Ahmed E (Phases of drug action) Flashcards
Drug action
Successful drug = activity + ADME + safety
ADME- reach site of action in good concentration to exert its biological activity.
ADME/T
Absorption
Distribution
Metabolism
Excretion (Elimination)
Toxicity
Drug journey
Solid drug –(dissolution)-> Drug in solution –(membrane transfer)-> Absorbed drug –(liver extraction)-> systemic circulation –(distribution)-> body tissues –(excretion)-> Outside body
Three phases of drug action
Pharmaceutical phase- for an orally administered drug, this includes the disintegration of a pill in the GIT, the release of the drug, and its dissolution.
Pharmacokinetic phase- ADME
Pharmacodynamic phase- involves the mechanism by which a drug interacts with its molecular target and the resulting pharmacological effect.
Physiochemical properties and phases of drug action- pharmaceutical phase
Process = drug dissolution- depends on the pH of the medium. Weakly acidic drugs are better dissolved in the alkaline regions of the GIT and vice versa.
Physiochemical property
- Ionisation
- Lipophilicity and hydrophilicity
Physiochemical properties and phases of drug action- pharmacokinetic phase
Process = Absorption- drug passage through GIT membrane to circulation. Types of absorption- passive/active diffusion, facilitated/carrier mediated.
Physiochemical property:
- Ionisation
- Lipophilicity
- Size and shape
- Drug should be unionised and lipophilic to be able to dissolve in the lipophilic cell membrane.
Process = Distribution- once in the blood drugs are simultaneously distributed throughout the body.
Physiochemical property:
- Ionisation
- Lipophilicity
- Size and shape (if compound is too small it can pass through the junctions)
- Plasma protein binding- depends on the ionisation and the lipophilicity of the drug. Longer release until dose is completely secreted. Competes with other drugs at plasma binding site
- Blood Bran Barrier- drug with high lipophilicity can pass through the BBB to the brain and this can be toxic.
- Adipose tissue- highly lipophilic drugs distributed rapidly to the adipose tissue. Stored initially in adipose tissue and released gradually.
Process = Metabolism- main site of metabolism is liver (and main site of detoxification of drugs). Drugs pass through liver first- called first pass metabolism. Higher lipophilicity = faster metabolism of drug.
Physiochemical property:
- Lipophilicity
Process = Excretion- compounds with suitable size pass the glomerular membranes and that are soluble in water at the Turin pH are expected to be excreted in the urine. Lipophilic compounds are usually excreted in bile.
Physiochemical property:
- Size- small compounds pass through membrane
- Solubility- need to be soluble in urine
Physiochemical properties and phases of drug action- pharmacodynamic phase
Process = Drug binding site interaction- through the different type of binding interactions.
Physiochemical property:
- Ionisation (electrostatic, ionic and H-bond interactions)
- Lipophilicity (hydrophobic interactions)
- Size and shape (VDW and repulsive interacion)
Physiochemical properties
Hydrophobicity/lipophilicity
Ionisation (electronic properties)
Size and shape (steric properties)
They are dependant on the chemical structure of the drug and any change in the structure will lead to a change in the physiochemical properties and subsequently on the behaviour of the drug in the different phases of drug action and so its biological activity.
Hydrophobicity
The partition coefficient (P)
- The parameter used to measure hydrophobicity of a drug
- P = conc of drug in octanol/ conc of drug in aqueous solution
- Hydrophobic compounds dissolve into octane layer and have a high P value whereas hydrophilic compounds dissolve into aqueous layer and have a low P value
- Vary substituents on the lead compound will produce a series of analogues having different P values and biological activity
- Hydrophobicity is expressed as logP
- Drugs must be hydrophobic enough to move through membrane and hydrophilic enough to be absorbed in GI fluid
Correlation between hydrophobicity and biological acitivity
Biological activity increases up to a certain logP.
If logP is too high
- The drug may become so hydrophobic that it is poorly soluble in the aqueous phase (GIT)
- It may be ‘trapped’ in fat depots and never reach the intended site
- Hydrophobic drugs are more susceptible to metabolism and elimination
There are relatively few drugs where activity is related to logP alone (e.g. general anaesthetics).
Drugs which are to be targeted for the CNS should have a logP value of approx. 2.
Drugs which are designed to act somewhere else in the body should have logP values significantly different from 2 in order to avoid CNS side effects.
In some drugs the hydrophobicity has only a slight contribution in their biological activity (e.g. anti-malarial drugs)
Ionisation (electronic properties)
Dissociation constant Ka (measures the extent of ionisation at a certain pH).
Weak acid:
Low pKa (the lower the pKa the stronger the acid).
%ionisation = 100/1+10^pKa-pH
Exist in the stomach (pH = 1-2) mostly in unionised form.
Weak base:
High pKA (the higher the pKa the stronger the base).
%ionisation = 100/1+10^pH-pKa
Exist in the small intestine (pH = 6-8) mostly in unionised form.
Shape and size (steric properties)
Molecular volume - measures the steric extent.
Determines transport characteristics of molecules, such as intestinal absorption or BBB penetration.
Molar refractivity (MR)- measure of the volume occupied by an atom or a group of atoms.
Higher molar refractivity = bigger compound size
