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Pharmacology > Drug elimination 2 (L7) > Flashcards

Drug elimination 2 (L7) Flashcards

1
Q

what is elimination?

A

metabolism + excretion = elimination

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2
Q

what are the major systems concerned with elimination?

A
  • kidneys
  • hepato-billiary system
  • lungs
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3
Q

what is metabolism of drugs?

A

when drugs are made more water soluble prior to elimination

enzymatic modification of drug

2 sequential phases: I and II

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4
Q

phase I metabolism reactions usually consist of what?

A
  • oxidation
  • reduction
  • hydrolysis
  • cytochrome P450s
  • functionalisation
  • decrease lipid solubility but may increase pharmacological or toxicological activity
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5
Q

what are cytochrome P450s?

A
  • large superfamily of heme cofactor containing enzymes
  • often called ‘CYPs’
  • metabolise thousands of endogenous and exogenous compounds
  • increase water solubility of drugs
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6
Q

location of CYPs

A

main locations: intestine and liver
• liver = hepatocytes
• intestine = enterocytes

small amounts in kidney, white blood cells and nasal passages

always in the endoplasmic reticulum of the cell

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7
Q

how can functionalisation affect a drug?

A
  • changes the metabolite
  • will bind in a different way
  • different stereochemistry
  • effects how well the drug binds
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8
Q

ethanol metabolism

A

ethanol isn’t metabolised by P450s but by enzyme expression

process predominantly catalysed by alcohol dehydrogenase but also some CYP2E1

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9
Q

phase II reactions

A

conjugation reactions
functional group serves as a point of attack for conjugation systems

large groups attached
• glucuronyl
• sulphate
• acetyl

further decreases lipid solubility and almost always results in pharmacologically inactive metabolites

conjugate excreted in urine or bile

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10
Q

glucuronidation

A

most common conjugation reaction

important for both endogenous and exogenous compounds

mediated by UDP-glucuronyl transferases - an enzyme system with broad substrate specificity

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11
Q

paracetamol metabolism

A

is metabolised and detoxified relatively quickly

mainly by conjugation with sulphate and glucuronic acid

only a minor proportion is metabolised by CYP450 to a toxic metabolite

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12
Q

what is the toxic intermediary in paracetamol metabolism?

A

NAPQI

  • the more active form of paracetamol
  • if too much is produced we see liver damage
  • can be detoxified to mercapturic acid by glutathione
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13
Q

what happens in paracetamol overdose?

A

saturates the normal metabolic processes

pathways of conjugation are saturated and co-factors are depleted so more paracetamol is metabolised via CYP450 to make the toxic metabolite

toxic metabolite reacts with liver proteins into of glutathione

tissue damage occurs leading to hepatic necrosis

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14
Q

internal factors affecting drug metabolism

A

endogenous factors
• genetics
• age
• disease

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15
Q

external factors affecting drug metabolism

A

exogenous factors
• drugs
• smoking/alcohol
• diet

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16
Q

genetic factors

A

a person is either a ‘fast’ or a ‘slow’ metaboliser

can have implications for therapeutic efficacy and/or toxicity of certain drugs

17
Q

fast metabolisers

A
  • normal enzyme activity
  • low plasma conc of parent drug
  • higher conc of metabolite
  • generally normal therapeutic response
18
Q

slow metabolisers

A
  • low enzyme activity
  • high plasma conc of parent drug
  • low conc of metabolite
  • may lead to exaggerated therapeutic response at normal doses
19
Q

how does age affect metabolism?

A

individuals at extremes of age are affected

neonates (premature)
elderly

20
Q

drug metabolism in neonates

A

low CYP and conjugating activity

express metabolising enzymes in different ways - lack of enzymes

lack of use of morphine in labour - babies cannot metabolise it so causes respiratory issues
• baby goes blue

21
Q

drug metabolism in the elderly

A

CYP activity declines with age

more variability of half-life of many drugs
• issues for drug development

22
Q

chemical exposure on a daily basis

A
  • pharmaceuticals
  • cosmetics
  • food additives
  • industrial chemicals
  • pesticides
  • smoking
  • alcohol

these compounds either induce or inhibit drug metabolising enzymes

23
Q

what happens when drug metabolising enzymes are induced?

A

increased synthesis of enzymes (phase I and II)

results in increased metabolism of inducing agent and other drugs

smoking and ethanol are both inducers

24
Q

implications of induction

A

decreased drug effectiveness on chronic exposure

need to increase drug dose

may be issues when inducer is withdrawn from regime

25
Q

how is paracetamol metabolism effecting by ethanol consumption?

A

alcohol increases amount of CYP2E1 which increases amount of NAPQI

increases liver damage

happens when overdose is involved with alcohol consumption

26
Q

what happens when drug metabolising drugs are inhibited?

A

reduced rate of metabolism and increased pharmacological effect

inhibition of the CYO system is caused by many drugs
• a component of grapefruit juice inhibits CYP3A4 so inhibits metabolism of CYP3A4 substrates (terfenadine and nifedipine)

27
Q

3 major processes in renal excretion

A

glomerular filtration

tubular reabsorption

tubular secretion

28
Q

what happens to water soluble drugs?

A

excrete unchanged through the kidneys

29
Q

what happens to lipid soluble drugs?

A
  • filtered in the glomeruli
  • reabsorbed in the distal portion of nephron
  • metabolised to more polar compounds
  • excreted in urine
30
Q

extent of tubular reabsorption depends on…

A

drug lipid solubility (pKa)

pH of tubular fluid

31
Q

what happens if tubular fluid becomes more alkaline?

A

acidic drugs ionise and becomes less lipid soluble

reabsorption diminishes

elimination occurs

32
Q

what is pH portioning?

A

impacts upon the rate at which drugs permeate membranes and distribution of drug between aqueous compartments

weak acids accumulate in compartments if relatively high pH, whereas weak bases tend to do the opposite

33
Q

where are weak bases ionised best?

A

at acid pH

drug gets ionised and can’t be reabsorbed

34
Q

where are weak acids best ionised?

A

at alkaline pH

Pharmacology (24 decks)

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