretion

• For a drug to be excreted in urine:
  • The drug must be polar to be soluble in urine.
  • Weakly acidic drugs are better excreted in alkaline urine and vice versa.