= when administration of 1 drug (specific type of food) influences by any way the effect of another drug

result of interaction is:

- quantitative change

- qualitative change

of organism response to drug

InteractionsInteractions

Possitive interaction: summation

1+1=2

potentiation

1+1=3

Negative interaction: decreased effect

InteractionsInteractions

drug – drug

drug – food

wanted – therapeutic effect

toxicity

unwanted – most of them, can be reason of ADRs or therapy failure

InteractionsInteractions

Combinations of DrugsCombinations of Drugs

wanted: hypertension

severe infections

TBC

malignity

unwanted: result in limitation of usage + iatrogenic damage

5R5R

• Right drug – drug for the diagnosis • Right dose – estimated therapeutic dose• Right time – drugs at developped disease loose

effectivity• Right form - drugs as insulin must be

administered as s.c. injection, if administered perorally, they dissolve in GIT

• Right patient – is the one who needs the drug and we know his risk profile

• Polypharmacy• Polymorbidity• Treatment lasting long time• Chronic disease• Combination of drugs with similar effect• Low therapeutic index• Simultaneous ordination of more drugs by

different physicians• Abuses• Self-treatment

Factors Increasing Risk of Drug Factors Increasing Risk of Drug InteractionsInteractions

Drug InteractionsDrug InteractionsDrug with Risk

• narrow therapeutic window (digoxin, teophylline)

• steep dose-response curve (warfarin, sulhonylurea der.)

• enzyme inhibitors (azole antimycotics, erythromycin)

• enzyme inducers (rifampicin, carbamazepine)

• high toxic potential (aminoglycosides)

Patient with Risk

• polymorbidity• polypharmacy• disorders of

elimination functions

• abusus• non-compliance• self-treatment

• Peroral antidiabetics

• Peroral anticoagulants

• Heart glykosides

• Antiepileptic drugs

• Antimanic drugs

• NSA

• Antibiotics

Drugs with High RiskDrugs with High Risk

according to the level at which they arise:• pharmaceutic – physical and chemical

incompatibility

• pharmacocinetic – absorption distribution biotransformation excretion

• pharmacodynamic

DivisionDivision

AbsorpAbsorptiontion

• pH in GIT – antacids

• motility of GIT – prokinetics antidiarrhoea drugs drugs causing

obstipation

AbsorpAbsorptiontion

• some drugs in combination with other substances or food form insoluble and non-absorbable complexes /tetracyclines + antacids, black tea + iron/

• reduced absorption of several drugs after milk intake

• parenteral administration of vasoconstricting additives – slowing down of absorption from the site of i.m. or s.c. injection

DistributionDistribution

• Insufficiency of plasmatic proteins – hepatopathy

• Binding to plasmatic proteins• Benzodiazepine site• Warfarin site

DistributionDistribution

• limitation of drug binding to plasma proteins • competitive displacement of substances at

biding site – a substance with higher affinity is displacing a substance with a lower affinity to receptors – increasing the portion of free molecules = more intense and shorter effect

• mainly substances with high protein binding – more than 90% + with small distribution volume

• warfarín, sulfonylurea der.

BiotransformationBiotransformation

• the most frequent interactions

• some drugs were deregistered for this type of interactions (mibefradil, astemizole, terfenadine...) => serious ADRs, even death

• cytochrome P450 – change of activity = change in rate of activation and inactivation of drugs

• stimulation of met. = enzyme induction

• inhibítion of met. = enzyme inhibítion

BiotransformationBiotransformation

Inductors of cyt. P450 - barbiturates, benzodiazepines, hydantoin antiepileptics, glucocortikoids, rifampicin, griseofulvin, St. John´s wort, smoking, grilled meat, chronic alcohol intake – increase biotransformation = decrease the effect of several drugs, e.g. cardiotonics, steroid hormones, coumarin anticoagulants

BiotransformationBiotransformation

• Inhibitors of cyt. P450 - some macrolides, quinolones, sulfonamides, some antimycotics (e.g. ketoconazole, fluconazole), isoniazid, metronidazole, chloramphenicol, amiodarone, verapamil, diltiazem, SSRI, proton pump inhibitors, cimetidine, garlic, ginkgo, grepefruit juice

Pharmacodynamic InteractionsPharmacodynamic Interactions

• antagonism: opioids-naloxon, benzodiazepines-flumazenil, warfarin-vit. K, caffeine+hypnotics, acetylcholine+atropine neutralization of the effect

• synergism: alcohol-antihistamines, antidepressants, ACEI-diuretics, ASA-warfarin, analgesics-antidepressants amplification of the effect

Pharmacodynamic InteractionsPharmacodynamic Interactions

• Most often potentiation of sedative effect on CNS (benzodiasepines and alcohol)

• Also potentiation of bradycardia (verapamil a betablockers)

• Dangerous simultaneous administration of warfarin and aspirin

• Character a intensity depends on type and ammount

acute, chronic intake

• Chronic alcoholism:– Enzyme induction absorption and utilization of vitamines– Adaptive changes in neurotransmitters (DOPA system)

• Genetic polymorphism - atypical ADH Japanese, Chinese sensitivity

• Acute intoxication:– Rather inhibits CYP; depents whether the individual is

an alcoholic or not

Interactions with AlcoholInteractions with Alcohol

• 80-89% of alcohol is metabolized in liver alcohol dehydrogenase (ADH) to acetaldehyde than aldehyde dehydrogenase (ALDH) to acetate (innoxious acetic acid)

• Disulfiram inhibits ALDH => acetaldehyde => ADRs: tachycardia, feeling hot, nausea and vomiting effective even 14 days after stopping of treatment

Interactions with AlcoholInteractions with Alcohol

                      

                            

                      

                            

                      

                            

                      

                            

normal eye Marijuana,Hasis

red eye

Speed, LSD,Ecstasy, Cocaine

mydriasis

Opiates:heroin,

codeine,morphine

miosis

CaseCase

Young 35 year old woman, who previously took contraceptive therapy, after a broken leg had thromboembolic events.

Followed anticoagulant therapy (warfarin 5 mg; INR - 2.5).

At regular controll found hypertriglyceridemia and started was therapy with gemfibrozil 1.2 g daily.

At menstruation appeared serious bleeding, INR - 4.

After reducing warfarin dose to one half (2.5 g), INR was stabilized to 2.5.

CaseCase

Gemfibrozil is an inhibitor of CYP3A4 and reduced biotransformation of warfarin, resulting in increased plasma levels of warfarin to values with the risk of bleeding.