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PHYSIOLOGICAL AND PATHOLOGICAL
FACTORS INFLUENCING DRUG EFFECTS
Factors influencing drug effects
• factors related to the drug
• factors related to the drug and organism
• factors related to the organism
- hyperergic reaction
- hypoergic reaction
- normoergic reaction
Factors influencing drug effects
1. Factors related to the drug
• A Physico-chemical properties
• B Drug dosage form and way of administration
• C Effect of meal, nutrients
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A Physical and chemical
properties of the drug
• lipid and water solubility
• onset of action, distribution
• the size and shape of the molecule
• chemical configuration
• acid-base properties
The relationship of chemical structures
and the nature of the effect
Examples:
atenolol x metoprolol /hydrophilic vs. lipophilic /
longer vs. shorter half-life
Cis-trans isomers: only the cis form of
chlorprothixene is effective
ISDN more lipophilic than the ISMN:
• ISDN can be given sublingually
• ISMN almost does not undergo hepatic FPE
B Drug dosage form
• the ultimate form of processing of active
substances and excipients
• the composition and the shape = predestiny
for the intended use
• influences pharmaceutical availability
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B Drug dosage form
• Pharmaceutical stage
• Pharmacokinetic stage
• Pharmacodynamic stage
• desagregation,
• desintegration
• dissolution
• ADME
DRUG DOSAGE FORM GENERATIONS
• 1st generation – conventional DDF
• 2nd generation - DDF with controlled release
• with prolongated release (SR,XR...)*
• transdermal therapeutic system (TTS)
• gastrointestinal therapeutic system
• 3rd generation - DDF with targeted drug delivery
* SR=sustained release, slow release
• LA=long acting, SA=slow acting, XR=extended release
• CR=continuous (controlled) release, retard, etc.
3. generation „Drug targeting“
• targeted therapy - selective action on specific cellular
or subcellular targets
- some liposomal LF
- most of biological drugs (monoclonal antibodies)
- antibody drug conjugate - e.g brentuximab –vedotine
• delivers an antineoplastic agent that results in
apoptotic cell
• death selectively in CD30-expressing tumour cells
• - antisense therapies
• - gene therapy
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C Concomitant food + drug intake
Pharmacodynamic interactions
- non-selective inhibitors of MAO increase the
• bioavailability of tyramine from food (fermented food is
• risky, e.g. some cheese, red wine, smoked meat, bananas)
• there is a risk of excessive wash out of catecholamines and
hypertensivee crisis
- food with high content of vitamin K (e.g. broccoli) can
• decrease the effect of warfarin (vitamin K antagonist)
C Concomitant food + drug intake
Pharmacokinetic interactions
- more often- influence at the level of absorption, but also
at the site of metabolism and excretion
- food can:
• slow down the absorption without the change of
• extension of bioavailability
• (inappropriate in analgesics, hypnotics…)
• decrease bioavailability
• increase bioavailability
2. Factors related to the drug and organism
A Dose (dose-response curve)
B Drug Combinations
C Repeated administration
D Delayed effects
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3. Factors related to the organism
• age
• sex (males/females)
• body weight, physiognomy
• circadian rhythms
• pathological condition of the body
• genotype / phenotype
Pharmacogenetics focuses on the study of genetically
conditioned variability in the response to a drug; examines the
relationship of drug effect on the level of the whole genome,
respectively transcriptome (e.g. GENETIC POLYMORPHISM OF
BIOTRANSFORMATION ENZYMES )
EFFECT OF OTHER PATHOLOGIES/
DISEASES ON THE EFFECT OF DRUGS
• heart failure (centralization of circulation) - possible slowdown
and reduced absorption after oral administration
- possible increase of bioavailability of substances with extensive
first pass effect
• absorption slow down after IM
• gastrointestinal disorders ( malabsorption , gastric ulcers and
• conditions inducing nausea , vomiting )
• thyroid disorders (hyperfunction - generally increased intensity of
metabolism), hyperfunction - potentiated effect of warfarine
• fever (^ ventilation and GF, increased elimination of gentamicine)
• edemas (^ Vd gentamicine)
• obesity
• impact of liver disease: there is no reliable quantitative measure
of impaired liver elimination capability for drugs (creatinine
clearance analogy with kidney disorders); therefore - empirical
approach
• liver function tests (ALT, AST, albumin, clotting factors) are not a
good guide for the drug dosage schedule - nonspecific
• reduce the dosage in advanced liver diseases:
diazepam, paracetamol, phenobarbital, phenytoin, valproic acid
mesocaine, morphine, theophylline, calcium channel blockers
• carefully: antidiabetics, diuretics,anticoagulants,
antihypertensives
• therapeutic drug monitoring (TDM)- appropriate for antiepileptics,
theophylline, cytostatics (low TI), AMG antibiotics, antipsychotics
EFFECT OF DISEASES ON THE EFFECT OF
DRUGS - OTHER PATHOLOGIES
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ADVERSE DRUG EFFECTS
Classification according to frequency
• Very frequent .1/10 patients
• frequent .1/100 patients
• Less frequent 1/100 - 1/1 000 patients
• Rare 1/1 000 - 1/10 000 patients
• Very rare . 1 / 10 000 patients
Classification according to the intensity of ADRs:
• mild - no action needed
• moderate - results in change of dosing or treatment
• severe - potential harm, necessity of drug withdrawal
LEGISLATION - Pharmaceutical act (378/2007 SB.)
• SADR – serious adverse reaction
• UADR – unexpected adverse drug reaction
• USAR – unexpected serious adverse reaction
• SUSAR - suspected unexpected serious adverse
reaction
PHARMACOVIGILANCE
• monitoring of adverse drug reactions in routine
clinical practice - the active drug safety
ADVERSE DRUG EFFECTS
ADVERSE DRUG EFFECTS
A – augmented – (95 %) caused by the same mechanism as
pharmacotherapeutical effects, •predictable
•directly dependent on the dose •frequent, seldom fatal,
insuline > hypoglycaemia, anticoagulants> bleeding
B – bizzare – (5 %) - caused by a genetic mechanism (idiosyncrasy)
or by an imunological mechanism (allergies)
•unpredictable •do not depend on the dose •less
frequent (1:1 000 až 1:10 000) •higher mortality
C – chronic – are caused by a long term drug administration
•e.g. analgetics > nefropathy, •prednisolon >
iatrogenic Cushing’s syndrome
D – delayed – show after a longer period of latency (mutagenesis, terat.)
•become apparent after a longer period of latency
(or in children of the treated patients)
E – end-of-use - syndrom caused by discontinuation of a drug
• tachycardia after discontinuing betablockers