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= 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.
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