Pharmacology, therapeutics + prescribing

Question 1

What is bioavailability?

Answer 1

• Proportion of the drug that reaches systemic circulation
  > Defined by area under a curve of a graph of plasma conc vs time

Question 2

What are the 3 routes of administration?

Answer 2

Enteral
* by way of the GI tract*
Parenteral
* systemic, not through the GI tract
Topical
* directly to site of action

Question 3

Drugs need to get from circulation to site of action what does this depend on?

Answer 3

Depends on perfusion of tissues and ability of drugs to cross membranes
* lipophilic drugs diffuse easily but are largely protein-bound
* hydrophilic drugs require facilitated or paracellular diffusion

Question 4

Define:
Unbound drug fraction in plasma
Unbound drug fraction in tissue

Answer 4

Question 5

What is volume of distribution?

Answer 5

> Fluid volume that would be required to the total amount of absorbed drug in the body at a concentration equivalent to that in
the plasma at steady state
- A high Vd means the drug is distributed widely, potentially into tissues and organs beyond the bloodstream. A low Vd means the drug remains primarily in the bloodstream.

Question 6

An analogy to help understand volume of distribution.

Answer 6

Vd is a concept used to describe how a drug is distributed in your body

Imagine you have a single pill of medicine, and you swallow it. The medicine starts to enter your bloodstream, which is like a transportation system that carries it throughout your body.

Now, the Vd is like a number that tells you how much space in your body the medicine is acting in. It helps you understand whether the medicine stays mostly in the bloodstream or if it goes into your tissues, organs, and cells.

Question 7

Metabolism of drugs involves what?

Answer 7

• Metabolism commonly converts toxic/pharmacologically active substance to inert product
  > Often via highly reactive intermediate
• LIVER
  (Sometimes prodrugs are metabolised to active products)

Question 8

How are hydrophilic and lipophilic drugs metabolised?

Answer 8

• Hydrophilic drugs may be excreted unchanged
• Lipophilic drugs must usually be metabolised to produce water- soluble products (bound to protein)
• allows more rapid filtration
• prevents excessive renal reabsorption

Question 9

What is first pass metabolism?

Answer 9

> Enterally administered drugs enter portal circulation
* first destination = liver
* hepatically metabolised drugs are extensively cleared before reaching systemic circulation

However via rectum there is small first-pass effect as only 1/3 of rectal drainage occurs via portal system .. 2/3 via middle/inferior rectal vein (systemic)

*affects bioavailability

Question 10

What is 2 step metabolism of drugs?

Answer 10

• Sequential biochemical transformations that a drug undergoes in the body to convert it into more water-soluble and easily excreted compounds.

Question 11

Summarise what happens in Phase 1 and phase 2 of 2 step metabolism of drugs.

Answer 11

Phase 1
* Phase 1 reactions convert drugs into reactive compounds, readily able to conjugate
(Products are often toxic + short lived)

Phase 2
* Phase 2 reactions conjugate reactive metabolites to large endogenous molecules to make them more water-soluble

Question 12

Explain what is happening in phase 1 reactions.

Answer 12

1- Biotransformation of drugs by introducing or masking functional groups
* Oxidation (most common)
> catalysed via cytochrome P450 in liver
* Reduction (in liver, less common)
* Hydrolysis (in plasma, less common)

Question 13

What are Cytochrome P450. What are the common 6?

Answer 13

• Enzymes found in Liver
• Haem-containing isoenzymes
• Microsomal mixed-function oxidase (MFO)

Question 14

What other enzymes are used in phase 1 reactions of metabolism?

Answer 14

• Monoamine oxidase
  > Breaks down biologically active amines, e.g. tyramine in diet
• Xanthine oxidase
  > Inactivates 6-mercaptopurine
• Alcohol dehydrogenase
  > Cytoplasmic enzyme breaks down alcohol
• Reductive and hydrolytic reactions

Question 15

What happens in phase 2 reactions of drug metabolism?

Answer 15

Large endogenous molecules can be added to parent drug compounds or metabolites to make the drug more water soluble and pharmacologically inactive (Conjugation reactions)

• Types of phase 2 reactions are:
• glucuronidation
• sulfation
• methylation
• acetylation
• glutathione conjugation * glycine conjugation

Question 16

2 step metabolism of paracetamol.
What happens if you have a toxic dose of paracetamol?

Answer 16

• Paracetamol > (oxidation) via Cytochrome P45 = form a reactive intermediate called N-acetyl-p-benzoquinone imine
• NAPQI is rapidly conjugated with glutathione. The reaction between NAPQI and glutathione forms a non-toxic and water-soluble compound called mercapturic acid.
• more NABQI
• depletes glutathione stores * fatal hepatotoxicity

Question 17

Why is drug elimination less efficient in the very and and young?

Answer 17

1- Renal excretion rate
* GFR is only about 20% of adult rate in neonates
* GFR declines with age
50 y = 25% loss
75 y = 50% loss

2- Expression of metabolising enzymes
* metabolic enzymes take 8 weeks to achieve adult levels

Question 18

How can genetics make a difference to how drugs are metabolised?
Isoniazid (antimycobacterial agent) as an example.

Answer 18

> metabolised by acetylation by acetyl-CoA & acetyltransferase
1- genetic polymorphism
* fast acetylators and slow acetylators
2- single recessive gene for
low hepatic acetyltransferase

Question 19

What are the 5 routes of drug elimination, specify the most common.

Answer 19

Question 20

Excretion is dependent on what 3 things?

Answer 20

– Filtration
* renal blood flow
* filtration pressure
* proportion free in solution (bound to protein not eliminated in glomerulus)
– Secretion (rapidly eliminated)
– Reabsorption (slowly eliminated)

Question 21

Elimination is the product of what?

Answer 21

• Metabolism and excretion

Question 22

What is clearance?

Answer 22

• Volume of plasma apparently cleared of drug in a unit time

> Clearance is dependent on rate at which parent drug is metabolised and/or excreted
accumulation of metabolites inhibits metabolism
* slow excretion of metabolites
= slower metabolism

Question 23

How do you get elimination constant? (k)

Answer 23

Half life (time taken for plasma conc to fall by 50%) if plotted on logarithmic scale ( -1 x gradient of straight line = elimination constant)

Question 24

A 52-year-old man volunteers for a phase-1 trial of of a potential new drug for treatment of rheumatoid arthritis. A single dose of 20 μg is administered by intravenous injection and blood samples are collected at intervals for measurement of plasma drug concentration.

• What may be calculated directly from the gradient of the graph?

Answer 24

• Elimination constant
• You can directly calculate the elimination constant (k) from the gradient (slope) of the logarithmic plasma drug concentration vs. time graph during the elimination phase.

Question 25

• How would you calculate half life if you know K?

Answer 25

• t½ = 0.693 / k

Question 26

What do we mean by repeated doses?

Answer 26

• Giving repeated doses helps maintain these therapeutic levels over time.
• We want a steady state concentration.
  > Giving a higher initial dose then lower dose every 12 hours at the half life to achieve this.