Farmakologický stav1
Factors influencing
drug effects.
Overview of factors
A. Factors related to drug:
Physical and chemical properties
Dose
Drug form
Combination of drugs
Food administered together with a drug
Repeated administration
B. Factors related to organism:
Age
Gender
Weight and body constitution
Circadian rhytms
Pathological state of organism
Genotype/fenotype
(Race group/ethnic group)
A. Factors related to drug
I. Physical and chemical properties
II. Drug dose
III. Drug dosage form
IV. Drug combination with other drugs
V. Food administered together with a drug
I. Physical and chemical properties
of drug
Influence on the transport trough membranes
̶ Chemical configuration
̶ Size and shape of the molecule
̶ Solubility in water and fats
̶ Acidobasic properties
Relationship of chemical structure to PK
ISDN
ISMN
ISDN is more lipophilic than ISMN
ISDN may be administrated sublingually
ISMN is almost not subject to the hepatic FPE
Another example: atenolol x metoprolol
Stereoisomerism
̶ Cis-trans isomerism: only the cis form of chlorprothixene is efficient
Drug information sources
̶ SPC = summarizing information about MP
(Summary of Product Characteristics)
part of the marketing authorisation of a
medicinal product
̶ AISLP - electronic drug information database for MP
̶ SÚKL MP database (State authority for control of drugs)
̶ Czech pharmacopoeia
II. Drug dose - dosis
̶ In preclinical trials
̶ In clinical trials phase I: MTD (maximal tolerated dose)
III. Drug dosage form
̶ definition: a substance or combination of substances
presented as having therapeutic or preventive
properties administered to set the medical diagnosis.
III. Drug dosage forms
1st generation – conventional DDF
2nd generation with controlled release
with prolongated release (SR,XR...)*
transdermal therapeutic system (TTS)
gastrointestinal therapeutic system
3rd generation with targeted drug delivery
*SR=sustained release, slow release
LA=long acting, SA=slow acting, XR=extended release
CR=continuous (controlled) release, retard atd.
Liposomal vers. conventional drug ( e.g. amphotericin B)
Stealth liposomes = PEGylated (daunorubicin, doxorubicin)
Nano-liposomes
IV. Combinations of drugs
The effect is
S y n e r g i s m
Summation: both drugs have the same (similar) effect and,
if we combine them, the final effect is a sum of all effects,
which the drugs would have when administered in
monotherapy
one-sided : analgetics anodynes + narcotics
two-sided : combination of cytostatics
Potentiation
one-sided : Ca2+ + digoxin
two-sided : digoxin + thiazide diuretics
IV. Combinations of drugs
The effect is
A n t a g o n i s m
pharmacological (ACH + atropin)
physiological (ACH + adrenalin)
chemical (heparin + protamin sulfate)
(metals + dimerkaprol, EDTA)
V. Food intake
PD interactions
- non-selective inhibitors of monoaminooxidase increase the bioavailability
of tyramine from food (fermented food is risky, e.g. some cheese, red wine,
smoked meat, bananas) -> risk of excessive wash out of catecholamines and
hypertensive crisis
- food with high content of vitamin K (e.g. broccoli) can decrease the effect
of warfarin (vitamin K antagonist)
PK interactions
- more often- influence at the level of absorption, but also
in metabolism and excretion
V. Pharmacokinetic interactions with food
Food can:
slow down drug absorption without changing its
bioavailability
(inappropriate in analgetics, hypnotics…)
decrease bioavailability
increase bioavailability
B. Factors related to organism
Age
Gender
Weight and body constitution
Circadian rhythms
Pathological conditions of organism
Genotype/phenotype
Age
Administration of medicinal product (MP)
to children
to elderly people
Administration of MP to children
approximate dose for children
=
body surface area (m2) x dose for adult
1,7 (m2)
Administration of MP to children
A child is not a miniature of an adult
particularities of PD
particularities of PK
Particularities of PK of drugs in child
Particularly on newborns (especially premature):
relatively bigger volume of extracellular liquor
lower binding on plasma proteins
unfinished development of hematoencephalic barrier
immaturity of enzymatic systems
Immaturity of renal functions
Administration of MP to old people
60 – 74 older person
75 – 89 elderly
> 90 longevity
physiological changes
multimorbidity
polypragmasia (administration of many drugs together,
risk of drug interactions is increasing)
higher incidence and severity of adverse effects
Changes of PK of drugs in old age
absorption (passive diffusion of subacid substances
thanks to hypoacidity, active transport is decreasing)
binding on plasma proteins
elimination: decrease of blood flow through kidneys
and GFR, flow through liver and activity of redox
enzymes
=> Prolongation of t1/2
(e.g. digoxin, aminoglycoside atb)
Changes of PD in old age
Very variable
Tissue hypoxia
Dysfunction of regulatory mechanisms
Change of sensibility of target structures
= hyperergic reaction
Changes of PD in old age
Examples:
ATB aminoglycosides:
lower doses in case of lower GF (correction according to CL CR)
Antihypertensives: orthostatic hypotension, psychical alternations
(confusion)
Anticoagulants: bleeding from GIT (decreased absorption of
vitamin K and decreased synthesis of prothrombin)
NSAID: in 25% hematemesis
Anticholinergic drugs: higher toxicity, depression, confusion
Gender
Women are in general more sensitive to effects of some
drugs, e.g. because of lower weight, but also of lower CL
(olanzapine)
Specific periods are:
menstruation
gravidity
lactation
menopause
Pregnancy
slowed stomach and intestinal motility
increased volume of plasma, body water can be raised
up to 8 litres more
hypoalbuminemia, occupancy rate of plasma proteins
by hormones
increased blood flow through kidneys and increase of
GFR
Weight and body constitution
In many cases drugs are dosed in consideration to the weight of the
patient (it’s recommended to use dosing per 1kg of body weight,
respecting the patient’s age)
Dosage mode: dose per time period
Dose: mg/kg, mg/kg/age, mg/m2
Pathological state of organism
Influence of lesion/renal dysfunction, liver and thyroid gland on
pharmacokinetics
Influence of pathological state on pharmacodynamics
Hypofunction of kidneys
The most common reason for a drug dose adjustment
Customisations of dosage in accordance to the tables – GFR is a clue
For the majority of drugs, the customisation of the dosage means
prolongation of intervals (AMG, vancomycin)
In drugs with very long t1/2 we keep the same interval, but administer
a lower dose (digoxin)
Influence of liver diseases
No reliable quantitative criteria is available for measuring impaired liver
elimination capacity (analogy CLcr in kidney dysfunctions)
empirical attitude
Liver function tests (aminotransferases, albumin, blood coagulation
factors) are not a good clue for the dosage of drugs
In persons with liver diseases
Prefer drugs eliminated mostly by kidneys, if possible (or those whose
kinetics is not disturbed by liver hypofunction) e.g. atenolol
Prefer drugs acting directly – without activation of
biotransformations in liver (lisinopril x enalapril)
Think about the possibility of increased biol. availability when drugs
with high first-pass effect are administered orally
(e.g. metoprolol)
Genetic factors
The drug response varies among individuals qualitatively and
quantitatively
interindividual variability – polymorphism
Genetic factors influence PD and also PK
Genetic factors
Genetic polymorphism = existence of several (at least two) alleles for a concrete
gene, the least frequent one of which has the population frequency at least 1%
Pharmacogenetics
focused on studies of genetically conditioned variability in response of the
organism to a drug
(Pharmacogenomics investigates the relationship of drug effect at the level of the
whole genome)
Adverse effects
Adverse effects
AE frequency - SPC
very common (with occurrence frequency ≥10 %)
common (1 %- 10 %)
uncommon (0.1 % - 1 %)
rare (0.01 %- 0.1 %)
very rare (< 0,01 %)
Type A – 95%
dose dependent
pharmaceutical, pharmacokinetic
Type B – 5%
dose non-dependent
immunological reactions, pseudoallergic reactions,
pharmacogenetic variations
Type C
during longer application
Type D
delayed reactions
Type E
after withdrawal
Adverse effects – type A
pharmaceutical reasons:
unsatisfactory clean preparations – admixtures of pyrogens, bacteria, etc.
expired preparations
pharmacokinetic variant
liver diseases (hepatitis, cirrhosis) - lower production of blood
albumines during cirrhosis
kidney disease (accumulation of medical substances eliminated by
glomerular filtration or tubular secretion)
heart diseases (decreased blood flow in liver and kidneys, impaired
absorption from GIT absorption from GIT due to lower blood flow
and gut mucous membrane oedema)
Adverse effects – type A
thyroid gland disorders - changed metabolization during
hyperthyreosis or hypothyreosis
interactions of medical substances
Adverse effects – type A
Adverse effects – type B
immunological
- hypersensitivity (allergies)
pseudoallergic reactions
- clinical symptoms are like in hypersensitivity, but
there are no immunological markers
reaction to the same drug will not necessary develop
after the next administration
Adverse effects – type C
(after longer administration)
tolerance
dependence
specific for various substances
corticosteroids – adrenal cortex atrophy
phenacetin – kidney inflammation
Adverse effects – type D
(delayed)
carcinogenic
hormonal interventions during pregnancy
genetic toxicity
cyklophosphamide → ca of gall-bladder
immunosuppression
immunosuppressive substances → ca of
liver, biliary tract
Adverse effects – type D
(delayed)
interfere with reproduction
decrease in fertility
teratogenic effects
cumulation in breast milk
Adverse effects – type E
„rebound“ phenomenon deterioration
of the original difficulties after stopping of administration
anxiolytic drugs → anxiety
antihypertensive drugs → hypertension
withdrawal syndrome in addictive substances