Pharmacokinetics Flashcards
(37 cards)
What are the 4 main processes when a drug enters the body?
Absorption
Distribution
Metabolism
Elimination
What are the two methods of drug administration and 3 or their subtypes
Enteral (into GI): sublingual, rectal, oral
Parenteral (anywhere else): intravenous. intramuscular, subcutaneous
What type of drugs can be absorbed by passive diffusion
Small, lipophilic (neutral) molecules- the proportion of a weak acid/base that is neutral can be determined by its pKa, the envrionmental pH and the henderson- hasselbalch equation
Other than passive diffusion, describe two other methods of drug absrbtion
Facilitated diffusion using solute carrier proteins. This is for drugs with a net charge. They’re transported with organic anion/ cation transporters (OAT/ OCTs), especially found in GI, liver and kidney.
Secondary active transporters. Eg prozac with Na+ and penicillin with H+
What does pKa tell you?
The pH when 50% of the drug in an equilibrium is ionised
How long is the transit time through the intestines?
4-5 hrs
What factors can affect drug absorption?
- GI length (smaller in kids)
- pKa of drug (less protonated= more diffusion)
- Expression of SLC proteins
- Blood flow to GI (increased post meal)
- GI mobility (slow post meal, fast if diarrhoea
- foods pH (can destroy drugs)
- Bacteria/ enzymes in gut (can denature some drugs)
- Speed of first pass metabolism
Define bioavailability (F)
The relative amount of a drug that reaches a specific body compartment (usually systemic circulation)
What is the bioavailability of a drug by oral administration (Foral) dependant on ? How can it be measured?
Absorption and first pass metabolism
Integrate to get area under curve for oral administration route to find total amount reaching systemic circulation and divide this by area under curve by intravenous route (total drug dose)
How is the drug distributed around the body?
Bulk flow in blood then diffusion into interstitial fluid & cells
What factors affect drug volume of distribution (Vd)?
- Capillary permeability (in brain there are tight junctions)
- Drug lipophilicity (more lipophillic means more easily able to leave capillary and more attracted to fatty tissue)
- Drug hydrophilicity (means the drug is dependant on SLC presence, capillary permeability, pKa of drug and pH of environment
- Degree of drug biniding to plasma and tissue protein (more binding to albumin, globulins ect mean they distribute to other compartments more slowly).
Define volume of distribution (Vd)
The volume that would be necessary to contain the total amount of administered drug in the same concentration that it is found in the blood plasma- basically indicates the ability for a drug to penetrate from the blood plasma to the interstitial and intercellular compartments.
How is Volume of distribution calculated? State its units
Vd= drug dose (same as amount in body if IV)/ concentration of drug in plasma at time 0
L (assumes 70kg) or L/Kg
How does volume of distribution work/ what does it assume? If a drug distributes quickly (lipophillic, doesn’t bind to plasma proteins), will Vd be low or high?
It assumes the drug distributes fully throughout body compartments instantly. Therefor if it moved out of plasma well there would be little conc on blood plasma and so Vd would increase.
What can cause a change in Vd for the same drug?
Pregnancy, age (significantly younger or older), renal failure, changes in body weight and composition (more or less fat), anaesthetics, hypo/eralbunimea
What is the overall aim of first pass metabolism?
To increase the ionic charge on the drug to inactivate it and enhance renal excretion- because lipophillic drugs will diffuse back into plasma at renal tubules
Describe the enzymes which carry out phase 1 metabolism and their action.
Done by cytochrome p450 enzymes
3 super famillies- cyp1, 2 or 3
Many isoenzymes- family coded for by suffix (CYP3A4)
Located on external face of ER
An isozyme may metabolise specific drugs optimally but do show overlap
They reduce, oxidise, dealkylation, hydrolyse
Give an example of a prodrug which is activated by phase 1 metabolism, its cytochrome and the polymorphic effects of this cytochrome
Codeine converted to morphine which has 200x greater affinity to u- opioid receptor
CYP2D6- poor, normal/high and ultrarapid metabolisers leading to lack of pain relief/ or ADR/ morphine intoxication
Describe location, specificity, rate of kinetics and mode of action of the phase 2 metabolising enzymes
Cytosolic, generalists (like cyp450s) but more rapid
They catalyse sulphation, methylation, N- acetylation…
What factors affect drug metabolism
Age (varibale in kids, reduced in elderly), sex (females metabolise alcohol slower), General health (hepatic failure), gentic factors can affect CYP450 isozyme expression
Describe the induction of a cyp450 isozyme. (mechanism, time period, effects)
- Specific drugs can induce specific CYP450 isozymes
- Induction mechanisms include increase transcription and translation or slower degradation
- Causes plasma levels of the drug/ metabolite to fall (too low is dangerous)
- Takes 1-2 weeks
Give an example of a CYP450 inducer
CBZ is anti-epileptic which is metabolised by and induces same CYP34A, thus lowering its own levels and affecting its ability to control epilepsy. It also can causes faster metabolism of other drugs such as warfarin and birth control pills
Describe method and speed of CYP450 inhibition
Much faster
Can be competitive or non competative
Give an example of a CYP450 inhibitor
Grapefruit juice
CYP34A inhibited
Can lead to fainting due to low BP, if pt is on verapimil (treats high BP)
