Pharmacotherapeutic

complications

2009

Martin trba, PharmD. PhD.

Department of Pharmacology

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

Adverse and toxic

effects of drugs

Adverse toxic reactions

terminology

Is far from being unified

Unwanted, adverse, side or toxiceffects/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
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.
E.g. weak sedation with H1-antihistamines, constipation with opioids, dry
mouth with antimuscarinics

Attention! The term side effects is often used as a synonym to adverse

effects.

Adverse toxic reactions

terminology

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.
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

Adverse drug reactions

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

Adverse effects
Type A (augmented)

Examples:
Anticoagulants (e.g., wafarin, heparin) bleeding
Antihypertensives (e.g.. 1-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 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 drugrelated anamnesis, 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

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

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

Adverse effects - Type B

Allergic reactions - classification

They are divided according to the prevailing

immunological mechanism into 4 groups (GellCoombs 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. Tcells), specificity of the cytokine signaling and different
effectors (monocytes, eaosinophils, CD8 T-cells,
neutrophils)
TYP IV a, b ,c, d

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

Clinical manifestation: urticaria, itching, nose/eye hyperemia

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

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, elderly
pharmacological treatment: adrenalin + glucocorticoids i.v.,
antihistamines

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.

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 bleeding to the skin and mucosa,
GIT and urogenital tract bleeding
Reversibility: in usually in 3-5 days

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

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

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 Tcells 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

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

Pseudoalergic urticaria

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)

Examples of Type A a B adverse reactions

Drug
ampicillin
chlorpromazine
naproxen

Type A
pseudomembranous
collitis
sedation
Peptic ulcer
development

Type B
Interstitial
nephritis
hepatotoxicity
agranulocytosis

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 glandadrenal 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

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, ROS?,
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

Adverse effects
Type D Delayed

They manifest themselves with

significant delay
Teratogenesis,
Mutagenesis/cancerogenesis
others: e.g., tardive dyskinesis
during L-DOPA Parkinson disease
treatment

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

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 nonrodent)
Interspecies differences in morphology of placenta

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, fetal
hypotension, pulmonary hypoplasia or intrauterine death
Phenytoin fetal hydantoin syndrome (craniofacial malformations,
microcephalon and cleft palate)
Carbamazepine craniofacial malformations

Adverse effects
Type D Teratogenicity
thalidomide

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)

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

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

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

TOXIC EFFECTS

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

Toxic effects

Possible molecular consequences of the druginduced 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

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)

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

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

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

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

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

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

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

Hepatotoxicity of paracetamol
Ac-glucuronide

Ac

Ac-sulfate

Reactive electrophilic
compound (NAPBQI*)
GSH

Cell macromolecules
(proteins)

GS-NAPBQI NAPBQI-protein
Ac-mercapturate

Hepatic cell death

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

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