Bez nadpisu

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Pharmacotherapeutic complications
2009 Martin terba, PharmD. PhD. Department
of Pharmacology
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Pharmacotherapeuticcomplications

• 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

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Adverse and toxic effects of drugs
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Adverse ? toxic reactionsterminology

• 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.

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Adverse ? toxic reactionsterminology

• 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

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Adverse drug reactions
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Adverse effectsType 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

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Adverse effects Type A (augmented)

• Examples
• Anticoagulants (e.g., wafarin, heparin)
  bleeding
• Antihypertensives (e.g.. a1-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)

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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, 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

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Adverse effects - Type B Allergic reactions

• Based on immunological mechanism
• They require previous exposition before actual
  manifestation
• Molecular weight of most drugs is low (Mrlt1000)
  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

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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

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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

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Allergic reactions TYPE IIgE-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 drugcarrier 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

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Allergic reactions TYPE IIgE-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

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Allergic reactions TYPE IICytotoxic

• 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.

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Allergic reactions TYPE IICytotoxic

• 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

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Allergic reactions TYPE IIIImmunocomplex
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 1-3100 000 patients

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Allergic reactions TYPE IIIImmunocomplex
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

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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

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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

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Pseudoalergic urticaria
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Adverse effectsType 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)

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Examples of Type A a B adverse reactions
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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

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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

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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

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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 (Mrlt 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

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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

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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

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Adverse effects Type D Teratogenicity
thalidomide
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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)

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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

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• 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

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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
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TOXIC EFFECTS
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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

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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

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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)

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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

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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

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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

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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
• Single high dose induced acute renal failure with
  oligouria (due to the vasoconstriction and drop
  in GF)
• Chronic analgesic nephropathy papillary
  necrosis, chronic interstitial nephritis
  (ischemia?). Irreversibility !!!
• Interstitial nephritis (rare) increased
  creatininemia with proteinuria (reversible,
  return to normal after 1-3 months

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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

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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

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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

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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
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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

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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