1. Martin Štěrba, PharmD. PhD. Department of Pharmacology
Pharmacotherapeutic
complications
2015
Martin Štěrba, PharmD. PhD.
Associate Professor
Department of Pharmacology

2. What do you know already about drug-drug interactions:
The effects can
s y n e r g i sm
summation of effects
one-way : opioid analgesics + narcotics
two-way : combination of cytostatics or ATBs
potentiation of effects
one-way : Ca++ + digoxine
two-way : digoxine + thiazide diuretics

3. What do you know already about drug-drug interactions:
a n t a g o n i s m
pharmacologic: ACh + atropine
physiologic: ACh + adrenaline
chemical: heparin + protamine
The effects can

4. Drug-drug interactions
Interactions can be:
Desirable: intended and beneficial resulting into:
Increase of effect (synergism): e.g. combination of cytostatics or ATBs
Decrease of effect (antagonism): e.g., in the treatment of overdose with antidotes
Undesirable – unintended and potentially harmful and very dangerous resulting into:
Decrease of effect (antagonism): failure of therapy (mostly one way) with potentially serious consequences
e.g., pulmonary embolism during anticoagulation therapy, transplanted organ rejection during immunosuppressive treatment, serious infections during ATB treatment
Increase of effect – induction of adverse or even toxic drug reactions

5. Unintended drug-drug interactions as a pharmacotherapeutic complications
Clinical outcomes: from trivial to life-threatening !!!
additional costs
Pay attention also on OTC drugs
Careful drug anamnesis with question on use of OTC drugs
Patient education and interdisciplinary cooperation
Increased risk:
In combination of many drugs
In combination of drugs with
narrow margins of safety
poorly predictable dose-response
Impact on drug biotransformation
Newborns and elderly patients
Most of interactions occur in in-patients in hospital
Higher frequency of multiple drug treatment
Setting of pharmacotherapy and introduction of new drugs
More frequent parenteral routes of drug administration

6. Mechanisms of drug interactions I. Chemical/pharmaceutical interactions
Interaction is based on chemical or physico-chemical properties of drugs:
Before administration into the body (syn. pharmaceutical incompatibilities)
e.g. in syringe, infusion sol., compounded drugs.
In commercially available drugs - solved by pharmacists and approved and supervised by national authority
Follow tightly procedures for preparation of injectable parenterals (SPC)
Visual inspections
Compounded (individually prescribed drugs)– follow the literature (Preascriptiones magistrales, Preascriptiones Pharmaceuticae) and/or consult a compounding pharmacist

7. Mechanisms of drug interactions I. Chemical/pharmaceutical interactions
At the site administration: e.g., GIT – mostly result to decreased drug absorption
E.g., Ca2+, Mg2+ or Fe3+ ions or antacids which contain them or Al3+ interact with tetracyclines or quinolones?!
Medicinal charcoal, diosmectid – adsorption of number of drugs
Cholestyramine, cholestipol – hypolipidemic resins (drug adsorption)
Sucralfate – adsorption, barrier for drugs absorbed in the stomach
Antacids – pH manipulation, adsorption, ions – chelate formation
The time-gap between these and other drugs is needed (at least 2h) !!!

8. Mechanisms of drug interactions II. Pharmacokinetic interactions
Interactions at the A D M E level
Absorption(impact on total absorption or time-profile)
Chemical/physico-chemical interaction (see previous slide)
Drugs affecting GIT motility:
Absorption is decreased by laxatives (purgatives) – increased passage through GIT (small intestine) may affect absorption and BAV
Slowed absorption – antimuscarinics may decrease gastric emptying
Modulation of transporters – e.g. drugs inhibiting efflux transporters (e.g. P-gp) - ↑ BAV of co-administered drugs (verapamil vs digoxin)
Distribution
Competition for plasma protein binding
Displacement of one drug by another
Very high binding and narrow margins of safety to be clinically important (eg, warfarin, salicylates, oral antidiabetics, phenytoin)
Clinical relevance? Mostly another mechanism is needed
Warfarin + aspirin
Valproate + phenytoin
Displacement from tissue proteins: quinidine may displace digoxin (in addition to decease of its renal excretion) – digoxin intoxication

9. Mechanisms of drug interactions II. Pharmacokinetic interactions
Metabolism (biotransformation)
Localization: mainly liver, also intestinal wall
Effects
induction: LOWERING pl. concentrations and ↓ effects of other drugs – failure of therapy
Inhibition: INCREASING pl. concentrations ↑ effects of other drugs – failure of therapy
Time needed
Induction - typically slower onset (max. in 7-10 days) and persistence after drug withdrawal (days - weeks)
Inhibition – faster onset
Impact on:
1st phase biotransformation (involvement mainly CYP450! = most cases of important PK interactions)
2nd phase biotransformation (transferases: UDP-glucuronide or acetyl -transferase)

10. II. Pharmacokinetic interactions
Metabolisms (biotransformation)
Impact on cytochrome P450
There are different isoforms of CYP450
The most important are CYP450 3A4, 2D6 (the drugs which are substrates can be found in tables)
Inducers: phenytoin, carbamazepine, barbiturates, rifampicin, griseofulvin, extract from St. Johns worth (Hypericum perforatum)
Inhibitors: ketoconazole, erythromycin, clarithromycine, chloramphenicol, amiodarone, verapamil, quinidine, cimetidine…
In some isoforms also: amiodarone, omeprazole, fluoxetine, valproate,
Troublesome drugs: warfarin, cyclosporine, oral contraceptives, antiepileptics and glucocorticoids
Impact on UDP- glucuronide transferase: antiepileptics
Induction: phenytoin, carbamazepine, barbiturates
Inhibition: valproate

11. Mechanisms of drug interactions II. Pharmacokinetic interactions
Clinically important interactions at the CYP450 level

12. Mechanisms of drug interactions II. Pharmacokinetic interactions
Excretion – mainly renal
Inhibition of tubular secretion
Uricosuric drug probenecid decrease tubular secretion of some drugs, e.g. penicillins,
Verapamil, diltiazem, spironolactone…inhibit P-glycoprotein → ↓ excretion digoxin → ↑ pl. concentrations → ↑ toxicity
Thiazide diuretics
cause relative Na+ depletion and thereby they indirectly increase Li+ reabsorption
Decreased renal clearance of Li+ = CNS toxicity

13. Mechanisms of drug interactions II. Pharmacokinetic interactions
Excretion – inhibition of tubular secretion:

14. Mechanisms of drug interactions III. Pharmacodynamic interactions
Increased or decreased pharmacological effects through effect on same receptor or same or different physiological or biochemical pathway:
Clinically important examples:
warfarin + aspirin – increased risk of bleeding (both PK and PD interaction, aspirin is OTC drug!)
Diuretics (eg. furosemide) + digoxin
Hypokalemia during diuretic therapy increase toxicity of digoxine (competition for Na+K+-ATPase)
ACE-inhibitors + potassium sparring diuretics
ACE-I increase kalemia already increased by potassium sparing diuretics (e.g. spironolactone) – risk of hyperkalemia and arrhythmias
B-blockers a verapamil (Ca2+ blockers): potentiation of negative chronotropic, dromotropic a inotropic effects: serious bradycardia and heart arrest, manifest heart failure
B-blockers and insulin: sudden hypoglycemia without any warning

15. Prevention of drug interactions
Avoid polypragmazia
Avoid drugs with significant interaction potential
use alternative drug if possible
Be careful when drugs with vital indication is coadministered or when drug has a narrow safety margins
Use SPC, or specialized databases (Micromedex) or drug information center

16. Pharmacotherapeutic complication interactions with food
Co-administred food may have a significant impact on drug PK and PD
Most often after oral drug administration
Interaction with drug PK
Impact on A D M E
Absorption
Often delayed
Quantity and quality of stomach content matters
Problem when rapid onset of dug action is needed (e.g. antipyretics)
May be incomplete (↓ BAV) – recommend: 1 h before or 2 h after meal
Formation of inabsorbable complexes : diary + tetracyclines or quinolones
Adsorption on food: in ampicillin, erythromycin, lincomycine, furosemide, glibenclamide
competition with active transport: phenylalanine in food rich on protein – competition for absorption with L-dopa
Absorption may be enhanced: with slower gastric emptying (rarely a problem)

17. Pharmacotherapeutic complication interactions with food
Interaction with drug PK
Presystemic metabolism and transport from GIT
grapefruit juice (impact on up to 85 drugs)
Irreversible inhibition of CYP450 3A4 – mainly in intestinal mucosa important role of furanocumarines (more than flavonoids)
One glass effects, long inhibition: >24-72h
↑BAV of drugs → adverse effects and toxicity
↑ Cmax/BAV up to 2-9x higher (adverse eff. and toxicity): statins (not all), amiodaron, Ca2+ blockers, buspiron, sunitinib, cyclosporin or some glucocorticoids
Also some particular other juices (bitter sevilla orange or pomelo)
Inhibition of influx transporter (OATP) → ↓ Cmax/BAV a ↓ effects flavonoids (nariginine), e.g. ciprofloxacine or aliskiren (competitive and short lasting ≈ 4h)
Food tend to ↑ BAV of oral lipophilic basic drugs like metoprolol or verapamil

18. Pharmacotherapeutic complication interactions with food
Interaction with drug PK
Impact on drug elimination
Vegetarians and vegans
Decreased renal clearance of weak basis (e.g. memantine) due to the more alkaline urine
↑ C, ↑ T1/2, ↑ AUC (increased drug reabsorption )

19. Pharmacotherapeutic complication interactions with food
Interactions with drug PD
Tyramine (cheese and wine reaction) in monoamineoxygenase inhibitors (MAO-A-inhibitors)
Enhanced BAV of tyramine from fermented food (e.g. wine, beer, bananas)
Hypertension crisis – tyramine act as indirect sympathomimetic
Food with high vit K content – may decrease anticoagulant effects of warfarin