Pharmacokinetics Flashcards
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)
State the main and other routes of drug elimination
Main: Kidneys
Other: bile, lungs, breast milk, sweat, ters, genital secretions, saliva
What are the 3 processes of renal elimination
Glomerular filtration- unbound drug leaves blood to tubules
Proximal tubular secretion- OATs/ OCTs take ionised drugs out of blood to tubules by facilitated diffusion/ active transport. Lipophilic drugs reabsorbed into blood as water re- enters. If pH & pKa favourable, weak acid/ bases reenter.
Distal tubular reabsorption- some lipophillic drugs can be reabsorbed and some are reabsorbed by OAT/OCTs
What is clearance? What 2 factors is it made up from? and state its usual units
Rate of elimination of a drug from your body- the amount of blood plasma cleared per unit time
Clearance= hepatic clearance + renal clearance
ml/min
What is a drugs half life, how is it calculated?
Amount of time needed to decrease a drugs plasma concentration by 50%
(0/7x Vd)/ clearance
What is first order (linear) kinetics?
Where the rate of clearance depends solely on the concentration of the drug (high conc= lots of clearance)
Clearance graph is linear when log[drug]
What is zero order kinetics?
When the elimination processes become saturated- elimination cannot go any faster due to all enzymes, OATs/ OCTs working at maximum capacity
What does zero order kinetics look like on a graph of [drug] against time?
linear from top right down to bottom left
What will a graph of rate of elimination (Y) vs [drug] (x) look like?
Increase then plateau (hyperbolic)
Because at start more elimination processes (enzymes ect) than drug so incease drug= increase rate of elimination- first order kinetics
Then elimination processes become saturated, and increasing [drug] will not increase elimination- zero order kinetics
What is relevance of zero order kinetics to drug doses?
Some drugs will exhibit zero order kinetics at or near therapeutic dose because you wanna give enough drug for sustained and therapeutic effect.
But since elimination rate wont increase when you increase dose past saturation level, a small increase in dose will lead to a large increase in plasma conc of drug and so you’re more likely to get toxicity/ ADR- smaller therapeutic window
Give examples of drugs that exhibit zero order kinetics at therapeutic dose
MDMA, Alcohol, Prozac
How many paracetamols do you have to have before you saturate phase 1 and 2 metabolism and hit zero order kinetics?
> 20, but after this it can be fatal
Can you calculate half life of drug w/ zero order kinetics? What clinical consequences does this have?
Nope
Cannot predict how long drug stays in system and at what level
What factors can affect clearance of a drug?
HRH
Heart- affects blood flow to organs of elimination
Renal- affecting renal elimination
Hepatic- affects hepatic elimination (into bile)
