Transcript The Semantic Web in Ten Passages

Factors Involved In Drug Activity
Ján Mojžiš
Department of Pharmacology
Medical Faculty, UPJŠ
Košice
Overview
I. Factor related to the drug
a)
b)
c)
1
dose
way of administration
drug formulation
II. Factors related to the
organism
a) age
b) body weight
c) gender
d) genetic factors
e) diseases
f)
drug interactions
Way of administration
2

Local application
local effect e.g. plv, ung, crm, pst, tbl vag, gtt
oph/nas/oto
systemic effect. e.g. patches or spr. with analg.
or hormones

Enteral administration
Orally: tbl, cps, non-steril., effect of food and pH,
„first pass effect“
Sublingually: tbl slg, rapid effect
Rectally: supp, first pass effect -/+, in vomiting,
children
Way of administration

Parenteral administration
Intravenously: inj. apyr. steril. H2O-solutions,
bolus, infusion
Intramuskularly: 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
3
Overview
Age
Gender
Genetics
Disease
Repeated (intermittent, continuous)
dosing
Drug interactions
4
Age
5
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.
Drugs in infants and children
 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)
6
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
7
Postnatal development of specific hepatic and renal
function
8
Drugs in infants and children
differences in pharmacodynamics
 higher dose of antihistamines can cause excitation
of the CNS (convulsion) in children while sedation in
adults
Breast-feeding



9
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 elderly
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
10
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
11
GENDER- pregnancy
DRUGS IN PREGNANCY
the 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.
12
GENDER- pregnancy
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
•
13
GENDER- pregnancy
the stage of gestation
fertilization and implantation
organogenesis/embryonic stage
fetogenic state
delivery
14
GENDER- pregnancy
fertilization and implantation ( < 17 days)

animal studies suggest that interference with
the fetus causes abortion, i.e. if pregnancy
continues the fetus is unharmed
15
GENDER- pregnancy
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
16
GENDER- pregnancy
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), sulphonamidestrimethoprim
17
Gross malformations
thalidomide
phocomelia
18
GENDER- pregnancy
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
dependence
warfarin - intracerebral bleeding
aminoglycosides - fetal VIIIth nerve damage
19
GENDER- pregnancy
delivery
some drugs can cause particular problems
pethidine – administered as an analgesic can cause
fetal apnea,
warfarin – it predisposes to cerebral haemorrhage
during delivery
20
GENDER- pregnancy
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
21
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
22
23
Disease
Renal failure
Cardiac failure
Liver disease
24
Renal failure
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, methotrexate
25
usual doses can therefore result in elevated
plasma concentrations and impaired eliminationaccumulation and intoxication
Cardiac failure
• 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)
26
Liver disease
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)
27
PHARMACOGENETICS
The study of genetically
controlled variations in drug
response
Efficacy
Toxicity
28
GENETIC
POLYMORPHISMS
Pharmacokinetic
•Transporters
•Plasma protein binding
•Metabolism
29
Pharmacodynamic
•Receptors
•Ion channels
•Enzymes
•Immune molecules
Pharmacokinetic GP
30
Cytochrom P450 and drug metabolism
31
Enzyme
Drug metabolised (%)
CYP2A6
3
CYP2B6
3
CYP2E1
4
CYP2C19
8
CYP1A1/2
11
CYP2C8/9
16
CYP2D6
19
CYP3A4/5
36
ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM
RELATIVE HEPATIC CONTENT
OF CYP ENZYMES
CYP2D6
2%
% DRUGS METABOLIZED
BY CYP ENZYMES
CYP2E1
7%
CYP 2C19
11%
CYP 2C9
14%
CYP2D6
23%
CYP 2C
17%
OTHER
36%
CYP 1A2
14%
CYP 1A2
12%
CYP 3A4-5
26%
32
CYP 3A4-5
33%
CYP2E1
5%
CYP2D6
 catalysis of hydroxylation or demetylation in
the liver




33
-blockers, antidysrhytmics
antipsychotics, antidepresants
antiemetics
Analgetics – codeine, dihydrocodeine,
dextrometorphan hydrocodone, oxycodone,
tramadol
Polymorphism CYP2D6
 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
34
CYP2D6 – incidence (%)
White
35
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
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
36
Tramadol
 moderate – severe pain
 agonist of -opioid receptors
 inhibition of „re-uptake“ NA
 release of 5-HT
37
Tramadol-metabolism
 main metabolic pathway – demetylation to Odesmethyltramadol (CYP2D6)
 200 x  affinity to -receptorom
 PM   O-desmethyltramadol  weak
analgetic activity of tramadol
38
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
39
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
40
Gene product
Consequence
Dihydropyrimidine
dehydrogenase
5-FU
neurotoxicity,
myelosuppresion
Thiopurine methyltransferase
azatioprin,
thioguanine
Glutathioóntransfera
se
Alkylating
drugs, TOPO
II-i
Irinotecan
A: myelosuppresion
Ch: secondary
tumors
 sensitivity to toxic
and anticancer
effects
diarrhea,
myelosuppresion
Glucuronyl
transferase
Methylene tetrahydrofolate reductase
41
Drug
MTX
 risk of mukositis
Pharmacodynamic GP
42

Abnormal reactions

quantitative
changes in receptor: density, structure, function,
afinity (insuline, glucocorticoids)

qualitative (idiosyncratic reactions)
hereditary defects of some enzymes (rare)
43
Idiosyncratic reactions
44
Enzme
Drug
Side effect
Deficiciency of
G-6-PD
Sulfonamides, dapson,
nitrofurantoine
Hemolytic anemia
Deficiency of
methemoglobine
reductase
Nitrites, dapson
Methemoglobinemia,
hemolysis
-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
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