Pharmacokinetics and metabolism

Question 1

What is the basic route of the drug through the body?

Answer 1

Administration
ADME- absorption, distribution, metabolism then excretion
Is important because it will determine the dose each tissue receive- no overdose

Question 2

Give some exemples of drug administration methods. What 2 categories can they fall into?

Answer 2

eg: Inhalation, injection, ingestion, dermal, subcutaneous
2 categories- systemic or local administration
Depends where you want the drug to go
(systemic means want it to go to different area to administration)
Enteral vs parenteral (via GI or not)

Question 3

What 2 ways do drug molecules move in the body? What does that imply for the drug?

Answer 3

Bulk flow transfer (move with the fluid)-eg:blood
or
Diffusional transfer-molecule by molecule over short distance
The drug needs to be water soluble AND lipid soluble

Question 4

How do drugs cross lipid barriers?

Answer 4

Simple diffusion, through pores, active transport (with carrier protein) or pemocytosis ( membrane pinch intakes drug)
aqueous pores is least relevant-only if very small non lipid soluble
if lipid soluble-pass alone

Question 5

What are the main location for bulk flow abostion and diffusion flow?

Answer 5

Usually start with a diffusion (GI to blood/Lung to blood, etc)-passes wall OUT of GI, then another wall INTO blood
Once in blood, bulk flow
Then diffuses out of blood vessel
Then usually targets are outside of cell-no need to diffuse in cells

Question 6

What ionised state do drugs exist in?

Answer 6

Most drugs are weak acid or weak bases
They exist in a ionised (polar) and no ionised (non polar)
-Depends on pH, and affects water solubility

Question 7

How can the henderson Hasselbach equation help provide the ratio of ionised/unionised drug in the body?

Answer 7

pKa=pH+Log(AH/H) or BH/B
means 10^(pKa-pH)=AH/A or BH/B
Meanin as pKa doesnt change for drugs-then as pH in body change can know ratio

For acid- if pH

Question 8

What is the general relation between pKa, pH and ionised states of drugs?

Answer 8

For acid- if pH

Question 9

Why does the ionised state of drugs matter to absorption?

Answer 9

You get ion-trapping, where the pH causes drugs to localise
eg: aspirin-very unionised in stomach so diffuses easily, but as soon as reaches blood, mostly equal ratio so a lot just stays around

Question 10

What are the 4 main factors in distrubution of drugs?

Answer 10

Regional blood flow-the more blood to a tissue, the more drug-at rest, Liver, brain, kidney (and changes with exercise)
Extracellular binding (plasma protein binding)
Capillary permeability
Localisation in tissue

Question 11

Explain how plasma protein binding affect distribution of a drug

Answer 11

Well if a drug is plasma protein bound-cannot get it out
Need to adapt the dose to be sure enough gets out
eg: Warfarin is 90% protein bound-so need to be sure the 10% unbound is sufficient dose
It mostly affects acidic drugs
Also-drugs can interfere, and displace each other, releasing huge amounts

Question 12

Explain how plasma cappilary permeability affect distribution of a drug

Answer 12

Once it reaches tissue, how easy can it exit
if drug is very lipid soluble-then no issue
If Water soluble-need to escape in gaps between cell or need a mechanism to move to tissue
Depends on continuous, tight, fenestrated, discontinuous cappillary (brain is difficult to get out of blood)

Question 13

Explain how localisation in tissue affect distribution of a drug

Answer 13

Some drugs can be stuck in certain parts of the body-
eg: lipid soluble drugs get stuck within adipose tissue (up to 75% of the drugs that pass by it)-general aneathetics go to adipose a lot and release later-got to adapt the dose)

Question 14

What are the 2 major routes of drug excretion?

Answer 14

Kidney (urine) and Liver (bile)

Question 15

Explain how drugs are excreted by the kidney

Answer 15

20% of plasma is filtered by glomerulus-but only low MW drugs pass there
Active secretion with transporters-for basic acidic drugs in tubule
Lipid soluble drugs in the tubule can diffuse back into the blood (depends on urine pH and drug metabolism)

Question 16

Explain how drugs are excreted by the liver

Answer 16

Bile excretion.
Liver capillaries are discontinuous-drugs enter liver tissue easily, get metabolised. then active transport into bile duct-into GI-faeces

Question 17

What is the main issue with excreting drugs in the bile?

Answer 17

Enterohepatic recycling-
Gut bacteria can break down what the liver did to excrete the drug-then can either diffuse, or get take back in with the bile-and continues acting

Question 18

Define bioavailability, Volume of distribution, biological half-life and clearance

Answer 18

Proportion of administered drug that is available within body to exert its effect-oral drugs ~20%
Volume of distrib-volume in which drug appears to be distributed-indicates pattern of distrib eg: lipid can diffuse in more
Half-life-how long the drug stays in body (before being metabolised)
Clearance- how past the drug is cleared from system

Question 19

Why would you want a drug to be water soluble?

Answer 19

Water soluble-Easier to transfer and excrete, less tissue acess
Lipid soluble drugs can get to tissue and be therapeutic (bidirectional)
The main job of drug metabolism is to make lipid soluble drugs water soluble

Question 20

What is the main concept of drug metabolism, and what are the 2 main phases

Answer 20

Taking lipid soluble drugs and making metabolites-water soluble
Seperated in Phase 1 and 2
Phase 1- aim is to intoduce a reactive group on drug
2-add to functional group a big water soluble conjugate to get rid of the drug

Question 21

What are the 3 methods of Phase 1 metabolism

Answer 21

Drug-oxidised (electrophiles) or hydrolised/reduced (nucleophiles)
RedOx creates new functional groups
Hydrolysation unmasks
Then phase 2 adds on top of this

Question 22

Where does phase 1 metabolsim occur? and by what?

Answer 22

Mainly in liver by Cyt P450-57 subtypes that each work on different products (and people have different levels)

Question 23

Using the exemple of asipirin, explain phase 1 metabolism

Answer 23

Most common phase 1 meta is hydroxylation (adding OH)

In aspirin-remove COOH group for a H

Question 24

What are the different types of produce phase 1 metabolism can produce?

Answer 24

Inert metabolites
commonly-active metabolites
Inactive drug –phase1–> active drug (prodrugs)

Question 25

WHat is the base principles of Phase 2? Give a brief overviews of the 3 main methods

Answer 25

Adding a large side chain on the phase 1 metabolite
Electrophiles (natrually very reactive) take gluthathione
Nucleophiles can take either UDP-glucoroic acid, AcCOA and sulfation

Can also get methylation and amino acid conjugation

Question 26

WHat is the most common Phase 2 metabolism?

Answer 26

Glucoronidation-adding glucoronic acid
WHat happends to aspirin
Low affinity but high capacity-most aspirin goes out

Question 27

How does Phase 2 metabolism affect paractamol?

Answer 27

Paracetamol is sulfated (high affinity, low capacity)
But as paracetamol is increased, switched to glucoronidation (high capacity)
That accounts for most of it
But in high doses paracetamol can make an electrohiles (in phase 1)-leading to NAPQI (very toxic). fine with glutathione conjugation
But in overdose, use up glutathione stores and toxic NAPQI can destroy liver

Question 28

What are the consequences of drug metabolism on the drugs?

Answer 28

Reduction of the half life-duration of exposure is reduced, less accumulation, potency change
=>affects toxicity