Drug Absorption Flashcards
What is the difference between pharmacodynamics and pharmacokinetics?
Pharmacodynamics is the effect that drugs have on the body.
Pharmacokinetics is the study of the way in which drugs move through the body during ADME. Before a drug can begin to exert any effect on the body it has to be absorbed into the body systems.
What is ADME and why is it important?
ADME stands for Absorption, Distribution, Metabolism and Excretion.
They are key factors in determining the speed of onset of a drug’s effects, their duration of action and the potential for problems in special cases.
What is ADME used for?
- it’s essential for the safe and intelligent use of medicines by all doctors, ie. it’s essential for treatment
- designing dosing regimens
- monitoring treatment compliance
- substance of abuse monitoring
- medicine licensing requirement
Define drug absorption.
It is the process by which unchanged drugs get from the site of delivery to the circulation.
Medicines need to be absorbed unless they are given directly into the circulation.
The choice of the delivery route in drugs is a compromise. List some factors that it compromises between.
- speed of onset
- convenience (iv or oral?)
- bioavailability (proportion of administered drug reaching the systematic circulation, 100% for iv-administered drugs)
- side effects, specificity of action
How do drugs get through cellular barriers during absorption?
Absorption requires drugs to cross biological barriers (layers of cells with semi-permeable, lipophilic membranes).
Most absorption occurs through the cells (transcellular), some occurs between the cells (paracellular). Most drugs are absorbed paracellularly.
What are the three ways in which absorption can occur by?
- active transport through cells (very few medicines)
- facilitated diffusion through the cells (few medicines)
- passive diffusion (most medicines)
What does Fick’s Law state?
Fick’s Law essentially states that the rate of diffusion of a gas across a permeable membrane is determined by the chemical nature of the membrane itself, the surface area of the membrane, the partial pressure gradient of the gas across the membrane, and the thickness of the membrane.
This can be illustrated by the Fick’s Law equation:
rate of diffusion = surface area x concentration difference x permeability
What does permeability depend on?
- molecular size
- lipid solubility
- presence of uncharged/ionisable groups
The last two factors are key determinants.
Are drugs ionisable? Expand.
Most drugs are weak acids or bases and are thus ionisable.
A weak acidic drug is a proton donor, while a weak basic drug is a proton acceptor.
The extent of ionisation depends on the pH of the environment and the acid-base dissociation constant of the drug.
Following up on drug ionisability, how does it affect the drug’s permeability to membranes?
To diffuse across cell membranes, medicines must be uncharged.
- non-ionisable, lipophilic drugs are absorbed most efficiently
- ionised (charged) drugs are absorbed least efficiently
Because most drugs are ionisable, they must change to their uncharged form to cross the membrane, then they may change back if necessary.
What is the use of the Henderson-Hasselbach equations?
The Henderson-Hasselbach equations predict the extent of ionisation.
FOR ACIDS:
pH = pKa - log[non-ionised]/[ionised]
FOR BASES:
pH = pKa + log[non-ionised]/[ionised]
How does the pH affect the ionisation of different drugs?
ACIDIC DRUGS: more of the drugs stay unionised as pH becomes more acidic/drops
BASIC DRUGS: more of the drugs stay unionised as pH becomes more basic/increases
What is ion trapping, and what does it have to do with the drug’s site of absorption?
Ion trapping is the concept of ions staying in a certain area due to them staying in their charged form, based on the environment they are in.
Acidic drugs are absorbed efficiently from the stomach (pH: 1-2) because when they pass the membrane into a relatively more basic environment (circulation, pH: 7.4), they will exist in their charged form, preventing them from being absorbed back, essentially ‘trapping’ them.
Basic drugs are absorbed less efficiently from the stomach, but are absorbed better from the intestine (pH: 6.6-7.5). This is due to the larger surface area and the fact that it’s slightly more alkaline.
What are the Lipinsky rules, and what do they state?
It is a rule-based approach to ADME optimisation.
An orally-active drug has no more than one violation of the following:
- molecular weight < 500
- no more than 5 H-bond donors
- no more than 10 H-bond acceptors
- log P < 5 (partition coefficient)
H bonds related to metabolism, regulates its sensitivity to certain enzymes, particularly Cytochrome P450.
