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Z YEAR 2 Pharm > Pharmakinetics 2 > Flashcards

Pharmakinetics 2 Flashcards

1
Q

Do you want drugs to be lipid soluble for excretion? Why?

A
  • No
  • drug would be more effectively retained in the blood (drugs would not diffuse out of the blood into tissues) and more of the drug would be delivered to the various excretion sites
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2
Q

Do you want drugs to be lipid soluble for therapeutic effect? Why?

A

partially lipid soluble, so that they can easily access tissues to produce their effects

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3
Q

What does metabolism involve to help excretion?

A

conversion of drugs to metabolites that are as water soluble as possible and easier to excrete

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4
Q

What is the major metabolic tissue for. drug metabolism and enzyme?

A
  • liver

- cytochrome P450 enzymes

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5
Q

What are the two stages of drug metabolism?

A
  1. main aim is to introduce a reactive group to the drug

2. main aim is to add a conjugate to the reactive group

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6
Q

What do the two stages of drug metabolism aim to achieve?

A

decrease lipid solubility which then aids excretion and elimination

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7
Q

What is the aim of phase 1?

A

introduce reactive polar groups into their substrates

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8
Q

How can phase 1 reactions occur?

A
  1. oxidation
  2. reduction
  3. hydrolysis
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9
Q

What is the most common phase 1 metabolism?

A

oxidation

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10
Q

How do all oxidation reactions start?

A
  • a hydroxylation step utilising cytochrome P450 system

- aim is to incorporate oxygen into non-activated hydrocarbons

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11
Q

Which functional groups would likely be. incorporated to the parent drugs in phase 1?

A

-OH, -COOH, -SH, NH2

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12
Q

What may phase 1 reaction also unmask?

A

existing functional groups

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13
Q

What is the general rule of the end of phase 1 reactions?

A

end result of phase 1 metabolism is to produce metabolites with functional groups that serve as a point of attack for the conjugating systems of phase 2

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14
Q

What do phase 1 reaction usually produce?

A

pharmacologically active drug metabolites

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15
Q

What are pro-drugs?

A
  • parent drug has no activity of its own, and will only produce an effect once it has been metabolised to the respective metabolite
  • So metabolism is required for pharmacological effect
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16
Q

Can active metabolites be dangerous?

A
  • active metabolites can have negative unintended effects

- Liver damage as a result of paracetamol overdose, is due to a certain metabolite and NOT paracetamol itself.

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17
Q

What is the result of phase 2?

A
  1. Phase 1 adds the functional groups that are susceptible to conjugation in phase 2
  2. The attachment of a substituent group, and the resulting metabolite is nearly always inactive and far less lipid soluble than the phase 1 metabolite
18
Q

Why does phase 2 help?

A

facilitates excretion in the urine or bile

19
Q

What group are phase 1 enzymes predominately part of?

A

cytochrome p450 family

20
Q

What group are phase 2 enzymes predominately part of?

A

transferases to transfer the substituent group onto the phase 1 metabolite

21
Q

Why do drugs not reach the systemic circulation well?

A
  1. Orally administered drugs are predominantly absorbed from the small intestine and enter the hepatic portal blood supply
  2. First pass through the liver before they reach the systemic circulation.
  3. Drug can be heavily metabolised
  4. little active drug will reach the systemic circulation (although first pass metabolism is a prerequisite for activity of prodrugs).
22
Q

How do you ensure enough of the orally. administered drug reaches the circulation? What could be the problem with this?

A
  1. Administer a larger dose of drug to ensure enough drug reaches the systemic circulation
  2. extent of first pass metabolism varies amongst individuals, and therefore the amount of drug reaching the systemic circulation also varies
  3. drug effects and side effects are difficult to predict
23
Q

How can drugs be excreted?

A
  1. Lungs (the basis of the alcohol breath test is to measure alcohol excreted via the lungs)
  2. Breast milk (and therefore care needs to be taken that drugs excreted in milk do not affect the baby)
  3. kidney (in urine)
  4. liver (in bile).
24
Q

What are the 3 major routes for drug excretion via the kidney?

A
  1. Glomerular filtration
  2. Active tubule secretion (or reabsoprtion)
  3. Passive diffusion across tubular epithelium
25
Q

What does glomerular filtration depend on?

A
  • size
  • drugs with a molecular weight less than 20,000 have an additional route for excretion (glomerular filtration) compared with larger drugs – as a result, this should result in a quicker rate of excretion
26
Q

What does active secretion depend on?

A

available transporters

27
Q

What does passive reabsorption depend on?

A

urine pH and extent of drug metabolism

28
Q

Why is active tubular secretion. the most important?

A
  1. more drug is delivered to the proximal tubule than the glomerulus
  2. in proximal tubule capillary endothelial cells are two active transport carrier systems
29
Q

Why are the two active transport carrier systems good?

A
  • One very effective at transporting acidic drugs
  • One very effective at transporting basic drugs
  • Both are quite capable of transporting drugs against a concentration gradient
30
Q

What does passive diffusion lead to?

A

to reabsorption from the kidney tubule

31
Q

What happens if drugs are particularly soluble?

A

reabsorbed, passively diffusing across the tubule back into the blood

32
Q

What factors influence extent of reabsorption?

A
  1. Drug metabolism

2. Urine pH

33
Q

How does drug metabolism influence the extent of reabsorption?

A

phase 2 metabolites tend to be considerably more water soluble than the parent drug and are therefore less well reabsorbed

34
Q

How does urine pH influence the extent of reabsorption?

A
  • this can vary from 4.5-8
  • Based on the pH partition hypothesis mentioned previously, acidic drugs will be better reabsorbed at lower pH and basic drugs will be better reabsorbed at higher pH.
35
Q

If drug A is a weak acid and urine pH increases for 6.5 to 8 will the effect. be prolonged or reduced?

A
  1. Drug A will become more ionised in higher pH (alkaline environment)
  2. So Drug A less lipid soluble
  3. Less of the drug will be reabsorbed in the kidney tubule,
  4. More will be excreted
    - The drug effect will be reduced due to this more effective excretion.
36
Q

How does the liver cells transport. some drugs from plasma to bile?

A

via transporters similar to those in the kidney.

37
Q

What is the liver to bile excretion system effective for?

A

removing phase 2 glucuronide metabolites

38
Q

What happens to the drugs taken to the bile?

A
  1. excreted into the intestines

2. eliminated in the faeces

39
Q

What does enterohepatic recycling do?

A

significantly prolong drug effect

40
Q

What is an example of enterohepatic recycling?

A
  1. Glucuronide metabolite is transported into the bile
  2. Metabolite is excreted into the small intestine, where it’s hydrolysed by gut bacteria releasing the glucuronide conjugate.
  3. Loss of the glucuronide conjugate increases the lipid solubility of the molecule.
  4. Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver
  5. The molecule returns to the liver where a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body
41
Q

What is the basis of pharma?

A
  • More lipid soluble easier to cross membranes and. if ionised then less lipid soluble
  • If lipid soluble stays in body if water soluble excreted.

Z YEAR 2 Pharm (9 decks)

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