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CTP > Lecture 2: Clinical pharmacokinetics and pharmacodynamics > Flashcards

Lecture 2: Clinical pharmacokinetics and pharmacodynamics Flashcards

1
Q

What is elimination of a drug?

A

Metabolism and excretion

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2
Q

What is the importance of pharmacokinetics?

A
  • population and patient specific tailoring

- predicting toxicity, review all medications (the addition of one new agent could be significant)

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3
Q

What pharmacokinetic properties need to be considered by the MRHRA (medicines and healthcare products regulatory agency)?

A
  • bioavailability
  • half-life
  • drug elimination
  • inter-subject variability
  • drug-drug reactions
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4
Q

What factors influence some pharmacokinetic principles?

A
  • renal function
  • stress
  • pyrexia
  • alcohol/smoking
  • age/sex
  • exercise/diet/occupational exposure
  • infection
  • lactation
  • liver/CVS/GI function
  • pregnancy
  • immunisation
  • circadian and seasonal variations
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5
Q

What is bioavailability (F)?

A

Measure of drug absorption where it can be used

  • drug administered via IV has 100% bioavailability
  • for other routes it is referenced as a fraction of IV
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6
Q

What is bioavailability affected by?

A

Absorption

  • formulation (composition of the drug)
  • age (luminal changes)
  • food (with or without food)
  • vomiting/malabsorption
  • previous surgery (bariatric)

First pass metabolism
-metabolism before reaching systemic circulation (gut lumen/gut wall/liver/lungs)

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7
Q

What can plasma concentration-time graphs show us?

A

Y axis: plasma conc of drug
X axis: time

  • can show distinct phases e.g. absorption-rise in plasma conc, distribution- small pronounced drop, elimination- run off phase
  • if absorption is slow, the absorption and distribution phases are resolved separately
  • initial gradient of line- rate of absorption
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8
Q

What are modified release preparations (e.g. tablet capsule/type)?

A

Used to prevent rapid large fluctuations in plasma drug concentration due to rapid elimination

  • more gradual absorption (plasma conc becomes more dependant on rate of absorption rather than rate of elimination)
  • increases adherence
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9
Q

What is distribution of a drug?

A

We need adequate plasma levels to reach the target organs

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10
Q

What factors affect the distribution of a drug/theraputic agent?

A
  • blood flow/capillary structure
  • lipophilicity/hydrophilicity
  • protein binding (albumin: acidic drugs, causing sequestering/glycoproteins: basic drugs/globulins/lipoproteins)
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11
Q

How do you interpret a concentration time graph for distribution?

A

In plasma:

  • first drop is due to movement of drug in plasma to the well perfused tissue
  • second drop due to perfusion of poorly perfused tissues

Well perfused tissues:

  • first increase due to conc in well perfused tissue increasing from plasma
  • drop in initial conc in well perfused tissues as the poorly perfused tissues are increasing in conc

Poorly perfused tissues:
-slow increase due to conc increasing in these tissues from plasma (distribution catching up in poorly perfused tissues)

=reach equilibrium: matching conc with plasma conc, well-perfused tissues and poorly perfused tissues

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12
Q

What model does rate of distribution and equilibration follow?

A

Multiple compartment model

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13
Q

How does drug protein binding affect distribution of a drug?

A

Only a free drug will be able to afford response at target receptor site and/or be eliminated

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14
Q

Why is drug-protein binding clinically important?

A
  • high protein bound
  • narrow theraputic index (toxic)
  • low Vd
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15
Q

What could happend if a second drug was administered which binds to proteins more readily in comparison to the first drug?

A

Increased free first drug

  • second drug dsiplaces first drug from binding proteins
  • more free first drug to elicit a response
  • could potentially cause harm (important in pregnancy, renal failure, hypoalbuminaemia)
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16
Q

What is volume of distribution?

A

-we can’t measure whole body drug concentration (only plasma)
Vd= dose/plasma conc of drug
e.g. 100mg divided by plasma conc of 20 mg/L= 5L (Vd= 5L)

17
Q

How would you describe concentration?

A

Amount per volume

e.g. 100 mg/L

18
Q

When would you get a very high Vd?

A

If the drug is very lipophilic (drug sequestered by body tissue)

19
Q

What does the Vd tell you about the drug?

A
  • smaller apparent Vd: suggests drug is confined to plasma and ECF
  • larger apparent Vd: suggests drug is distributed throughout tissues
20
Q

What is the clinical relevance of Vd?

A

Dose= Vd x drug plasma conc (allows us to know what dose to give to achieve a particular plasma concentration)

21
Q

What affects metabolism of a drug?

A

Several sites of activity, liver having the most numerous and diverse metabolic enzymes

  • phase 1 and phase 2 enzymes/metabolism
  • size, lipophilicity, hydrophilicity, structural complexity affect route and mechanism
  • more hydrophilic species needed to enable elimination via the kidneys (lipophilic species would be reabsorbed and stay in the system-forms a cyclical nature where drug remains in body)
22
Q

What are CYPs?

A

Cytochrome P450
-majority of phase 1 catalysed reactions utilise the P450 system
-oxidation reactions are the most important
-found abundantly in SER in hepatocytes
(9 superfamilies of CYPs, 1-4 being really important in drug metabolism)

23
Q

What do CYP’s do to drugs?

A
  • active > inactive (most drugs)
  • inactive > active (perindopril > perindoprilat: ACEI)
  • active > active (codeine > morphine) (diazepam > oxazepam)

CYPs can be induced or inhibited by endogenous/exogenous compounds affecting phase 1 metabolism

24
Q

What can affect the activity of CYP’s?

A
  • age reduces activity
  • hepatic disease reduces activity
  • blood flow (increased/decreased activity depending on flow)
  • chronic alcohol increases activity
  • cigarette smoking increases activity
25
Q

What inhibits CYP3A4?

A

Grapefruit juice

-this CYP is important in the breakdown of statins

26
Q

Why is CYP2D6 important?

A

(absent in roughly 7% of Caucasians: likely to get drug toxicity)
(hyperactive in 30% of East Africans)
-substrates include beta blockers, some opioids, many SSRIs (selective serotonin reuptake inhibitors)
-inhibited by some other SSRI’s, other anti-arrhythmic agents, other antidepressants

27
Q

What are the clinical importance of CYPs?

A
  • important for drug prescribing and complexity of polypharmacy
  • over the counter/herbal preparations have influences on CYPs
  • other factors e.g. race/sex: women slower ethanol metabolisers/species: trials)
  • self induced metabolism (carbamazepine): induces CYP3A4
28
Q

What are some routes of drug excretion?

A

Fluids:
-primarily by the kidney (typically low molecular weight, polar metabolites)
-sweat/tears/genital secretions/saliva/breast milk
Solids:
-faeces/hair
Gases:
-volatile compounds

29
Q

How is renal excretion of drugs affected?

A
  • GFR and protein binding
  • competition for transporters e.g. organic anion transporters
  • lipid soluability (tubular reabsorption), pH, flow rate
30
Q

How are high molecular weight metabolites excreted?

A

Hepatic (conjugated with glucoronic acid)
-bile important route for conjugates (increases molecular weight)
-excreted in faeces or reabsorbed
(Abx drug interactions: can disrupt ability of drugs to be excreted due to disruption of flora e.g. warfarin/morphine, so dose may need adjusting)

31
Q

How do you recycle drugs?

A

Enterohepatic circulation

CTP (4 decks)

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