the topic include basic details on adverse drugs reaction their classification types of adverse drug reaction etc

1. Adverse drug reaction
Ravish Yadav

2. Pharmacotherapeutic
complications
• Adverse and toxic effects of drugs
• Drug interactions (drug-drug)
• Food and drug interactions
• Drug dependence and abuse
• There is no ideal drug which is free of risks of
pharmacotherapeutic complications
• The knowledge and understanding of
pharmacotherapeutic risks is essential for safe use of
drugs in clinical practice
• Consequences of pharmacotherapeutic complications
• Health related
• Legal
• Ethic
• Economic

3. Adverse and toxic
effects of drugs

4. Adverse  toxic reactions
terminology
• Is far from being unified
• Unwanted, adverse, side or toxic…effects/reactions
• Effects (of drugs) vs reaction (of patients)
• adverse drug reaction (WHO def.) = unintended and noxious
(harmful) response that occurs at normal doses of the drug used
for prophylaxis, diagnosis and treatment of diseases

5. •A, B, C, D, E – CLASSIFICATION !!!
•They often require change of dose/dosage
schedule or drug withdrawal.
•Sometimes Side effects (collateral effects) are
distinguished – the weak form of the adverse
effect which is unpleasant but generally
acceptable. The marked changes in dosage
schedule or drug withdrawal are usually not
necessarily.

6. • E.g. weak sedation with H1-antihistamines, constipation with
opioids, dry mouth with antimuscarinics
• The term side effects is often used as a synonym to adverse
effects.

7. •Toxic drug reaction
• Unintended, primarily harmful and reactions occurring at high
(supratherapeutic) doses and/or after long treatment (acute or chronic
overdose).
• Toxic effects are often associated with morphologic changes which
might be irreversible.
Adverse  toxic reactions
terminology

8. • Reasons:
• Iatrogenic intoxication – medication error, critical
situations when high drug doses are needed
• Non-compliance and patients errors (multiple pharm.
prep. with same active drug), self-administration
(overdose) in children
• Suicidal attempts (antidepressants...)
• Paracelsus: only the dose makes the difference between
the drug and poison
• Precise preclinical characterization of toxic drug effects is a
mandatory part of the request for approval of the drug for
clinical investigation and the same applies for final
approval for its clinical use

9. Adverse effects
Type A (augmented)
• Are induced by
• same pharmacological mechanisms as the therapeutic effects
• By increase of the therapeutic or other pharmacological effect of the drug
• Is directly dose-dependent (or plasma concentration dependent)
• It is mostly associated with inappropriate dosage schedule (inappropriately high
dose and/or short dosing interval)
• It can arise from changes in drug pharmacokinetics (e.g., impaired drug
elimination or plasma protein binding)
• As a result of the pathology (kidney, liver failure and hypoalbuminemia)
• As a result of aging (e.g. Lower renal elimination in elderly)
• It can arise from changes in drug pharmacodynamics
• Predisposition due to the concomitant pathology
– pay appropriate attention on CONTRAINDICATIONS
• Or patient non-compliance (e.g. failure to follow all instructions)
• Are well predictable with respect to both – their clinical manifestation and
probability of onset
• Type A is the most frequent type of adverse effects (76%)
• They have relatively less dangerous outcomes with lower rate of mortality

10. • Examples:
• Anticoagulants (e.g., wafarin, heparin) – bleeding
• Antihypertensives (e.g.. α1-antagonists) – hypotension
• Antidiabetics (e.g. insulin) - hypoglycemia
• 1-blockers (e.g. metoprolol)
• Symptomatic heart failure inpatients with previous systolic dysfunction
• Bronchoconstriction in patients with COPD
• Antiepileptics blocking Na+ channel (e.g., phenytoin) – neurological
symptoms - vertigo, ataxia, confusion
• Intervention – dose reduction in most cases, use of antagonist in
serious circumstances
• Prevention: dose titration, adverse effects monitoring,
pharmacotherapy monitoring (PK and PD principle)
Adverse effects
Type A (augmented)

11. Adverse effects
Type B (bizzare)
• Develop on the basis of:
• Immunological reaction on a drug (allergy)
• Genetic predisposition (idiosyncratic reactions)
• Have no direct relationship to
• the dose of the drug
• The pharmacological mechanism of drug action
• Are generally unexpected and therefore unpredictable
• They appear with much lower frequency (0,1-0,01%)
• Have more serious clinical outcomes with higher overall mortality
• Intervention: instant drug withdrawal, symptomatic treatment
• pharmacological approach in allergy: antihistamines, adrenalin
(epinephrine) , glucocorticoids …
• Prevention: troublesome, the risks can be reduced by dutiful drug-
related anamnesis (re-occurrence), by avoiding certain drugs with
known significant risk of B-type reactions
• Allergy: dermatological testing, in vitro testing (mixed outcomes),
desensitization
• Idiosyncratic reactions: genotyping, phenotyping

12. Adverse effects - Type B
Allergic reactions
• Based on immunological mechanism
• They require previous exposition before actual manifestation
• Molecular weight of most drugs is low (Mr<1000) which is NOT
enough for direct immunogenicity
• Exception: peptides and proteins of non-human origin
• Immunogenicity can be acquired
• By binding of LMW drug (as a hapten) on the macromolecular
carrier
• Covalent bond is usually needed
• Carrier is usually protein – e.g.. Plasma proteins (albumin) or proteins on the
cell surface
• E.g. penicillin is covalently bound to albumin
• LMW drug (prohapten) is metabolized to the reactive metabolite,
which acts as a hapten and is bound to the carrier
• E.g., sulfamethoxazole
• LMW drug interacts with receptors of immunity systems
• Direct binding to T-cell receptors (TCR), enhanced by MHC system

13. Adverse effects - Type B
Allergic reactions
• Route of administration impact
• Higher probability of both occurrence and increased severity after
parenteral (injectional) administration !);
• mind the effectiveness of antigen presenting process
• Relatively high probability after application on the skin
• Significantly lower probability after p.o. administration
• Not only a active substance can be responsible for
allergic reactions
• excipients – antimicrobial agents, preservants
- E.g., parabens
- must be listed in the Summary of Product
Characteristics (SPC!)
- In the case of known allergy to common excipients the generic
prescription should be avoided
- Drug decomposition products, impurities etc.: they are under
control of the national authorities (FDA…)
- appropriate storage, use and expiration should be followed

14. Adverse effects - Type B
Allergic reactions - classification
• They are divided according to the prevailing
immunological mechanism into 4 groups (Gell-
Coombs classification system):
• TYPE I (IgE-mediated, immediate reactions)
• TYPE II (cytotoxic reactions)
• TYPE III (immunocomplex reactions)
• TYPE IV (delayed, cell-mediated reactions)
• Newer classification:
• Taking into account T-cell subtypes (Th1/Th2, Cytotox. T-
cells), specificity of the cytokine signaling and different
effectors (monocytes, eaosinophils, CD8 T-cells, neutrophils)
• TYP IV – a, b ,c, d

15. Allergic reactions – TYPE I
IgE-mediated• Sensitisation phase
• Immunogenic complex (drug-carrier) induces production of specific
IgE antibodies
• IgE ab is bound on the cell surface of mast cells and basophiles via
high affinity receptors
• Allergic reaction triggering
• After re-exposition, the drug+carrier is directly bound on the IgE
• Cross-linking of the IgE
• Degranulation of the mast cells = release of histamine, leukotriens,
prostaglandins → inflammatory reaction!
• Rubor, calor, dolor a tumor (heat pain and swelling)
• Clinical manifestation: urticaria, itching, nose/eye
hyperemia(excess of blood supply to the particular body part) and
secretion, soft-tissue swelling, bronchospasm, anaphylactic
reaction
• Time window: after previous sensitization the onset is very rapid
one (seconds to minutes)
• Examples: penicilins, cephalosporins, quinolones, macrolides,
streptokinase, thiazides, salicylates and skeletal muscle
relaxants, local anesthetics

16. Allergic reactions – TYPE I
IgE-mediated
• Anaphylactic reactions
• More complex (multiorgan) and more serious type I reactions
• Onset mostly within 15 min after drug administration
• First symptoms: itching (mostly palmar, plantar a axilles)
• Thereafter: diffuse erythema (first on the trunk – becomes generalized),
urticaria
• Soft-tissue edema (peri - orbital, -oral, - genital)
• Laryngeal edema (difficulties with speaking, swallowing, breathing)
• Pressure on the chest and dyspnoe – bronchospasm
• Hypotension, arrhythmias
• 75% of cases are due to the penicillins
• Anaphylactic shock
• Shock or shock-like status as a result of fully blown multiorgan
anaphylaxis with possible progression into the total collapse
• Lethal in 1-2% cases
• Risk factors: higher dose, asthma, atopic anamnesis(recollection of
episode), elderly
• pharmacological treatment: adrenalin + glucocorticoids i.v.,
antihistamines

17. Allergic reactions – TYPE II
Cytotoxic
• Drug (hapten) is bound on the surface of target
cells (these are carriers)
• Antibody production: IgG (IgG1 and IgG3), rarely IgM
• After re-exposition – the drug is bound again on the
cell surface and IgG is attached
• The activation of the complement system and NK
cells execute the cytotoxic reactions
• The cell is destructed and/or taken up by the RES
• The main target cells: erythrocytes, leukocytes,
trombocytes, hematopoietic cells –
• Clinical outcome: anemia or - penia
• Drugs: quinidine, heparin, sulfonamides,
cephalosporins, penicillins, anticonvulsants….

18. Allergic reactions – TYPE II
Cytotoxic
• Hemolytic anemia
• Associated with cephalosporins, penicilins, quinidine,
levodopa, methyldopa, some NSAIDs
• Symptoms: like in other anemia + jaundice, dark urine
• Lab. picture: erythrocytopenia, reticulocytosis and billirubin
(unconjugated); hemoglobin a hemosiderin in urine
• Thrombocytopenia
• Associated with heparin (up to 5% patients), quinine
quinidine, sulfonamides and biologicals (-mabs, e.g.,
bevacizumab)
• Symptoms: petechial(reddish) bleeding to the skin and
mucosa, GIT and urogenital tract bleeding
• Reversibility: in usually in 3-5 days

19. Allergic reactions – TYPE III
Immunocomplex reactions
• Drug-carrier or drug as a chimeric protein induces
production of IgG antibodies
• Formation of IgG-drug(carrier) complexes
• Normally these complexes are cleared by the RES with
only some decrease in the clinical response
• In some circumstances (huge amount of complexes,
deficient decomposition system) it results to
development of symptomatic reaction
• Time window: 1-3 weeks after exposition
• Epidemiology: 1-3:100 000 patients
• Arthus reaction: A reaction after vaccination.

20. Allergic reactions – TYPE III
Immunocomplex reactions
• Clinical manifestation: vasculitis and/or serum sickness,
• Urticaria, dermatol. affections, pruritus, fever, arthritis/arthralgia,
glomerulonephritis, lyfmadenopathy
• Serum sickness first described after passive immunization
with animal serum
• Within 4-10 day the abs were produced and formed complexes
with antigenic proteins.
• These complexes were deposited in postcapillary venules and
attracted neutrophils
• Development of inflammation with release of proteolytic enzymes
destructing vessel and surrounding tissue
• Drugs: chimeric abs (e.g., infliximab) or cephalosporins (cefaclor,
cefalexin), amoxicillin, sulfamethoxazole/trimethoprim, NSAIDs,
amiodaron

21. Allergic reactions – TYPE IV
Delayed, cell-mediated reaction
• Cellular reaction mediated by T-cells
• General principle: drug-carrier complex is presented by
APC to T-cells with their following clonal proliferation
• After re-exposition the drug gets into contact with T-cells
with release of specific cytokines and inflammatory
mediators which activate the target cells
• Clinical manifestation: mostly drug-related contact
dermatitis (rash) in many forms + pruritus, tuberculin
reaction, maculopapular exanthema or e.g. allergic
hepatitis
• Drugs: aminoglycosides, penicillins…..
• Time window: 2-8 days

24. Pseudoalergic reactions
• Are NOT immune reactions
• The are induced by direct activation of mast cells or by
displacing histamine from granules
• IgE are NOT increased
• Are as frequent as true type I reactions (IgE-mediated)
• Clinical manifestation is very close or even indistinguishable
from type I reactions
• Mostly less severe (erythema, urticaria)
• Onset can be slower then in true type I
• May require higher doses
• Anaphylactoid forms can occur
• Drugs: NSAIDs, vancomycin, opiates, radiocontrast agents

25. Adverse effects
Type B – idiosyncratic reactions
•Do not require any prior sensitization
•Are primarily genetically determined
deviations in the human metabolism or
biotransformation of the drugs
• atypical acetylcholinesterase (AChE) abnormally
slow degradation of the suxamethonium
(depolarizing peripheral myorelaxans)
• Apnoe is lasting up to 2 hours instead of 2min
• Deficient glucosa-6-phosphate dehydrogenase – higher
susceptibility of Ery to hemolytic anemia development (
e.g., in quinidine)

26. Examples of Type A a B adverse reactions
Drug Type A Type B
ampicillin pseudomembranous
collitis
Interstitial
nephritis
chlorpromazine sedation hepatotoxicity
naproxen Peptic ulcer
development
agranulocytosis

27. Adverse effects
Type C – Chronic (continous) use
• Are not as frequent as type A
• They are mostly associated with cumulative-long term
exposition inducing a toxic response
• Mostly the accumulation is not humoral but is that of
functional and/or ultrastructural changes induced by a drug
• Direct relationship to the cumulative dose
• Example: suppression of the hypothalamus-pituitary gland-
adrenal cortex by long term systemic treatment with
glucocorticoids
• Toxicity of the drug after long-term treatment with therapeutic
doses
• Analgesic (NSAID) nephropathy – interstitial nephritis, papillary
sclerosis, necrosis,
• Mechanism: unclear, deficit of prostaglandins?! NSAIDs
inhibit their formation

28. Adverse effects
Type C – Chronic (continous) use
•Anthracycline cardiotoxicity – with increasing
cumulative dose the degenerative changes
within cardiomyocytes occurs (loss of
myofibrils, vacuolization of cytoplasm,
• dilated cardiomyopathy with HF
• Ethiopathogenesis: unknown,
• mitochondriopathy, apoptosis….
• Treatment: troublesome, largely irreversible in higher
cumulative doses
• General prevention: cumulative dose reduction,
limitation of time of exposure, monitoring, prevention of
non-compliance and drug abuse

29. Adverse effects
Type D – Delayed
• They manifest themselves with significant delay
• Teratogenesis,
• Mutagenesis/cancerogenesis
• others: e.g., tardive dyskinesis(repetitive body movement) –
during L-DOPA Parkinson disease treatment

30. Adverse effects
Type D –– Teratogenicity
• Drug induced deviation from normal prenatal development
• Time window: from zygota to birth
• Possible consequences: embryo/fetus death, morphologic
malformations, functional defects and defects (incl. behavioral),
developmental retardation…
• Prerequisite: penetration of placental barrier
• Small molecules (Mr< 500), lipophilic enough
• Utilization of endogenous transporting mechanisms
• Protective mechanisms: efflux transporters (P-gp) and CYP450
• According to the materno-fetal distribution we distinguish drugs into
3 groups:
• Homogenous distribution between mother and fetus: amoxicillin,
morphine, paracetamol, nitrazepam
• Higher concentration in foetus: valproate, ketamine, diazepam
• Higher concentration in mother: prazosin, furosemide

31. Adverse effects
Type D –– Teratogenicity
• Teratogenic effects largely depends on the phase of
intrauterine development
• Blastogenesis (0.-14. day) – mostly dead, or damage is
compensated without further consequences Organogenesis
(15.-90. day) – gross anatomic malformations of different
type
• Fetal development (90.-280. day) – no gross anatomic but
rather different functional deficits of the target tissue (often
CNS)
• All drugs must be carefully tested for teratogenicity
during their preclinical development
• At least two animal species (one rodent and one non-rodent)
• Interspecies differences in morphology of placenta

32. Adverse effects
Type D –– Teratogenicity
• Certain teratogens
• Thalidomide – phocomelia („flipper-like hands)
• Antifolates – abortus, suppression of hematopoiesis
• Isoretinoin and vitamin A (high doses) – heart malformation and
hydrocephalon
• Warfarin – chondrodysplasa, facial abnormalities, CNS defects
• Valproate – defect of the neural tube: spina bifida
• Teratogens suspect
• Tetracyclines – teeth and bone defects
• Lithium – heart malformation
• Glucocorticoids – growth retardation, cleft palate
• ACE-inhibitors – renal failure in fetus, oligohydramnion (deficiency of
amniotic fluid), fetal hypotension, pulmonary hypoplasia or intrauterine
death
• Phenytoin – fetal hydantoin syndrome (craniofacial malformations,
microcephalon and cleft palate)
• Carbamazepine – craniofacial malformations

33. Adverse effects
Type D –– Teratogenicity
thalidomide

34. Adverse effects Type D
– mutagenicity and carcinogenicity
• Mutation = suddenly occurring and persisting change in the genome which
is spreading further by cell replication
• Some mutations may impair tight regulation of the cellular proliferation and
differentiation resulting into the tumor formation – carcinogenesis
• 60-70% of carcinogenic events are induced by chemical compounds (i.e.
also with drugs)
• This is specifically important for most of anticancer drugs, especially for
those directly interacting with DNA – alkylating cytostatics, cisplatin etc
• Risk of secondary malignancies !!!
• Test for mutagenicity: in vitro Ames test – cultivation of S. typhimurium, i.e.
strain which is unable to biosynthesize histidine (it must be supplied in the
media).…upon exposure to drug in histidine-free media it is sought whether
any drug-induced mutation can allow the bacteria to synthesize histidine
again
• In vivo testing for carcinogenicity – long-lasting, time and work-consuming
tests, sometimes uneasy to predict translatability to humans (applies for
suspicious drug intended for long-term use)

35. Adverse effects
Type E – End of use
• Drug withdrawal syndromes and rebound phenomenons
• Typical example – sudden withdrawal of long term therapy
with -blockers can induce rebound tachycardia and
hypertension)
• Reason: Up-regulation of the receptors during chronic
treatment)
• Withdrawal of long-term systemic treatment with
glucocorticoids – adrenal insufficiency with risk of coma
and death
• Withdrawal syndrome in drug dependence
• Prevention: rather avoid abrupt withdrawals, slow
decrease in dose is helpful, avoid long treatment with
such drugs if possible

36. Adverse drug effects inpractice:
According to Ritter (1995)
Up to 80 % adverse reactions are of A type
• 3 % emergency cases
• 2-3 % in the care of GPs
• In the hospital they make up to 10-20 % of all treatments
• mortality rate is 0,3-1 %.
• Additional costs!
Risk factors:
• age (newborns and young children, elderly)
• females
• liver and renal disease in anamnesis
• any such adverse reaction in anamnesis
Onset
• 1st-9th day after starting the pharmacotherapy

37. Most adverse reactions occur during the
treatment with:
DIGOXINE, ANTIBIOTICS, DIURETICS,
POSTASSIUM, ANALGESICS, SEDATIVES AND
NEUROLEPTICS, INSULIN, ASPIRIN,
GLUCOCORTICOIDS, ANTIHYPERTENSIVES AND
WARFARIN.
To recognize the adverse reaction is of same
importance as to be able to make right diagnosis
of a disease

38. Toxic drug effects
• Are induced by high single doses or long-term
therapy leading to high cumulative doses.
• Doses/duration of treatment is supratherapeutic!
• The safety for therapeutic use is defined by TI
• Drugs with low TI values are approved to get in to the clinical
practice only in the case of life-saving indications where risks
do not overweight the benefits
• They can be induced and manifested by
• As extremely escalated therapeutic effects (e.g., overdose
with anticoagulant drugs induce life-threatening bleeding
• By totally different mechanisms and symptoms with no
relationship to pharmacological action
• Covalent interactions often occur with destruction of
biomolecules and histopathological findings which might be
irreversible

39. Toxic effects
• Possible molecular consequences of the drug-
induced toxicity
• ROS production (often the metabolite is reactive
radical) with subsequent oxidative damage to
biomolecules (lipids, proteins, DNA)
• Ca2+ overload – activation of Ca-dependent
proteases, Ca accumulation in mitochondria and
impact on MPTP – depolarization of mitochondria
• Impaired ATP production
• Direct impact on gene expression
• Activation of proteolytic cascades
• Triggering of apoptosis

40. Toxic effects
• Prevention: reduction of individual dose, number of
individual dosage forms, monitoring of
pharmacotherapy
• Treatment:
• Non-specific treatment: to prevent or reduce
further drug absorption, to accelerate drug
elimination and support of vital functions
• Specific treatment: with antidotes taking
advantage of specific antagonisms (mostly
pharmacological)

41. Evaluation of toxic
effects of drugs
• Overlap of pharmacology and toxicology
• Paracelsus postulate
• MUST involve in vivo testing on experimental animals
• In vitro testing has only limited values for regulatory purposes
• Indispensable part of preclinical files of each drug which should be
• Approved for testing on human beings
• Approved for use in clinical practice
• Acute toxicity studies (TD50, LD50 – TI determination), subchronic toxicity
studies (90 days) and chronic toxicity studies (at least 1 year)
• Choice of animal species, strain, age, sex is of critical importance
• Control group – receives only drug vehicle, otherwise all must be same as in the
tested group
• Animal randomization into the groups (tested and control)
• After repeated administration testing – the investigators look for the signs of
drug accumulation, link to toxicokinetics
• Evaluated parameters: general toxicity – e.g., changes in appearance,
behavior, weight gain…
• Identification of target organ toxicities using histopathological an
biochemical, hematological approaches

42. Drugs and organ toxicity
• Nephrotoxicity
• Aminoglycosides, cyclosporin, ACE-inhibitors, NSAIDs, cisplatin,
amphotericin B, paracetamol
• Hepatotoxicity
• Paracetamol, isoniazid, halothan, methotrexate
• Neurotoxicity – vinca alcaloids
• Ototoxicity – gentamicin, furosemide
• Cardiotoxiicty
• anthracyclines, trastuzumab, tytosinkinase inhibitors,
catecholamines
• digoxin, antiarrhythmics
• GIT-toxicity – NSAIDs, cytostatics
• Phototoxicity – piroxicam, diclofenac a sulfonamides,
hydrochlorothiazide

43. Drugs and organ toxicity
- nephrotoxicity
• Special attention must be paid on elderly patients and
patients with prior kidney disease
• Renal function biomarker: creatininemia
• Aminoglycosides: active (saturable) transport into the
tubular cells
• ROS production, lysosomal enlargement and phospholipids inside,
apoptosis
• tubular toxicity
• Reduced glomerular filtration, increased
creatinineamia, and blood urea – renal failure!
• Once daily
• Special risks in newborn (esp. Immature)
• TDM

44. Drugs and organ toxicity
- nephrotoxicity
• Tubular toxicity also in: cisplatin, vankomycin
• Endotelial toxicity: cyclosporin, tacrolimus
• Decreased renal perfusion (due to the vasoconstriction):
NSAIDs, cyclosporin, tacrolimus, amphotericine B
• Crystaluria: sulfonamides, acyclovir
NSAIDs:
1. Single high dose induced acute renal failure with oligouria
(due to the vasoconstriction and drop in GF)
2. Chronic analgesic nephropathy– papillary necrosis,
chronic interstitial nephritis (ischemia?). Irreversibility !!!
3. Interstitial nephritis (rare) – increased creatininemia with
proteinuria (reversible, return to normal after 1-3 months

45. Drugs and organ toxicity
- nephrotoxicity
•Cyclosporin
• Acute reversible renal dysfunction (due to the
vasoconstriction)
• Acute vasculopathy (non-inflammatory injury to
arterioles and glomerulus)
• Chronic nephropathy with interstitial fibrosis
Renal hypertension is frequent!!!!
• Cisplatin – acute and chronic renal failure (focal
necrosis in in multiple segments of the nephron)
• Paracetamol – in overdose: necrosis of cells of
proximal tubules
•ACE-inhibitors – in higher doses, esp. captopril,
in bilateral stenosis of renal artery
– risk of severe acute renal failure

46. Drugs and organ toxicity
- hepatotoxicity
•The most important case: paracetamol
overdose
• Paracetamol is a very safe drug in normal doses (OTC drug)
• However, in overdose (10-15g in a healthy adults) it leads to
life-threatening hepatotoxicity and nephrotoxicity
• Responsible is a reactive metabolite N-acetyl-p-benzoquinon
imin, which oversaturates its detoxification metabolism based on
conjugation with GSH
This triggers a severe oxidative stress in hepatocytes which
results in to the damage of biomolecules and necrotic cell death
of hepatocyte
• Risk factors – age (more likely in children), alcoholism, liver disease
in anamnesis
• Treatment: acetylcysteine i.v. ASAP – donates SH to reduce GSH
depletion in the liver

47. Drugs and organ toxicity
- hepatotoxicity
•Risk of hepatocellular necrosis also in:
halothan and isoniazid
•Hepatic cirrhosis/fibrosis – methotrexate
after long-term use
•Cholestatic hepatitis: chlorpomazine,
estrogens, cyclosporin

48. Ac-glucuronide Ac Ac-sulfate
Reactive electrophilic
compound (NAPBQI*)
GSH Cell macromolecules
(proteins)
GS-NAPBQI NAPBQI-protein
Ac-mercapturate Hepatic cell death
Hepatotoxicity of paracetamol

49. Drugs and organ toxicity
- cardiotoxicity
• Impaired cardiac function – induction of arrhythmias
• Most of antiarrhythmics have also proarhythmogenic
effects
• DAD after digoxin – bigeminias, trigeminias etc
• Methylxantins – theophylline
• Tricyclic antidepressants - amitriptyline
• Drug-induced long QT syndrome - predisposition for
polymorphic ventricular arrhythmias of the torsade
de point type, which may be fatal
• Safety pharmacology- QT interval testing in new drugs
• Reason for drug withdrawal from market in many cases:
cisapride, terfenadine…
• The risk is present in some currently prescribed drugs:
drugs in psychiatry: some antidepressants and
antipsychotics, macrolides, fluoroquinolones…

50. Drugs and organ toxicity
- cardiotoxicity
•Induction of cardiomyopathy and/or chronic heart
failure
•Anthracyclines, trastuzumab, tyrosinkinase
inhibitors (sunitinib), tacrolimus, reverse
transcriptase inhibitors
• Anthracycline cardiotoxicity
• Acute – mostly subclinical ECG changes
• Subacute – myocarditis-pericarditis (rarely seen)
• Chronic (within 1 year)
• Delayed (late onset, 1-20 years after the chemotherapy)
• Chronic and delayed forms depend on the cumulative dose
• Options for prevention: pharmacological cardioprotection with
dexrazoxane, targeted distribution of anthracyclines (liposomes)
• Mechanism of toxic action? The classic „ROS and iron“ hypothesis
but it is rather multifactorial and less sure