adverse and toxic drug reactions

8/10/2019 Adverse and Toxic Drug Reactions

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Pharmacotherapeutic

complications

2009

Martin trba, PharmD. PhD.Department of Pharmacology


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Pharmacotherapeuticcomplications

Adverse and toxic effects of drugsDrug interactions (drug-drug) Food and drug interactions

Drug dependence and abuseThere is no ideal drug which is free of risks ofpharmacotherapeutic complications The knowledge and understanding of

pharmacotherapeutic risks is essential for safe useof 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 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 andnox

ious (harmful) response that occurs at normal dosesof the drug used for prophylaxis, diagnosis andtreatment 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 theweak form of the adverse effect which is unpleasant but generallyacceptable. The marked changes in dosage schedule or drugwithdrawal are usually not necessarily.

E.g. weak sedation with H1-antihistamines, constipation with opioids, drymouth with antimuscarinics

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


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Toxic drug reaction Unintended, primarily harmful and reactions occurring at high

(supratherapeutic) doses and/or after long treatment (acuteor chronic overdose).

Toxic effects are often associated with morphologic changes which might be irreversible .

Reasons:Iatrogenic intoxication medication error, critical situationswhen high drug doses are neededNon-compliance and patients errors (multiple pharm. prep. withsame active drug), self-administration (overdose) in childrenSuicidal attempts (antidepressants...)

Paracelsus: only the dose makes the difference between thedrug and poison

Precise preclinical characterization of toxic drug effects is amandatory part of the request for approval of the drug forclinical investigation and the same applies for final approvalfor its clinical use

Adverse toxic reactions

terminology


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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 pharmacodynamicsPredisposition due to the concomitant pathology pay appropriate attention on CONTRAINDICATIONSOr patient non-compliance (e.g. failure to follow all instructions)

Are well predictable with respect to both their clinical manifestation andprobability of onset

Type A is the most frequent type of adverse effects (76%)They have relatively less dangerous outcomes with lower rate of mortalit


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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 systolicdysfunctionBronchoconstriction 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 inserious circumstancesPrevention: dose titration, adverse effects monitoring,

pharmacotherapy monitoring (PK and PD principle)

Adverse effects

Type A (augmented)


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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 unpredictableThey appear with much lower frequency (0,1-0,01%)Have more serious clinical outcomes with higher overall mortalityIntervention: 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 significantrisk of B-type reactions Allergy: dermatological testing, in vitro testing (mixed outcomes),

desensitization Idiosyncratic reactions: genotyping, phenotyping

Adverse effectsType B (bizzare)


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Adverse effects - T ype BAllergic reactions

Based on immunological mechanismThey require previous exposition before actual manifestationMolecular weight of most drugs is low (Mr


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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 skinSignificantly lower probability after p.o. administrationNot only a active substance can be responsible forallergic reactions excipients antimicrobial agents, preservants

- E.g., parabens- must be listed in the Summary of ProductCharacteristics (SPC!)

- In the case of known allergy to common excipients the genericprescription should be avoided

- Drug decomposition products, impurities etc.: they are undercontrol of the national authorities (FDA)

- appropriate storage, use and expiration should be followed

Adverse effects - T ype BAllergic reactions


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They are divided according to the prevailingimmunological 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 differenteffectors (monocytes, eaosinophils, CD8 T-cells,neutrophils)

TYP IV a, b ,c, d

Adverse effects - T ype BAllergic reactions - classification


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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 hyperemiaand secretion, soft-tissue swelling, bronchospasm, anaphylacticreactionTime window: after previous sensitization the onset is very rapidone (seconds to minutes)Examples: penicilins, cephalosporins, quinolones, macrolides,

streptokinase, thiazides, salicylates and skeletal musclerelaxants, local anesthetics

Allergic reactions TYPE IIgE-mediated


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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 IIgE-mediated


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Drug (hapten) is bound on the surface of targetcells (these are carri ers)

Antibody production: IgG (IgG1 and IgG3), rarely

IgM After re-exposition the drug is bound again on thecell surface and IgG is attachedThe activation of the complement system and NKcells execute the cytotoxic reactions

The cell is destructed and/or taken up by the RESThe main target cells: erythrocytes, leukocytes,trombocytes, hematopoietic cells Clinical outcome: anemia or - peniaDrugs: quinidine, heparin, sulfonamides,cephalosporins, penici llins, anticonvulsants.

Allergic reactions TYPE IICytotoxic


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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 inurine

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 IICytotoxic


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Allergic reactions TYPE IIIImmunocomplex reactions

Drug-carrier or drug as a chimeric protein inducesproduction of IgG antibodies

Formation of IgG-drug(carrier) complexesNormally these complexes are cleared by the RESwith only some decrease in the clinical response

In some circumstances (huge amount of complexes,deficient decomposition system) it results todevelopment of symptomatic reactionTime window: 1-3 weeks after expositionEpidemiology: 1-3:100 000 patients


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Clinical manifestation: vasculitis and/or serum sickness,Urticaria, dermatol. affections, pruritus, fever, arthritis/arthralgia,glomerulonephritis, lyfmadenopathy

Serum sickness first described after passive immunizationwith animal serumWithin 4-10 day the abs were produced and formed complexeswith antigenic proteins.These complexes were deposited in postcapillary venules andattracted neutrophils

Development of inflammation with release of proteolyticenzymes destructing vessel and surrounding tissue

Drugs: chimeric abs (e.g., infliximab) or cephalosporins(cefaclor, cefalexin), amoxicillin,sulfamethoxazole/trimethoprim, NSAIDs, amiodaron

Allergic reactions TYPE IIIImmunocomplex reactions


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Cellular reaction mediated by T-cellsGeneral 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 inflammatorymediators which activate the target cellsClinical manifestation : mostly drug-related contact

dermatitis (rash) in many forms + pruritus, tuberculinreaction, maculopapular exanthema or e.g. allergichepatitisDrugs: aminoglycosides, penicillins.. Time window: 2-8 days

Allergic reactions TYPE IVDelayed, cell-mediated reaction


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Pseudoalergic reactions

Are NOT immune reactionsThe are induced by direct activation of mast cells or bydisplacing histamine from granules

IgE are NOT increased Are as frequent as true type I reactions (IgE-mediated)Clinical manifestation is very close or evenindistinguishable 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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Do not require any prior sensitization Are primarily genetically determined

deviations in the human metabolism orbiotransformation of the drugs atypical acetylcholinesterase (AChE) abnormally

slow degradation of the suxamethonium

(depolarizing peripheral myorelaxans) Apnoe is lasting up to 2 hours instead of 2minDeficient glucosa-6-phosphate dehydrogenase higher susceptibility of Ery to hemolytic anemiadevelopment ( e.g., in quinidine)

Adverse effectsType B idiosyncratic reactions


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Examples of Type A a B adverse reactions

Drug Type A Type Bampicillin pseudomembranous

collitisInterstitialnephritis

chlorpromazine sedation hepatotoxicity

naproxen Peptic ulcerdevelopment agranulocytosis


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Adverse effectsType C Chronic (continous) use Are not as frequent as type AThey are mostly associated with cumulative-long termexposition inducing a toxic response Mostly the accumulation is not humoral but is that of

functional and/or ultrastructural changes induced by a drugDirect relationship to the cumulative doseExample: suppression of the hypothalamus-pituitary gland-adrenal cortex by long term systemic treatment withglucocorticoids

Toxicity of the drug after long-term treatment with therapeuticdoses Analgesic (NSAID) nephropathy interstitial nephritis,papillary sclerosis, necrosis, Mechanism: unclear, deficit of prostaglandins?! NSAIDs

inhibit their formation


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Adverse effectsType C Chronic (continous) use

Anthracycline cardiotoxicity with increasingcumulative dose the degenerative changeswithin cardiomyocytes occurs (loss ofmyofibrils, vacuolization of cytoplasm, dilated cardiomyopathy with HF

Ethiopathogenesis: unknown, ROS?,mitochondriopathy, apoptosis.

Treatment : troublesome, largely irreversible in highercumulative doses

General prevention : cumulative dose reduction,limitation of time of exposure, monitoring, preventionof non-compliance and drug abuse


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Adverse effectsType D Delayed

They manifest themselves withsignificant delay Teratogenesis, Mutagenesis/cancerogenesis others: e.g., tardive dyskinesis

during L-DOPA Parkinson diseasetreatment


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Drug induced deviation from normal prenatal developmentTime window: from zygota to birth

Possible consequences: embryo/fetus death, morphologicmalformations, 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 into3 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 effectsType D Teratogenicity


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Teratogenic effects largely depends on the phaseof intrauterine development Blastogenesis (0.-14. day) mostly dead, or damage is

compensated without further consequencesOrganogenesis (15.-90. day ) gross anatomicmalformations of different type

Fetal development (90.-280. day) no gross anatomic butrather different functional deficits of the target tissue (oftenCNS)

All drugs must be carefully tested for teratogenicityduring their preclinical development At least two animal species (one rodent and one non-

rodent)

Interspecies differences in morphology of placenta



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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 Teratogenicitythalidomide
http://upload.wikimedia.org/wikipedia/it/0/05/Talidomide_struttura.PNG


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Mutation = suddenly occurring and persisting change in the genomewhich is spreading further by cell replication

Some mutations may impair tight regulation of the cellular proliferation anddifferentiation 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 forthose 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 themedia).upon exposure to drug in histidine -free media it is soughtwhether any drug-induced mutation can allow the bacteria to synthesizehistidine again

In vivo testing for carcinogenicity long-lasting, time and work-consumingtests, sometimes uneasy to predict translatability to humans (applies for

suspicious drug intended for long-term use)

Adverse effects Type D mutagenicity and carcinogenicity


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Drug withdrawal syndromes and rebound phenomenonsTypical example sudden withdrawal of long termtherapy with -blockers can induce rebound tachycardia

and hypertension) Reason : Up-regulation of the receptors during chronictreatment)

Withdrawal of long-term systemic treatment withglucocorticoids adrenal insufficiency with risk of comaand deathWithdrawal syndrome in drug dependencePrevention: rather avoid abrupt withdrawals, slowdecrease in dose is helpful, avoid long treatment with

such drugs if possible

Adverse effectsType E End of use


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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 thetreatment with:

DIGOXINE, ANTIBIOTICS, DIURETICS,POSTASSIUM, ANALGESICS, SEDATIVES ANDNEUROLEPTICS, INSULIN, ASPIRIN,GLUCOCORTICOIDS, ANTIHYPERTENSIVES AND

WARFARIN.

To recognize the adverse reaction is of sameimportance as to be able to make right diagnosisof a disease


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TOXIC EFFECTS


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Are induced by high single doses or long-termtherapy 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 indicationswhere 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 actionCovalent interactions often occur with destruction of

biomolecules and histopathological findings which might beirreversible

Toxic drug effects


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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 tobiomolecules (lipids, proteins, DNA) Ca 2+ overload activation of Ca-dependent

proteases, Ca accumulation in mitochondria andimpact on MPTP depolarization ofmitochondria

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, monitoringof pharmacotherapy

Treatment: Non-specific treatment: to prevent or reduce

further drug absorption, to accelerate drugelimination and support of vital functions

Specific treatment: with antidotes takingadvantage of specific antagonisms (mostlypharmacological)


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Evaluation of toxiceffects of drugs

Overlap of pharmacology and toxicologyParacelsus postulateMUST 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 (TD 50 , LD50 TI determination), subchronic toxicitystudies (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 anbiochemical, hematological approaches


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Drugs and organ toxicity

Nephrotoxicity Aminoglycosides, cyclosporin, ACE-inhibitors, NSAIDs,

cisplatin, amphotericin B, paracetamolHepatotoxicity

Paracetamol, isoniazid, halothan, methotrexateNeurotoxicity vinca alcaloidsOtotoxicity gentamicin, furosemideCardiotoxiicty

anthracyclines, trastuzumab, tytosinkinase inhibitors,catecholamines digoxin, antiarrhythmics

GIT-toxicity NSAIDs, cytostaticsPhototoxicity piroxicam, diclofenac a sulfonamides,

hydrochlorothiazide


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Special attention must be paid on elderly patients andpatients with prior kidney diseaseRenal function biomarker: creatininemia

Aminoglycosides : active (saturable) transport into thetubular cells ROS production, lysosomal enlargement and phospholipids

inside, apoptosis tubular toxicity

Reduced glomerular filtration, increasedcreatinineamia, and blood urea renal failure!

Once daily Special risks in newborn (esp. Immature)

TDM

Drugs and organ toxicity- nephrotoxicity


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Tubular toxicity also in: cisplatin, vankomycinEndotelial toxicity: cyclosporin, tacrolimusDecreased renal perfusion (due to the vasoconstriction):NSAIDs, cyclosporin, tacrolimus, amphotericine BCrystaluria: 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


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Cyclosporin Acute reversible renal dysfunction (due to the

vasoconstriction) Acute vasculopathy (non-inflammatory injury to

arterioles and glomerulus) Chronic nephropathy with interstitial fibrosisRenal hypertension is frequent!!!!

Cisplatin acute and chronic renal failure (focalnecrosis in in multiple segments of the nephron)Paracetamol in overdose: necrosis of cells ofproximal tubulesACE-inhibitors in higher doses, esp.captopril, in bilateral stenosis of renal artery

risk of severe acute renal failure



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The most important case: paracetamoloverdose 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 nephrotoxicityResponsible is a reactive metabolite N-acetyl-p-benzoquinonimin , which oversaturates its detoxification metabolism basedon conjugation with GSHThis triggers a severe oxidative stress in hepatocytes whichresults in to the damage of biomolecules and necrotic celldeath of hepatocyteRisk factors age (more likely in children), alcoholism, liverdisease in anamnesisTreatment: acetylcysteine i.v. ASAP donates SH to reduce GSHdepletion in the liver

Drugs and organ toxicity- hepatotoxicity


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Risk of hepatocellular necrosis also in:halothan and isoniazid

Hepatic cirrhosis/fibrosis methotrexateafter long-term use

Cholestatic hepatitis: chlorpomazine,estrogens, cyclosporin

Drugs and organ toxicity- hepatotoxicity


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Ac-glucuronide Ac Ac-sulfate

Reactive electrophiliccompound (NAPBQI*)

GSH Cell macromolecules(proteins)

GS-NAPBQI NAPBQI-protein

Ac-mercapturate Hepatic cell death

Hepatotoxicity of paracetamol


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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 fatalSafety pharmacology- QT interval testing in new drugsReason for drug withdrawal from market in many cases:cisapride, terfenadine The risk is present in some currently prescribed drugs:

drugs in psychiatry: some antidepressants andantipsychotics, macrolides, fluoroquinolones

Drugs and organ toxicity- cardiotoxicity


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Drugs and organ toxicity- cardiotoxicity

Induction of cardiomyopathy and/or chronicheart failure

Anthracyclines, trastuzumab, tyrosinkinaseinhibitors (sunitinib), tacrolimus, reversetranscriptase inhibitors Anthracycline cardiotoxicity

Acute mostly subclinical ECG changesSubacute 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)

adverse and toxic drug reactions

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