Factors Involved In Drug Activity Ján Mojžiš Department of Pharmacology Medical Faculty, UPJŠ Košice.

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