Pharmacokinetics

Question 1

What are the 4 main processes when a drug enters the body?

Answer 1

Absorption
Distribution
Metabolism
Elimination

Question 2

What are the two methods of drug administration and 3 or their subtypes

Answer 2

Enteral (into GI): sublingual, rectal, oral

Parenteral (anywhere else): intravenous. intramuscular, subcutaneous

Question 3

What type of drugs can be absorbed by passive diffusion

Answer 3

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

Question 4

Other than passive diffusion, describe two other methods of drug absrbtion

Answer 4

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+

Question 5

What does pKa tell you?

Answer 5

The pH when 50% of the drug in an equilibrium is ionised

Question 6

How long is the transit time through the intestines?

Answer 6

4-5 hrs

Question 7

What factors can affect drug absorption?

Answer 7

• 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

Question 8

Define bioavailability (F)

Answer 8

The relative amount of a drug that reaches a specific body compartment (usually systemic circulation)

Question 9

What is the bioavailability of a drug by oral administration (Foral) dependant on ? How can it be measured?

Answer 9

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)

Question 10

How is the drug distributed around the body?

Answer 10

Bulk flow in blood then diffusion into interstitial fluid & cells

Question 11

What factors affect drug volume of distribution (Vd)?

Answer 11

• 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).

Question 12

Define volume of distribution (Vd)

Answer 12

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.

Question 13

How is Volume of distribution calculated? State its units

Answer 13

Vd= drug dose (same as amount in body if IV)/ concentration of drug in plasma at time 0
L (assumes 70kg) or L/Kg

Question 14

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?

Answer 14

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.

Question 15

What can cause a change in Vd for the same drug?

Answer 15

Pregnancy, age (significantly younger or older), renal failure, changes in body weight and composition (more or less fat), anaesthetics, hypo/eralbunimea

Question 16

What is the overall aim of first pass metabolism?

Answer 16

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

Question 17

Describe the enzymes which carry out phase 1 metabolism and their action.

Answer 17

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

Question 18

Give an example of a prodrug which is activated by phase 1 metabolism, its cytochrome and the polymorphic effects of this cytochrome

Answer 18

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

Question 19

Describe location, specificity, rate of kinetics and mode of action of the phase 2 metabolising enzymes

Answer 19

Cytosolic, generalists (like cyp450s) but more rapid

They catalyse sulphation, methylation, N- acetylation…

Question 20

What factors affect drug metabolism

Answer 20

Age (varibale in kids, reduced in elderly), sex (females metabolise alcohol slower), General health (hepatic failure), gentic factors can affect CYP450 isozyme expression

Question 21

Describe the induction of a cyp450 isozyme. (mechanism, time period, effects)

Answer 21

• 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

Question 22

Give an example of a CYP450 inducer

Answer 22

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

Question 23

Describe method and speed of CYP450 inhibition

Answer 23

Much faster

Can be competitive or non competative

Question 24

Give an example of a CYP450 inhibitor

Answer 24

Grapefruit juice
CYP34A inhibited
Can lead to fainting due to low BP, if pt is on verapimil (treats high BP)

Question 25

State the main and other routes of drug elimination

Answer 25

Main: Kidneys
Other: bile, lungs, breast milk, sweat, ters, genital secretions, saliva

Question 26

What are the 3 processes of renal elimination

Answer 26

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

Question 27

What is clearance? What 2 factors is it made up from? and state its usual units

Answer 27

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

Question 28

What is a drugs half life, how is it calculated?

Answer 28

Amount of time needed to decrease a drugs plasma concentration by 50%
(0/7x Vd)/ clearance

Question 29

What is first order (linear) kinetics?

Answer 29

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]

Question 30

What is zero order kinetics?

Answer 30

When the elimination processes become saturated- elimination cannot go any faster due to all enzymes, OATs/ OCTs working at maximum capacity

Question 31

What does zero order kinetics look like on a graph of [drug] against time?

Answer 31

linear from top right down to bottom left

Question 32

What will a graph of rate of elimination (Y) vs [drug] (x) look like?

Answer 32

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

Question 33

What is relevance of zero order kinetics to drug doses?

Answer 33

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

Question 34

Give examples of drugs that exhibit zero order kinetics at therapeutic dose

Answer 34

MDMA, Alcohol, Prozac

Question 35

How many paracetamols do you have to have before you saturate phase 1 and 2 metabolism and hit zero order kinetics?

Answer 35

> 20, but after this it can be fatal

Question 36

Can you calculate half life of drug w/ zero order kinetics? What clinical consequences does this have?

Answer 36

Nope

Cannot predict how long drug stays in system and at what level

Question 37

What factors can affect clearance of a drug?

Answer 37

HRH
Heart- affects blood flow to organs of elimination
Renal- affecting renal elimination
Hepatic- affects hepatic elimination (into bile)