Podgorski - Pharmacokinetics II

Question 1

How does decreased cardiac flow affect metabolism rate?

With what drugs is it more pronounced?

Answer 1

Decreased cardiac output will decrease hepatic blood flow and can affect drug metabolism rates. This is more pronounced with drugs showing large 1st pass effects since drug delivery via hepatic blood flow rather than enzymatic activity is rate-­‐limiting for clearance.

Question 2

What is notable about phenobarbital metabolism?

Answer 2

The ability of phenobarbital to increase its own P450 metabolism

Question 3

What can happen when the rate of metabolism changes with aminoglycosides?

Answer 3

A serious problem can occur with the aminoglycoside class of antibiotics. Amikacin, for example, produces nephrotoxicity when present at toxic levels. Since amikacin is eliminated by the kidney, toxic accumulation leads to a vicious cycle of kidney damage.

Question 4

What affects codeine metabolism?

Answer 4

Decreased CYP2D6 activity prevents analgesia by codeine

Question 5

Potent CYP2D6 inhibitors

Answer 5

fluoxetine, paroxetine, and quinidine – potent CYP2D6 inhibitors

Question 6

What reduces the antiplatelet effects of clopidogrel?

Answer 6

Decreased CYP2C19 activity reduces the antiplatelet effects of clopidogrel

Question 7

What are potent CYP2C19 inhibitors?

Answer 7

Chloramphenicol, fluvoxamine

Question 8

All drugs have two effects:

Answer 8

A therapeutic effect and a toxic effect.

Question 9

How is parkinson’s disease brought on in a patient taking fluoxetine?

Answer 9

Parkinson’s disease brought on by inhibition of CYP3A4 by cimetidine (Tagamet®) in a patient taking fluoxetine (Prozac® )

Question 10

What 2 medications can cause hypertension?

Answer 10

Hypertension in a patient taking an antihypertensive medication and self-­‐treating a cold with a vasoconstrictor decongestant such as pseudoephedrine (Sudafed®).

Question 11

What does phenytoin inhibit?

Answer 11

CYP2C9 metabolism of losartan to its active metabolite is inhibited by phenytoin, with potential loss of antihypertensive effect.

Question 12

What does grapefruit juice inhibit? What are the adverse effects to?

Answer 12

Grapefruit juice inhibits CYP3A

Adverse effects of cyclosporine and some HMG-­‐CoA reductase inhibitors

Question 13

What is CYP2D6 is markedly inhibited by? (3)

Answer 13

CYP2D6 is markedly inhibited by:

• quinidine
• a number of neuroleptic drugs (chlorpromazine and haloperidol)
• the SSRIs fluoxetine and paroxetine.

Question 14

How does rifampin affect oral contraceptives?

Answer 14

Rifampin (synthetic antibiotic) -­‐ CYP3A4 inducer – 20 to 40 fold reduction in oral contraceptive levels.

Question 15

How does Ritonavir affect HIV regimens?

Answer 15

Ritonavir is a very potent CYP3A4 inhibitor that is sometimes added to anti-­‐HIV regimens decreases clearance, and hence increases efficacy, of other anti-­‐HIV agents

Question 16

What have calcium channel blockers been co-administered with? Why?

Answer 16

Calcium channel blockers have been deliberately co-­‐administered with cyclosporine to reduce its clearance and thus its maintenance dosage and cost

Question 17

What combination increases risk of bleeding?

Answer 17

Increased risk of bleeding as a result of combining antiplatelet agents (glycoprotein IIb/IIIa inhibitors, aspirin, clopidogrel) and anticoagulants (warfarin, heparins)

Question 18

What increases risk of bleeding from peptic ulcer?

Answer 18

Risk of bleeding from peptic ulcer due to nonsteroidal anti-­‐inflammatory drugs (NSAIDs) in patients treated with warfarin

Question 19

Why shouldn’t you use NSAIDs with antihypertensives?

Answer 19

Elevated blood pressure in patients taking NSAIDs (Indomethacin, piroxicam) that antagonize the antihypertensive effects of -­‐adrenergic receptor blockers, diuretics, ACE inhibitors, and other drugs.

Question 20

How do nitrates interact with sildenafil?

Answer 20

Profound hypotension upon co-­‐administration of nitrates (such as nitroglycerin) with sildenafil.

Question 21

Synergism:

Answer 21

Synergism – relates to both, additive and supra-­‐additive effect.

Question 22

Potentiation:

Answer 22

One drug shows no appreciable effect alone but causes an increased response from the second drug

Question 23

Phase I Trials:

Answer 23

Phase I Trials: use matched groups of animals or humans to study responses at various dose levels to determine tolerated doses and toxic doses.

Question 24

Phase II and Phase III double-­‐blinded clinical trials:

Answer 24

Phase II and Phase III double-­‐blinded clinical trials measure effective and lethal doses (in animals) and efficacy (in humans). Responses are typically measured using a quantal response.

Question 25

A “quantal” response:

Answer 25

A “quantal” response is an “all or nothing”

response (e.g. relief of headache; sleep, etc.)

Question 26

Median effective dose (ED50)

Answer 26

The dose at which 50% of individuals exhibit the specified quantal effect.

Question 27

Median toxic dose (TD50)

Answer 27

The dose required to produce a particular toxic effect in 50% of animals.

Question 28

Median lethal dose (LD50)

Answer 28

The dose at which toxic effect is death of the animal.

Question 29

TI=

Answer 29

The Therapeutic Index (TI) is the ratio of LD50/ED50.

Question 30

Problems with TI:

Answer 30

1. Data must be collected in animals since we want to avoid killing human patients. In human studies, Toxic Dose rather than Lethal Dose data are used.
2. Applicability of animal data to humans is uncertain.
3. ED50 is not a realistic dose to use. ED99 would be better, but it is difficult if not impossible to determine this with manageable numbers of patients in a clinical trial.
4. Assumption is that the ED and LD curves are parallel. This is not always the case. There may be significant overlap of effect and toxicity even with
   parallel curves when ED99 doses are used.

Question 31

Certainty Safety Factor (like TI)

Answer 31

TD1/ED99

Greater the ratio – less toxic the drug

Question 32

Therapeutic window:

Answer 32

The range of plasma (or serum or blood) concentration that lies in the effective
range without going into the toxic range.

Question 33

When should blood samples be taken?

Answer 33

To minimize variations due to absorption, blood samples should be collected at
the trough just before the next dose is administered.

Question 34

When do you moniter blood levels?

Answer 34

In cases where there is a significant toxicity whose threshold level is close to the therapeutic level

In life-­‐threatening situations where optimal plasma levels must be maintained.

Remember: it is the free drug, not protein-bound, that interacts with the receptors to produce the pharmacological action.