drug interaction and incompatibility in veterinary practice · 2019-12-11 · drug interactions...
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Drug interaction and incompatibility in veterinary practice
Practical XIV
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Types of drug interactions*
1. Outside of the body (extracorporal)
Physical or chemical incompatibility
2. Inside of the body (intracorporal)
+ additive/potentiation v. synergism
(e.g. CNS inhibitors/antibacterial agents)
- Therapeutic incompatibility
Pharmacodynamic interaction
Pharmacokinetic (ADME) interaction
*Not only drug-drug or drug-excipient interactions exist, but feed-drug, drug-toxin interactions and interactions with endogen metabolites are possible.
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Drug interactions outside the body
• Physical incompatibility
Change of the original dose form (consistency, shape, viscosity, etc.)
Mixing, dilution of infusion and injections (e.g. ivermectin)
Change in pH (tetracyclines + alkaline solutions)
Mixing of lipophilic and hydrophilic ointments, suppositorybases
Ionization (ratio of dissociated to undissociated compound, e.g. mixing of pentobarbital with xylazine, opioids, ketamine injections)
Eutectics e.g. menthol + camphor + (aspirin) v. antipyrin + sulfur
• Chemical incompatibility
Several type of chemical reactions, e.g.: Oxydation
Reduction
Hydroxylation
Double replacement
Insoluble complex formation: Ca2+ + oxytetracycline
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Pharmacodynamic interaction• Receptorial
Competitive (direct)agonist vs. antagonist or partial agonist(e.. fentanyl vs. butorphanol)
Non-competitive (non-direct) Same organ/tissue same receptor (allosteric, irreversible) Same organ/tissue different receptors (Danger, increasing
effect!)- Aminoglycosides + non-depolarizing muscle relaxants- H1-antihistamines + hypnosedatives- Combination of antihypertensives- Combination of antiarrhythmics
Physiological (e.g. adrenergic vs. cholinergic, androgens vs. oestrogens)
• Non-receptorialChelators, adsorbents, antacids (e.g. EDTA, activated carbon, MgO)
(see PK/absorption interactions also)
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Pharmacokinetic interactions, absorption
• Inhibited by:
- complex with ions (amoxicillin, tetracyclines, fluoroquinolones),
- adsorbents, adstringents, antacids, plant fibers
- lipophilic excipient (grizeofulvin: increase!)
- muscarinic agents (shorter transition time)
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Pharmacokinetic interactions, distribution
Competition in binding to transporting plasma proteins during transport processes:
e.g. coumarin-type anticoagulants, digoxin NSAID
Substance Bound
(%)
Unbound
(%)
Digoxin 77 23
Gentamicin 50 50
Teophylline 86 14
Phenytoin 22 78
Diazepam 4 96
Phenylbutazone 5 95
Furosemide 5 95
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• The most common type of pharmacokinetic druginteraction.
• During drug metabolism active substancestrasformed into inactive (sometimes toxic) metabolites.
• The amount of metabolites formed and the rate of conversion are influenced by the concomitant administration of other drugs.
• This may reduce or increase the duration of action of the medicines.
Pharmacokinetic interactions,
biotransformation
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Drug metabolism, overview
• Phase I. reactions: Convert parent compound into a more polar (hydrophilic) metabolite by adding or unmaskingfunctional groups
• Phase II. reactions: Conjugation with endogenous substrate to further increase aqueous solubility
• Formation of less reactive metabolites• Exemptions: prodrug, toxic, carcinogenic metabolites
• The same processes are taking place during drug metabolism as the body's own biochemical and physiological processes• Medicines are often synthetic endogenous substrates: steroid
hormones, bile acids
• Drugs resemble the natural compound
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• Aliphatic, aromatic hydroxylation
• Alkylation (Methylation)
• Dealkylation
• Ring cyclization
• N-carboxylation
• Dimerization
• Transamidation
• Isomerization
• Decarboxylation
• Epoxide, nitro group, N-oxide reduction
• Hydrolysis
Catalysts of phase I reactions: CYP450 (see later),
MAOs, FMOs, esterases, alcohol-dehydrogenases,
aldehyde-dehydrogenases, etc.
Phase I reactions
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Phase II., conjugation reactionsReaction Enzyme
(where)Cosubstrate Substrate
Glucuronidconjugation
UDP-glucuronosyltransferase(ER-membrane)
UDP-glucuronicacid
OH-, COOH-: morphine, chloramphenicol, oxazepam, diclofenac, furosemide
Sulphate-conjugation
Sulfotransferase(cytosol)
3′-phosphoadenosine 5′-
phosphosulfate (PAPS)See above, paracetamol, propofol, thyroxine
Glutation-conjugation
Glutathion-S-transferase(cytosol)
Glutathion Electrophil C-: epoxides
Amino acidconjugation
Acyl-CoA -synthetase + amino acid-N-acyltransferase (mitochondrion)
ATP + CoA + amino acid(glycine, glutamine, ornithine, arginine)
COOH-: salicylic acid,benzoic acid, nicotinic acid
Acetylation N-acetyltransferase (cytosol)
Acetil-CoA NH2-: sulfamethoxazole, sulfamethazine
Methylation Methyltransferase(cytosol)
S-adenosylmethionine OH-, N-, SH-:histamine, nicotine
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CYP450 enzyme system• Heme thiolate type monooxygenases
• NADH or NADPH
• NADPH-cytochrome-P450 reductase
• O2
• SER membrane-bound
• Liver tissue
• Classification of CYP450 gene family according to DNA sequence homology:
Family >40% Subfamily >55% Gene>90%
CYP2C3
Cytochrome P450
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CYP450 enzyme systemCYP family
Substrate Inducers Inhibitors
CYP1 caffeine, theophylline,paracetamol,albendazole, thiabendazole, mebendazole
omeprazolecharcoal-broiledmeat, smoking, dioxin,indole-3-carbinole(cabbage, broccoli)
ciprofloxacinefluvoxamincimetidineacyclovir
CYP2 phenytoin, warfarin,omeprazole, diazepam,antidepressants,β-blockers,halothane, paracetamol
phenobarbital,rifampin,ethanol,isoniazide
terbinafine, fluconazole, omeprazole
CYP3 benzodiazepinesclarithromycin, erithromycin,steroide hormones, codeine, fentanyl
phenobarbital,phenytoincarbamazepinerifampindexamethasone
pleuromutilines,macrolide antibioticsGrapefruit-juice: naringenin, bergamottin,azole antifungals: e.g. ketoconazole
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CYP-catalysed reactions
diazepam nordiazepam
N-dealkylation:
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CYP-catalysed reactions
propofol 4-hydroxy-propofol
Hydroxylation:
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CYP-catalysed reactions
thiopental pentobarbital
S
Oxidative desulfuration:
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CYP-catalysed reactions
Dehydrogenation:
paracetamol N-Acetyl-p-benzoquinone imine
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Determination of CYP450 activity, in vivo
Treatment• Whole liver, • Liver lobe,
• lobus caudatus• Liver biopsy
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Determination of CYP450 activity,
centrifugation
ex vivo
Treatment
in vivo
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Determination of CYP450 activity,
Isolation of primer hepatocytes
Organ culture
Tissue slice
Tissue culture
ex vivoinvitro
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Determination of CYP450 activity, in vitro
Test substances: stimulatory- and inhibitory agents, active substances of drugs
Luminescentsubsrate (specificfor CYP
isoenzyme)
Culture medium + detection reagent
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Determination of CYP450 activity withluminometry:
in vitro, in vivo, ex vivo
Proluciferin substrate
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Kontroll Fenobarbitál Ketokonazol
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nit
CYP3A6
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CYP450 activity:in vivo and in vitro
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CYP-mediated interactions
• Phenobarbital + many anti-infectious agents (macrolides, lincosamides, chloramphenicol, griseofulvin) - decreased efficacy
• Phenobarbital + corticosteroids (prednisolone) / progestagens(proligestone): decreased efficacy
• Rifampicin + antiarrhythmics / beta-receptor antagonists (metoprolol, nadolol) / anticoagulants / corticosteroids: decreased efficacy
• Pphenylbutazone + barbiturates: increased duration of action
• Ionophore coccidiostats (monensin, narasin, salinomycin) + tiamulin / valnemulin: chicken, turkey
• Cimetidine + lidocaine: increased level
• Monepantel induces CYP1A, 2B, 2C, 2E, 3A activity and expression of the 3A24 gene in sheep.
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Effect of tylosin, monensin and tiamulin on CYP activity in chickens
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monensin
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tiamulin
tylosin
monensin
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tiamulin
tylosin
monensin
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Quantification of metabolites formed
• Spectrophotometry, ELISA (high LOD, LOQ)
• Luminometry/Fluorimetry
• Indirect-RIA
• GC
• HPLC
• LC-MS
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Pharmacokinetic interactions, elimination
- urine pHbasic acidic : procaine, antihistamines,
caffeine, pethidine
basic acidic : barbiturates, sulfonamides
- interaction in tubular active transport
probenecid NSAID blood level
penicillin half-life