Molecular basis of drugs Flashcards
What are the pharmacokinetic properties of a drug?
Dissolution
Absorption
Distribution
Metabolism
Excretion
Which factors determine the toxicology of a drug?
distribution
metabolism
interaction with target proteins
interactions with other proteins
interactions with macromolecules
explain the four main types of interactions
ionic interactions are strong attractive forces between an anion and a cation. The strength of the bond depends on the solvent used. Polar solvents reduce the strength of the bond.
Hydrogen bonds are directional and are between a delta positive HBD and a delta negative HBA.
Van der Waals forces are either dipole-dipole interactions or London dispersion forces between neutral molecules. Dp-dp forces are between aligning dipoles in two opposite directions while Ldfs are between induced dps on adjacent atoms.
Pi-Pi interactions are either face- to face or edge to face. There can also be pi-cation interactions. Electron rich rings have stronger attraction.
The strongest type are covalent bonds and then in decreasing strength, ionic, hydrogen, pi-cation, pi-pi, dp-dp and Ldfs.
What is lipophilicity?
lipophilicity is the measure of the extent to which a compound has affinity for fat-like environments. The partition of lipohilicity is therefore P=[C organic] / [C aqueous] and value is given as logP. logP > 0 is lipophilic.
As lipophilicity increases it has a positive effect on potency and permeability a molecule. However, negativity effects include decrease in solubility, increase in metabolism , protein binding and toxicity.
LogD explains how ionised the solution is. For neutral compounds logD = logP. For ionised compounds logD <= logP
%ionised(acid) = 10^(pH-pKa)/ 1+ 10^(pH-pKa)
%ionised(base) = 1/ 1+ 10^(pH-pKa)
logDacid = logP + log (1/ 1+10^(pH-pKa)
logDbase = logP + log (1/ 1+10^(pka-pH)
logDacid = logP + pKa - pH (when difference between pH and pKa is greater than 1)
logDbase = logP - pKa + pH
(when difference between pH and pKa is greater than 1)
What are two ways to inhibit proteins?
first is competitive inhibition where more potent compound at higher concentration than the substrate moves the equilibrium towards enzyme- inhibitor complex.
second is irreversible inhibition inhibitor binds to the active site.
Both models modulate the amount of free enzyme availiable.
define area under the curve
measures total drug exposure
define cMax
maximum concentration of x
define Half life/ clearance
measures the rate at which a compound is extracted
define bioavailability
the percentage of dose that reached systemic circulation
define volume distribution
measures the extent of distribution from plasma to tissues
explain what is meant by a 100% bioavailable drug?
where all the compound reaches systemic circulation. For this to happen the drug must be completely released from the dosage form, be fully dissolved and stable in GI fluid, and be able to permeate into mesenteric circulation without being metabolised by first pass metabolism in the liver.
What is dissolution? What factors affect dissolution?
dissolution is when the concentration of drug formulated goes to drug aqueous or when concentration of drug solid goes to concentration of drug aqueous.
solution dosing, salt forms or amorphous form may be used to increase rate of dissolution. Using an enteric coating decreases rate of dissolution.
There are positive and negative factors that affect dissolution.
Negative factors include breaking lattice interactions, loss of entropy in solvent, breaking solvent-solvent interactions.
Positive factors include entropic gain from moving from solid to solution, interactions between solute and water.
what is the general solubility equation?
logS = 0.5-0.01(mp-25)-logP
explain absorption
during absorption only dissolved compound can permeate gut lining and enter blood. Passing of molecules between cells is called paracellular absorption while other compounds use active absorption mechanisms. Majority of compounds use passive diffusion through epithelial cell membranes.
Well absorbed compounds have 3-4 HBDs. They are also unionised molecules, hydrophilic enough to solubilise in the gut but lipophilic enough to pass through cell membrane. These factors increases a drugs Fabs (0 being poor, 1 being excellent)
Describe metabolism and clearance of a drug
metabolism primarily occurs in the liver. Phase I requires cytochrome P450 and is carried out in the liver. It can involve the reduction or hydrolysis of the drug, but is most commonly oxidation. The oxidation is catalysed by CYP450 and so there is a loss of electrons from the drug.
Phase II involves the conjugation of an ionised group- glutathione, methyl or acetyl groups- to the drug.
Clearance for phase I happens to by microsomes- mainly composed of endoplasmic reticulum and are obtained by centrifugation of liver cells.
Clearance for phase I and II can happen with fresh hepatocytes.
one of the ways to block metabolism is by introducing fluorine.
