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Pharmacokinetics
what the body does to the drug
physicochemical properties of drug affecting biological action
Nature of Drugs
Physical Nature : solid, liquid, gas
Drug size : 100-1000 MW (mostly)
Drug-receptor Bonds : Strong covalent, Weak electrostatic, Hydrophobic
Drug shape : Chirality
Pharmacokinetic Concepts
Permeation – drug permeates through the barriers to reach its site of action
1. Passive diffusion
– uncharged molecules
– requires concentration gradient
2. Special carriers
– very large, charged, insoluble molecules
a. Active transport – requires energy, selective, saturable
b. Facilitated – selective, saturable
Weak Acid
pH = pKa + log [A-]/[AH] protonated is neutral
Weak Base
pH = pKa + log [B]/[BH+] unprotonated is neutral
pKa
– negative log of the modified equilibrium constant (Ka) for an acid-base reaction with water as the base or
proton acceptor
LIBERATION
Release of drug from its dosage form for it to be absorbed by the body
2 prerequisites for absorption:
• must be in aqueous form – to pass thru membrane
o “dissolution” – rate limiting step in absorption (exception: true solutions)
• must be in unionized form – nonpolar, ↑ lipophilicity
Factors:
• Formulations of salts for easy absorption Phenytoin Na
• Formulation of a prodrug Inactive in their native form but active in vivo
Importance:
Enhance absorption Enalapril Enalaprilat
Facilitate drug to reach target site Enzymes in blood (esterases) and GIT (amylase, lipase, etc.) that
may destroy or render it inactive
To alter solubility Chloramphenicol palmitate (-16C) – ↑lipophilicity
Facilitate formulation of dosage form Methylprednisolone – slightly water soluble
Methylpred acetate – water insol (oint, susp)
Methylpred Na succinate – water soluble (IV, sol)
ABSORPTION
Drug enters systemic circulation (Exemption: IV drugs)
IV > solution > suspension > capsule > tablet
Factors:
• Chemical Structure Nonpolar will be absorbed (Aminoglycosides – polar, ↓absorption)
• Particle size ↓size = ↑absorption
• Surface Area ↑surface area = ↑absorption
Amorphous > Crystalline | Anhydrous > Hydrous
• Crystalline form
Ex. Insulin Semilente Lente Ultralente
Form 100% amorphous 70% cryst., 30% amorphous 100% crystalline
Length Short Intermediate Long
Onset 5 - 15 mins 1 - 3 hrs 4 - 6 hrs
Duration 3 - 4 hrs 16 - 24 hrs >32 hrs
Examples Lispro, Aspart, Glulisine Glargine, Detemir
Bioavailability (f) : the fraction of administered drug that reaches the systemic circulation unchanged
Volume of Distribution
Vd=Amt of drug in the body /plasma drug conc
Factors:
• Blood Flow High: heart, lungs, liver, kidneys, brain | Low: bones, skin, fat
• Capillary Permeability Liver: high | BBB: low
• Protein Binding Reservoir, prolongs duration of action
Albumin – major drug binding protein (acidic drugs)
ɑ-acid glycoprotein – basic drug (imipramine, propranolol, lidocaine)
Problem: Displacement
- Ex. Warfarin (95%) and Phenylbutazone (98%) → bleeding
• Drug-receptor interactions
ᴥ Affinity – ability to bind
ᴥ Intrinsic binding – exert action after binding to receptor
ᴥ Agonist – has affinity and intrinsic activity
ᴥ Antagonist – affinity only
METABOLISM
o Converts drugs into polar, water-soluble products that are readily excretable
o Detoxification processes (but metabolism is not always a detoxification process)
o Factors influencing biotransformation:
a. Genetic factors
b. Environmental – concurrent drugs
c. Physiological – pediatric or geriatric
Prodrugs – compounds that are inactive in their native form, but are easily metabolized to the active agent
Examples: Primidone Phenobarbital (DOC for febrile seizures)
Phenacetin Paracetamol
CYP2C19
Isosterism
describes the selection of structural components, the steric electronic, and solubility characteristics of a drug
which make it interchangeable with drugs of the same pharmacologic class
Isosteres
compounds or group of atoms having the same number and arrangement of electrons
group of atoms that impart similar physical and chemical properties to a molecule, because of similarities in size,
electronegativity, or stereochemistry
compounds may be altered by isosteric replacements of atoms or groups, to develop analogues with select
biologic effects, or to act as antagonist to normal metabolites
Example: replacement of the hydroxyl group of folic acid by an amino group
Elimination
First-order elimination
Rate of elimination is proportionate to concentration
Concentration decreases exponentially
Zero-order elimination
Elimination is constant regardless of concentration
Concentration decreases in linear fashion
ex. Phenytoin, Aspirin
Clearance (renal, liver, systemic, other) = concentration / rate of elimination
Half-life (t ½) = (0.693 x Vd) / clearance
Route Onset Indication Example
Topical ointment 1 hour Local on skin, eye, ear Cream
Oral 30-60 min Safe & convenient Tablet, capsule
Intradermal 30-60 min Long & continuous Contraceptive
Vaginal suppositories 15-30 min Local effect Cream, foam
Rectal 15-30 min Local effect Laxative
Sublingual Few min Rapid effects Nitroglycerin
Buccal Few min Convenient Androgens
SC Few min GI sensitive drigs Insulin, epinephrine
IM Few min GI sensitive drugs Narcotic, antibiotic
Intrathecal Few min Spinal cord effects Anesthesia
Intravenous 1 min Rapid & high absorption IV fluid, antibiotic
Intraarterial 1 min Local internal organ Cancer drugs
Inhalation 1 min Local respirator Antiasthma