Interactions
= 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
Interactions
Possitive interaction: summation
1+1=2
potentiation
1+1=3
Negative interaction: decreased effect
Interactions
drug – drug
drug – food
wanted –  therapeutic effect
 toxicity
unwanted – most of them, can be reason
of ADRs or therapy failure
Combinations of Drugs
wanted: hypertension
severe infections
TBC
malignity
unwanted: result in limitation of usage +
iatrogenic damage
5R
• 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
Factors Increasing Risk of Drug
Interactions
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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
Drug Interactions
Drug with Risk
• narrow therapeutic
window (digoxin,
teophylline)
• steep dose-response
curve (warfarin,
sulhonylurea der.)
• enzyme inhibitors
(ketoconazole,
erythromycin)
• enzyme inducers
(rifampicin,
carbamazepine)
• high toxic potential
(aminoglycosides)
Patient with Risk
• polymorbidity
• polypharmacy
• disorders of
elimination
functions
• abusus
• non-compliance
• self-treatment
Drugs with High Risk
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Peroral antidiabetics
Peroral anticoagulants
Heart glykosides
Antiepileptic drugs
Antimanic drugs
NSA
Antibiotics
Division
according to the level at which they arise:
• pharmaceutic – physical and chemical
incompatibility
• pharmacocinetic – absorption
distribution
biotransformation
excretion
• pharmacodynamic
Absorption
• pH in GIT – antacids
• motility of GIT – prokinetics
antidiarrhoea drugs
drugs causing obstipation
Absorption
• 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
Distribution
• Insufficiency of plasmatic proteins –
hepatopathy
• Binding to plasmatic proteins
• Benzodiazepine site
• Warfarin site
Distribution
• 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.
Biotransformation
• 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
Biotransformation
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
Biotransformation
• Inhibitors of cyt. P450 - some macrolides,
quinolones, sulfonamides, some
antimycotics (e.g. ketoconazole,
fluconazole), isoniazid, metronidazole,
chloramphenicol, amiodarone, verapamil,
diltiazem, quinidine, SSRI, proton pump
inhibitors, cimetidine, garlic, ginkgo,
grepefruit juice
Pharmacodynamic Interactions
• antagonism: opioids-naloxon,
benzodiazepines-flumazenil, warfarin-vit. K,
caffeine+hypnotics, acetylcholine+atropine 
neutralization of the effect
• synergism: alcohol-antihistamines,
antidepressants, ACEI-diuretics, ASAwarfarin, analgesics-antidepressants 
amplification of the effect
Pharmacodynamic 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
Interactions with Alcohol
• 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
Interactions 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
normal eye
Marijuana,
Hasis
red eye
Speed, LSD,
Ecstasy,
Cocaine
mydriasis
Opiates:
heroin,
codeine,
morphine
miosis
Case
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.
Case
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.