drug interactions pharmacokinetic Phase

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I/- DRUGS INTERACTIONS :

DEFINITION :

Drug interactions are modifications of the pharmacodynamic and / or clinically significant pharmacokinetic

observed in vivo, expected effects of a drug when co-administered with another drug, food, alcohol or tobacco. These interactions can be beneficial or harmful.

clinically significant, if intesité and / or duration of pharmacological variations it causes :

  • Are sufficient to alter the benefit / risk to the patient.
  • Require dosage adjustment.

SOUGHT THE INTERACTIONS :

  • Increase the benefit / risk (combination of two drugs with my same therapeutic indication and the various side effects.
  • Antagonize a toxic effect : antidote.
  • Decrease the cost of treatment.
  • Decrease taking frequency.

TYPE D’INTERACTIONS MEDICAMENTEUSES :

1/- pharmaceutical interaction : Physicochemical interaction between two active ingredients or between an AP and an excipient, observed on the solutions mix in the same syringe.

2/- pharmacokinetic interaction : A drug will affect the pharmacokinetics of another drug resulting in a variation of the drug blood levels.

3/- Interaction pharmacodynamique : A drug will alter the pharmacodynamics of another drug without changing the plasma concentration of the first drug.

CONSEQUENCES OF DRUG INTERACTION :

Synergy : the sum of the effects of both drugs is equal to the effects of both drugs taken alone.

potentiation : the sum of the effects of the two drugs is greater than the simple addition.

L & rsquo; antagonism : l & rsquo; & rsquo effect; a drug is reduced or eliminated during the & rsquo; administration of the second drug.

II/- DRUG INTERACTIONS Pharmacokinetic PHASE :

1/- DEFINITON :

Changing the pharmacological response caused by a change in the plasma of one of the two drug concentrations.

Occur at all stages of the fate of the drug in the body :

  • Absorption
  • Distribution
  • Metabolism
  • Elimination

2/- INTERACTIONS DURING THE STAGE OF ENTRY :

Are observed during the use of oral. They can result in a variation in the absorption rate and or the amount absorbed from which altered bioavailability

2.1/- Mechanisms for modifying the absorption of a drug by another :

2.1.1/- Change in diffusible form of the drug : The mechanisms are especially likely physicochemical.

2.1.1.1/- Variation of the ionization of a drug by altering the ph gastro intestinal :

A medicament which causes a rise in gastric pH may reduce the absorption of weak acidic drugs.

↑??→ ↓??????????→ ↓???????????????é→ ↓????→??is????????is ??is??????????

Exp : antiulcer (omeprazole), antisecretaoire acid (ranitidine).

2.1.1.2/- Creating a physical barrier gastrointestinal :

Digestive dressings represent an actual physical barrier lining the gastric lumen and part of the duodenum, preventing the absorption of the associated drug. Exp : (aluminum hydroxide).

↓??????????→ ↓???????????????é→??is????????is ??is??????????

Note : Observe a period of two hours between the intake of a gastric dressing and another oral form.

2.1.1.3/- Solubilizing a diffusible compound in a non-absorbable liquid :

Association of fat-soluble drugs (vit Adek) with mineral oil used as a laxative decreases absorption

2.1.1.4/- complexing not resolved :

  • Tetracyclines and calcium salts or iron form non-resorbed insoluble compounds.
  • Fluoroquinolones and calcium Sels.
  • calcium and iron salts.

Note : Always respect a period of two hours.

2.1.2/- Changing the gastrointestinal transit – intestinal :

2.1.2.1/- gastric emptying :

A drug that accelerates gastric emptying as the antiemetic metoclopramide such increase drug contact time with the intestinal mucosa increased absorption associated drugs.

↑??????????→ ↑???????????????é→ ?????? ?? ???????is

2.1.2.2/-intestinal peristalsis :

  • A drug slows the intestinal transit as diarrheal antis like loperamide increases the drug's contact time with intestinal mucosa increasing the absorption associated drugs.
  • Drugs that accelerate intestinal transit as laxatives reduce the absorption of the other particular drug has those enteric slows.

3/- INTERACTIONS DURING THE STAGE DISTRIBUTION :

↑ ????? ????? → ↑ ???????is

↓ ????? ????? → ↓ ???????is

Drug Risk
oral anticoagulants + aspirin haemorrhage
oral anticoagulants + miconazole haemorrhage

 

Example Protein Affinity Sites Saturation
weak acids :

AVK

AINS

Sulfamides

fibrates

albumin high + possible
weak bases :

B blockers Antidepressants

α-1 Glycoprot ac

Lipoprotéine

gammaglobuline

low +++ Unlikely

4/- INTERACTIONS DURING THE STAGE OF METABOLISM :

  • Drug detoxification :
  • Principale source d’interaction.
  • high variability.
  • Induced and / or inhibited !
Effect parent molecule metabolite
Induction effect decreased effect increased
Inhibition effect increased effect decreased

Cytochrome P540 :

  • Superfamille d’isoenzymes.
  • Located in the liver +++, but also in other tissues (rein, brain, lymphocytes… ).
  • oxidative metabolism (pharmaceuticals, xenobiotics, endogenous products (Fatty acids, prostaglandins, steroids)).
  • CYP1A2, 2C9, 2C19, 2D6, 3A4.
    + Inhibition = competition at the enzyme,
    + Induction = stimulates the synthesis of the enzyme.

4.1/- enzyme inhibition :


main inhibitors :

Class molecules involved
Antiinfective Fungal : ketoconazole, fluconazole ;

antiretrovirals : delavirdine ; protease inhibitors : ritonavir, nelfinavir ;

Quinolones 2 generation ; chloramphenicol ;

Isoniazide ;

metronidazole ;

Macrolides (except spiramycin).

anti depressants fluoxetine, fluvoxamine, paroxetine.
Divers cimétidine, calcium channel blockers

(diltiazem, verapamil, nicardipine).

Food Grapefruit juice.

4.2/- enzyme induction :


Key enzyme inducers :

Class molecules involved
Antiinfective Rifampicine, rifabutine ; antivirals ; Antiprotéases ; Fungal : griséafulvine.
anticonvulsants carbamazepine, phenobarbital, phenytoin.
Divers corticosteroids, Modafinil, Bupropion
Phytotherapy Wort
Other Tobacco, Alcohol

5/- INTERACTIONS DURING THE STAGE OF ELIMINATION :

L & rsquo; hepatic excretion may be slowed by decreased blood flow in the portal circulation-cellar (Beta-blockers ; anti-H2, omeprazole).

 

Mechanism : Elimination :

1/- glomerular filtration :

Modification of protein binding

Moving the free balance bound

Increased toxic active fraction

Increased renal clearance

2/- tubular reabsorption :

Course of Dr A. Ayadi – Faculty of Constantine