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Factors Involved In Drug Activity
Ján Mojžiš
Department of Pharmacology
Medical Faculty, UPJŠ
Košice
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Overview
I. Factor related to the drug
a) dose
b) way of administration
c) drug formulation
II. Factors related to the organism
a) age
b) body weight
c) gender
d) genetic factors
e) diseases
f) drug interactions
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Way of administration
Local applicationlocal effect e.g. plv, ung, crm, pst, tbl vag, gtt oph/nas/otosystemic effect. e.g. patches or spr. with analg. or hormones
Enteral administrationOrally: tbl, cps, non-steril., effect of food and pH, „first pass effect“Sublingually: tbl slg, rapid effectRectally: supp, first pass effect -/+, in vomiting, children
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Way of administration
Parenteral administrationIntravenously: inj. apyr. steril. H2O-solutions, bolus, infusionIntramuskularly: inj. apyr. steril. susp., emuls.Subcutaneously: inj.
Inhalatory: gas, vapour, aerosol (anesthesiology, asthma)Others: intraarterially, intrathecally, intracardially, etc.
Onset of action:
i.v. > i.m. > s.c. > per os
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Overview
AgeGenderGeneticsDiseaseRepeated (intermittent, continuous) dosingDrug interactions
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Age
Children Elderly
Absorption HCl, empting. HCl, empting., atrophy circulation motil.
Albumin bound in comparison with adults. (compet. with bilirub.)
albumins
Volume of distribution extracel. water. extracel. water.,
Metabolism conjug., plasm. ester. liver diseases
Excretion glom. filtr. and tub. sekr. glom. filtr.
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children are not miniature adults in terms of drugs handling: differences in pharmacokinetics
at birth extracellular volume is rather large while all renal mechanisms (filtration, secretion and reabsorption) are reduced
hepatic microsomal enzymes system is relatively immature (mainly in the preterm infants)
Drugs in infants and children
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Drugs in infants and children
plasma half-life of gentamicin eliminated by the kidney:
t 1/2 hours
premature infants < 48 h old 18
5-22days old 6
normal infants 1-4 weeks old 3
adults 2
chloramphenicol - gray baby syndrome
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Postnatal development of specific hepatic and renal function
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differences in pharmacodynamics higher dose of antihistamines can cause excitation
of the CNS (convulsion) in children while sedation in adults
Breast-feeding can lead to toxicity in the child if the drug enters the
milk in pharmacological quantities milk is weakly acidic, so drugs that are weak bases
are concentrated in breast milk. some drugs to be avoided: amiodarone, aspirin,
benzodiazepines.
Drugs in infants and children
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differences in pharmacokinetics in healthy individuals aged over 70, GF rate is <60-70
ml/min tubular function also declines with age Drugs that are mainly excreted via the kidney are
likely to a c c u m u l a t e in patients in their
seventies and eighties if given in doses suitable for
young adults. Examples of drugs requiring dose adjustment in the
elderly: aminoglycosides, atenolol, diazepam,
digoxin, oral hypoglycemic agents, warfarin, NSAIDs
Drugs in elderly
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Drugs in elderly
differences in pharmacodynamics
clotting factors synthesis by the liver is
reduced and old people often require lower
warfarin doses for effective anticoagulation
than young people
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GENDER- pregnancy
DRUGS IN PREGNANCYthe use is complicated by the potential for harmful effects on the growing fetus, and altered maternal physiology.
What are main conditions? • In the placenta maternal blood is separated from fetal blood flow by a cellular membrane. Drugs can cross it by passive/active transport• There are multiple placental enzymes, primarily involved with endogenous steroid metabolism, which may also contribute to drug metabolism.
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Factors that can influence the effects of drugs on the fetus:
• the stage of gestation, • the type of the placenta • the age of mother • properties of drugs
GENDER- pregnancy
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the stage of gestation
fertilization and implantation
organogenesis/embryonic stage
fetogenic state
delivery
GENDER- pregnancy
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fertilization and implantation ( < 17 days)
animal studies suggest that interference with
the fetus causes abortion, i.e. if pregnancy
continues the fetus is unharmed
GENDER- pregnancy
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organogenesis/embryonic stage (17 -57 days)
• at this stage the fetus is differentiating to form major organs this is the critical period for teratogenesis.
• teratogens cause deviations or abnormalities in the development to embryo that are compatible with prenatal life and are observable postnatally •drugs that interfere with organogenesis can cause gross structural defects confirmed, suspected and potencial teratogens
GENDER- pregnancy
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C o n f i r m e d teratogens (in h u m a n s):thalidomide (phocomelia), cytostatics-antimetabolites, lithium (cardiac defects), warfarin (chondrodysplasia punctata), sex hormones (cardiac defects, multiple abnormalities)
S u s p e c t e d teratogens (evidence is inconclusive, the impact of diseases?): antiepileptics (phenytoin, carbamazepine- craniofacial defects),
P o t e n t i a l teratogens (in a n i m a l s): chemotherapeutics (metronidazole), sulphonamides- trimethoprim
GENDER- pregnancy
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Gross malformations
thalidomide - phocomelia
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fetogenic state - at this stage the fetus undergoes further development and maturation. Even if organogenesis is almost complete, drugs can still have significant untoward effects on fetal growth and development
ACEI – fetal and neonatal renal dysfunction TTC - inhibit growth of fetal bones and stain teeth), opioids and cocaine taken regularly - fetal drug dependencewarfarin - intracerebral bleedingaminoglycosides - fetal VIIIth nerve damage
GENDER- pregnancy
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delivery
some drugs can cause particular problems
pethidine – administered as an analgesic can cause fetal apnea,
warfarin – it predisposes to cerebral haemorrhage during delivery
GENDER- pregnancy
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Summary and recommendations
Prescribing in pregnancy is a balance between
the risk of unwanted effects on the fetus and
the risk of leaving maternal disease untreated.
The effects on the human fetus are not reliably
predicted by animal experiments.
However, untreated maternal disease may
cause morbidity and /or mortality to mother
and/or fetus
GENDER- pregnancy
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THEREFORE:
MINIMIZE PRESCRIBING
use „tried and tested“ drugs whenever possible
to new agents
use the SMALLEST EFFECTIVE DOSE
warn the patient about the risks of smoking,
alcohol, over-the counter drugs - OTC- and
DRUGS OF ABUSE
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Renal failure
Cardiac failure
Liver disease
Disease
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permeability of the BBB (uremia) is enhanced -increased access of drugs to the CNS (cimetidine causes confusion)renal excretion is reduced in relation to GF
Drugs (and their metabolites) excreted predominantly by the kidney accumulate in renal failure:aminoglycosides, digoxin, lithium, enalapril, atenolol, methotrexateusual doses can therefore result in elevated plasma concentrations and impaired elimination- accumulation and intoxication
Renal failure
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• distribution - in compounds with large Vd distribution decreases (probably caused by decreased tissue perfusion and impaired elimination). Usual doses can therefore result in an elevated plasma concentrations, producing toxicity (lidocaine, quinidine)
• elimination by liver and /or kidney is diminished: decreased hepatic perfusion accompanies reduced cardiac output (theophylline)reduced glomerular filtration (aminoglycosides, digoxin)
Cardiac failure
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Prescribing for patients with liver disease:
• if possible, use drugs that are eliminated by routes
other than the liver• drug effects should be monitored (and therapy
adjusted accordingly)• predictable hepatotoxins (cytostatic drugs) should
only be used for the strongest of indications• avoid drugs that interfere with hemostasis
(anticoagulants, aspirin)
Liver disease
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PHARMACOGENETICS
The study of genetically controlled variations in drug response
Efficacy
Toxicity
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GENETIC POLYMORPHISMS
Pharmacokinetic Pharmacodynamic
•Transporters•Plasma protein binding•Metabolism
•Receptors•Ion channels•Enzymes•Immune molecules
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Pharmacokinetic GP
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Cytochrom P450 and drug metabolism
Enzyme Drug metabolised (%)
CYP2A6 3
CYP2B6 3
CYP2E1 4
CYP2C19 8
CYP1A1/2 11
CYP2C8/9 16
CYP2D6 19
CYP3A4/5 36
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ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM
RELATIVE HEPATIC CONTENT OF CYP ENZYMES
% DRUGS METABOLIZED BY CYP ENZYMES
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CYP2D6
catalysis of hydroxylation or demetylation in the liver
-blockers, antidysrhytmics antipsychotics, antidepresants antiemetics Analgetics – codeine, dihydrocodeine,
dextrometorphan hydrocodone, oxycodone, tramadol
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Extensive metabolism (EM) – typical for
most of the pts.
Poor metabolism (PM) – mutation and/or
deletion of both alleles – drug cummulation
Ultra extensive metabolism (UEM) –
increased gene amplification – increased
drug metabolism
Polymorphism CYP2D6
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CYP2D6 – incidence (%)
White Asiats Black S. Arabia
PM UEM PM UEM PM UEM PM UEM
7-10 1-10 1 0-2 0-20 2 1-2 10-29
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Codeine - metabolism
10 % - demethylated in the liver to morphine
analgetic effect
PM – low rate of demethylation – weak/no
analgetic efect
respiratory, psychomotoric effects are also
weaker
Risk of dependence in PM
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Tramadol
moderate – severe pain
agonist of -opioid receptors
inhibition of „re-uptake“ NA
release of 5-HT
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Tramadol-metabolism
main metabolic pathway – demetylation to O-
desmethyltramadol (CYP2D6)
200 x affinity to -receptorom
PM O-desmethyltramadol weak
analgetic activity of tramadol
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Tiopurine methyltransferase (TPMT)
caucasoid population:
cca 89% activity (homoz., wild type)
11% moderate activity (heteroz. with variant allele)
1 from 300 pts /0 activity (homoz., mutant alleles)
in pts. with activity of TPMT cumulation of
active metabolites (6-TGn) in haematopoetic
system – risk of hematotoxcity
metabolism of mercaptopurine, azatioprin,
thioguanine
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Clinical consequences of TPMT polymorphism
TMPTH /TMPTL heterozygotes (11%) good therapeutic effects, increased risk of myelosuppression
TMPTL/ TMPTL homozygotes (0,33%) high risk of toxicity secondary leukemias
TMPTH/ TMPTH homozygoti (89%) – variabile response
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Gene product Drug Consequence
Dihydropyrimidine dehydrogenase
5-FU neurotoxicity, myelosuppresion
Thiopurine methyl-transferase
azatioprin, thioguanine
A: myelosuppresionCh: secondary tumors
Glutathioóntransferase
Alkylating drugs, TOPO II-i
sensitivity to toxic and anticancer effects
Glucuronyl transferase
Irinotecan diarrhea, myelosuppresion
Methylene tetrahy-drofolate reductase
MTX risk of mukositis
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Pharmacodynamic GP
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Abnormal reactions
quantitativechanges in receptor: density, structure, function,
afinity (insuline, glucocorticoids)
qualitative (idiosyncratic reactions) hereditary defects of some enzymes (rare)
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Idiosyncratic reactions
Enzme Drug Side effect
Deficiciency of G-6-PD
Sulfonamides, dapson, nitrofurantoine
Hemolytic anemia
Deficiency of methemoglobine reductase
Nitrites, dapson Methemoglobinemia, hemolysis
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-receptor-polymorphism
1. patient
78-y., M, cancer larynx
metastasis – back pain
morphine 10 mg/day
brak therapy – side effect
-receptor – wild type
2. pacient
46-y. F, tumor with metastasis
morphine 990 mg/day
morphine 2000 mg/day epidurally – persistent moderate pain
-receptor - mutation
Hirota a kol., DMD , 677-680, 2003