Docstoc

Bez nadpisu

Document Sample
Bez nadpisu Powered By Docstoc
					Pharmacotherapeutic
   complications


           2009




 Martin Štěrba, 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 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
    – 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.. 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 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
            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 (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
     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 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
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                Type A                 Type B
  ampicillin      pseudomembranous            Interstitial
                        collitis               nephritis
chlorpromazine         sedation             hepatotoxicity
   naproxen           Peptic ulcer         agranulocytosis
                     development
    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
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 non-
      rodent)
    – 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 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
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