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What drugs undergo enterohepatal circulation?a/ tetracycline atibiotics

b/ morphine

What can you expect, if your patient is a heavy smoker of tobacco?Please, choose, only one correct answer.

1/ induction of biotransformation of some drugs

2/ decrease of drug metabolism

3/ it does not matter, nothing will happen

What can you expect after drinking grep juice with statins?

• a/ decrease of drug concentration

• b/ increase of statine concetration

• c/ nothing will happen

Majority of drugs that undergo biotransformation in liver by system cytochrome

P450 enzymes are metabolized by?

a/ 3A4

b/ 2D6

c/ 2E1

d/ 2C19

e/ 1A2

Practice general pharmacology III.yr.: med. students

Pharmacokinetic interactions at the level of biotransformation and elimination of drugs

Key words:

1. Elimination of drugs

2. Biotransformation

3. System of cytochrome P450

4. Pharmacokinetic drug interactions

Elimination of drugs = metabolism + elimination• Metabolism of drugs

(biotransformation)

increase of solubility in water and subsequently renal excretion in liver by microsomal enzymes

oxidases – cytochrom P450:

a/ induction of enzymes by St. Worth (tutsan,rose of sharon) rifampicin, carbamazepine or

b/ inhibition of enzymes during application of antimycotic drugs like ketokonazol, fluconazol, itraconazol or macrolide ATB,

or HIV protease inhibitors

• Excretion

1. renal

2. GIT

a/ mucosa

b/ gall – enterohepatal circulation3. pulmonary: inhalatory anesthetics

Where to find info about drug interactions? Several possibilities

I. SPC or PIL • 1/ SPC – point 4.5, in section 4 clinical data

II. Drug database

1/ AISLP

a/ comercially available CD with programmeb/ www.aislp.cz

2/ Micromedex:

http://pez.cuni.cz, micromedex, 3.LF

Where to find info about drug interactions?

III. Internet:

1/ www.uptodate.com2/ pubmed.com3/ www.drugs.com

IV. Books

1/ PDR: physician desk reference2/ Martindale : the complete drug reference

Pharmacokinet. interactions : other quiz questions or case study

• A/ simvastatin or lovastatin + Klacid SR (clarithromycin) = ?

• Demonstration:

1/ http://pez.cuni.cz,

2/ micromedex,

3/ 3.LF, micromedex,

4/ drug interactions

• B/ simvastatin or klaritromycin +grep juice?

• C/ sildenafil (Viagra) + grapefruit juice?

• D/ will it be OK to prescribe fluvastatin?

• E/ OK to prescribe another antibiotic instead of clarithromycin?

• Will you ask about smoking?

Quiz about other combinations• levonoregestrel (Postinor) ?+ other medicin. products?

• Tablets with extract of St. worth (Jarsin) + cyklosporin?

• Clarithromycine + solifenacine = ?• grep +sildenafil nebo vardenafil

• antihistamine rupatadine, or loratadine/desloratadine with grapefruit juice?

(contrariwise some other antihistamine drugs, like cetirizine, bilastine do not undergo biotransformation in liver)

• “toxicologic“ example:paracetamol + alcohol = ?

• Omeprazol+diazepam = • Omeprazol+citalopram

= ?

• NSAIDs +lithium = ?• Fluvoxamine+ enoxacine

=?

Genetic variability of PK

1/ azatioprin undergoes biotransform. by enzyme thiopurinmetyltransferase, if deficiency of this enzyme is present then it can be necessary to reduce dosis by 90% (the case of complete defic. of enzyme)

2/ genetic deficiency of CYP 2D6 leads in approximately 8% europeans to decrease of metabolizm of metoprolol, venlafaxine etc.

Interactions at the level of cyp P450 3A4

• inhibition of CYP 3A4

1/ macrolide antibiotics claritromycin, erytromycin

2/ antimycotic

ketokonazol, itrakonazol

3/ antivirotics inhibitors of HIV protease ritonavir/lopinavir

• induction CYP 3A4

1/ st. Worth extract (hypericum perforatum): CAVE can be present about 3 weeks after end of therapy

a/ teas, food suppl.

b/ medicinal product named Jarsin

2/ rifampicin

3/ carbamazepine (antiepileptic)

Intoxication by codeine

(morphine)62 yrs old patient used codein 25 mg 3 times daily, treatment with clarithromycine and voriconazole was started, leading to development of coma, respiratory depression, renal failure

showed: Ultrarapid Metabolizer CYP2D6 with increased ability of codeine biotransformation to morphine