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Drug absorption - Coggle Diagram
Drug absorption
Recap
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ADME
Absorption – process by which unchanged drug enters circulation (blood).
Distribution – dispersion of a drug among different compartments of body i.e. fluids & tissues of the body (some will remain in circulation).
Metabolism – transformation of a drug into daughter compounds i.e. metabolism (biotransformation).
Excretion – removal of drugs (parent drug)/metabolites from body.
Why is ADME important
Rule: ADME determines key properties of drug like speed of onset, duration, action and potential problems.
• Essential for safe use of treatment
• Important in designing reginmens
• Can be used to monitor treatment by doing a urine or blood test
• Used in the ER to monitor substance abuse
• A requirement to medicine licensing
BNF
Def: BNF – Books that give info on licensed medications including indications, cautions, dosage & side effects
Rule: Pharmacokinetics is most common reason for withdrawal of candidate drugs from development.
Example: Drug too poorly absorbed from oral dosage only absorbed well in IV and so not convenient for everyday usage
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Methods of absorption
Rules
Most medicines are absorbed via transcellular route using driving force passive diffusion where drug conc. gradient drives its movement through barriers
Some drug use facilitated diffusion (use carrier proteins)
Little drugs use active transport
Passive diffusion
Rule: Fick’s law
Equation: Rate of diffusion = surface area x conc difference x permeability
Rule: Permeability of a membrane to a particular chemical is determined by molecular size, lipid solubility & presence of charged/ionizable groups.
pH and charge
Rules:
Charge can be modified to modify a drugs solubility
Most drugs are weak acids and bases and so can be ionized into neutral form to cross barrier
MOA:
Weak acid = proton donor -> will donate protons & become negatively charged (anion).
Weak base = proton acceptor -> will accept protons & become positively charged (cation).
Extent of ionisation
Def: acid-base dissociation constant of drug = how easily the drug will accept or donate a proton based on its chemical structure.
Rule:
If drugs ionized too much ↓ likely to move thru membranes.
Extent of ionization of the drug depends on pH of environment and acid base dissociation constant.
Examples:
AH (acidic drug) -> passes through membrane as neutral -> depending on acid-dissociation constant of drug and pH of environment on the other side -> ionizes donating a proton to alkaline env. -> becomes active
Henderson hasellbach
Equations:
• For acids: pH = pKa – log [non-ionised]/[ionised]
• For bases: pH = pkA + log [non-ionised]/[ionised]
Def: pKa = acid-base dissociation constant.
Rules:
pH = pKa -> half of drug is ionized
Acidic drugs = the more acidic the environment the more unionized the drug will be.
Basic drugs = the more basic the environment the more unionized the drug will be.
Aspirin
Aspirin absorption
Def: aspirin = weak acid taken in oral form
Rule:
• A drug may be ionized (or not) in different compartments of body
• Acidic drugs are absorbed efficiently from stomach.
• Basic drugs are absorbed less efficiently (will bind protons & become positively charged).
MOA:
Aspirin must move through gastric mucosa. t/f can use Henderson-hasselbach equation to estimate absorption
Aspirin pKa = 3.5. t/f at pH 3.5 aspirin is 50% is ionised & 50% is unionised -> t/f 99.7% of the aspirin in stomach is uncharged, b/c of highly acidic environment.
Only small amount of aspirin is ionised form -> aspirin is effectively absorbed in the stomach.
Once in circulation pH is higher (neutral) -> aspirin donates protons protons & majority of aspirin is ionized (99.9%)
Alkaline urine trap & enhances the excretion of aspirin drugs. So ion trapping can be a blessing if you want to try excrete a drug.
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Lipinski rules
Def:
Lipinski rules = rules to optimize absorption and ADME properties of a drug
Partition coefficient (PC)= how well drug dissolves in lipid
Rules: an orally active drug should have no more than one violation of the following:
Molecular weight of less than 500.
No more than 5 H- bond donors.
No more than 10 H-bond acceptors
*The Lipinski rules are not to do with the pharmacodynamics & often contradict the desirable structures for activating or inhibiting receptors e.g. ADME optimization may minimize desirable properties (H bonding) for receptor binding..