4+5: Pharmacokinetics + Drug Metabolism

Question 1

What is pharmacokinetics?

Answer 1

The way of a drug through the body + what the body does to it

Question 2

What is the significance of pharmacokinetics?

Answer 2

It determines the does of the drug that is available to the tissue

Question 3

Which steps does a drug in the body undergo from Administration to removal?

Answer 3

A bsorbtion

D istribution

M etabolism

E xcretion

Question 4

What are the different routes a drug can be administered?

Answer 4

…

Question 5

Explain systemic and local administration

Answer 5

Systemic: entrire organism

Local: specific tissue of organism

Question 6

What is enternal and parenternal administration of drugs?

Answer 6

Enternal: via GI tract

Parenternal: without GI tract

Question 7

How do drugs move around in the body?

Answer 7

1. Bulk flow transfer
   
   • bloodstream, lymph
2. Diffustion transfer
   
   • molecule by moelcule over a short distance

Question 8

Why do drugs have to pass aqueous and lipid compartments?

Answer 8

Aqueous: to move around e.g. in bloodstream, lymph , extracellulra, intracellular fluid

Lipid: To reach their target (to cross membranes)

Question 9

Through which mechanisms do drugs cross cell membranes?

Answer 9

Question 10

What kind of molecules can cross via the following routes? Which one is the least important?

Answer 10

Diffusion: Fat soluble molecules (or very small)

Diffusion through aqueous pores: small watersolube molecules —> barly any drug –> least important

Active transport: the rest

Question 11

Which chemical feature do most drugs have in common? Why?

Answer 11

They are either weak acids or bases

–> can be ionised and unionised, depending on the environment (often therefore polar and non-polar)

Question 12

How does the Handerson Hasselbach equation look like to determine, how the ration between Ionised and unionised forms of bases/acids look like when pka and pH are known?

Answer 12

Question 13

Which factors influence drug distribution?

Answer 13

• Regional blood flow
• Extracellular binding (plasma protein)
• Capillary permeability
• Localisation in tissues
• Solibility (e.g. general anestetics are very fat soluble –> large proportion will be in fat even though only very little blood flow to it)

Question 14

How does regional blood flow influence distribution of drugs?

Answer 14

Highly metabolically active tissues have more blood flow + denser capillary networks (can change e.g. with exercise in skeletal muscle)

Question 15

How does extrcellular binding of drugs influence their distribution (passage of membranes)

Answer 15

Extracellular binding to plasma proteins

• determines availability e.g. if 95% is bound –> only 5% are able to cross membranes

Question 16

How does capillary permeability influence drug distribution?

Answer 16

• Fat soluble: can cross all membranes, into all tissues (even blood-brain barrier)
• Water soluble: often rely on transport emchanisms /pores –> will me distributed more unevenly (and more in capillaries with large gaps)

Question 17

How does localisation in tissues influence drug distribution?

Answer 17

Fat: 15% body weight, but 2% blood supply

Very fat soluble drugs – 75% partitioned in fat at equilibrium

–> disproportional high amounts of drugs in fat tissue (e.g. general anestetics)

Question 18

What is the aim of metabolism of a drug?

Why is that so?

Answer 18

To make the drug more water soluble for easier excretion

1. no diffusion back into bloodstream once in kidney nephron
2. more drug in bloodstream (less in tissue) hence more excretion

Question 19

Why are most drugs rather fat soluble?

Answer 19

To get into tissues (be able to cross cell membranes)

Question 20

What are the two phases in drug metabolism? What are their respective aims

Answer 20

• Phase 1: introduce(add/unmask) a reactive group to the drug (to increase polarity)
• Phae 2: add a water soluble conjugate to the reactive group

Question 21

What happens during phase one of drug metabolism?

Which reactions take place to let this happen?

Answer 21

Adding/unmasking a reactive group to the drug (increasing polarity)

• most reactions are oxidations (ofter start with hydroxylation)
• But also: redeuction, hydrolisis

Question 22

Which is the most common enzyme to oxidise drugs in phase 1 of drug metabolism?

What are its characteristics

Answer 22

Cytochrome P450

• 57 enzymes (each do different drugs)
• has low specifity

Question 23

Which characteristics can the metabolite have that is formed after Phase one of the drug metabolism?

Answer 23

Question 24

What is a prodrug?

Answer 24

A drug that is activated by Phase 1 of drug metabolism (not active at administration)

Question 25

What happens during phase 2 of drug metabolism? What are common reactions?

Answer 25

**Add a water soluble conjugate to the reactive group** there will be a conjugate and a conjugative agent Recations involve * Glucoronidation (most common) * Sulfation * Glutathionine conjugation Less common: * Acetylation * Methylation * Aminoacid conjugation

Question 26

What is the most common reaction in phase 2 of drug metabolism? What are its characteristics?

Answer 26

Glucoronidation low affinity/high capacity – more likely to occur at high drug dosages

Question 27

What is an example of a phase 2 drug high affinity low capacity metabolism?

Answer 27

Sulfation --\> More likely to occur at low drug dosages

Question 28

In which drug metabolism phase does glutathiodine conjugation take place? What does it require? What might be the problem with it?

Answer 28

Drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate --\> But electropiles are extremely reactive When overdosing --\> no glutathiodine available --\> electrophile might cause tissue damage

Question 29

Why is drug metabolism important? (What are the overall aims - not on a chemical level)

Answer 29

* The biological half-life of the chemical is decreased. * The duration of exposure is reduced. * Accumulation of the compound in the body is avoided. * Potency/duration of the biological activity of the chemical can be altered. * The pharmacology/ toxicology of the drug can be governed by its metabolism.

Question 30

Through which main organ systems are drugs excreted?

Answer 30

Mainly via the * kidney * liver

Question 31

How are drugs excreted in the kidney? Which factor influence each step?

Answer 31

1. **Glumerular filtration** * size dependant 2. **Active secretion** * dependant on available transporters + transport mechanisms 3. **Passive reabsorbtion** * urine pH (--\> determines ionisation) + drug characteristics, state of metabolism (fat soluble drugs just diffuse back into systemic circulation)

Question 32

How does drug excretion via the liver work?

Answer 32

1. Diffusion from sinusoids into hepativ tissue (via discontinuous capillaries/ diffusion through cells) 2. Active transport (or fat soluble --\> diffusion) into bile 3. Excretion via bile --\> Mint the Enterohepatic cycling! (reabsorbtion)

Question 33

How does the Enterohepatic cycling influence drug excretion?

Answer 33

Recycling of drugs can significantly increase half life and concentration of drugs!

Question 34

Other than the kidney and liver: Through which routes can drugs also be excreted?

Answer 34

* lungs * skin * gastrointestinal secretions * saliva * sweat * milk * genital secretions

Question 35

Define Bioavailability

Answer 35

Proportion of the administered drug that is available within the body to exert its pharmacological effect (dependant on absorbtion + distribution???)

Question 36

Define **Apparent volume distribution**

Answer 36

The volume in which a drug appears to be distributed - an indicator of the pattern of distribution

Question 37

Define **Biological half life**

Answer 37

Time taken for the concentration of drug (in blood/plasma) to fall to half its original value (linked to metabolism/excretion)

Question 38

Define **Clearance (**pharmacokinetics)

Answer 38

Blood (plasma) clearance is the **volume of blood** (plasma) **cleared** of a drug (i.e. from which the drug is completely removed) **in a unit time** (Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes)