PRESENTED BY: Dipesh H. Panchal M.Pharm Sem-III Roll no:18 DEPARTMENT OF PHARMACOLOGY, L. M.

COLLEGE OF PHARMACY, AHMEDABAD-09

 Drugs

induced CNS diseases Drugs induced Respiratory diseases Drugs induced blood disease Drugs induced Cardiovascular diseases Drugs induced Kidney diseases Drugs induced G.I. diseases

Drugs

induced diseases:

Any Drug which produced any condition that impairs normal function or any abnormal condition which affect the body of an organism.

Drugs induced Psychosis/Schizophrenia Excessive activity of Sympathomimetic activity by Drugs like Amphetamine, Cocain Toxic psychosis due to excessive anticholinergic intake Characterised by, dilated pupils, and blurred vision Amphetamine produced with single large doses but most often occur following long-term administration Manifestations include stereotypic behavior such as skin-picking, teeth-grinding, lip-biting, pacing, and pressured speech Physical signs with amphetamine toxicity, and indicating excessive sympathetic activity, include tachycardia, tachypnea, mild to moderate hypertension, hyperpyrexia, mydriasis with normal light reflex, and a fine tremor or muscle twitching Ingestion of high doses of amphetamines can lead to stroke, convulsions, cardiovascular collapse, respiratory depression, and death

 Cocaine psychosis similar to amphetamine and other sympathomimetic toxicities. Patient may exhibit euphoria, motor excitement, restlessness, and/or vivid auditory and visual hallucinations that take the form of a paranoid schizophreniform reaction with a tendency toward violent and as saultive behavior. Hallucinations thought to be specific for cocaine psychosis include delusions of parasitosis and of miniaturized visual perceptions Hyperreflexia, delirium, and death due to CV collapse or respiratory depression. Hyper pyrexia and generalized hypermetabolism may contribute to or cause CNS hemorrhage or convulsions LSD, has additional psychological manifestations. Acute panic reactions occur in about one in ten LSD uses

Acute psychotic reactions, occurring in one in 200 LSD users

Usually progress from a panic to a dissociative or schizophrenic like state

 LSD and psilocybin (mushrooms) are indole-containing hallucinogens that occur naturally and are related to the centrally-occurring neurotransmitter (5HT) Euphoria, impaired judgment, increased vividness of all sensory modalities, sensory distortions of a predominantly visual type, pseudohallucinations Mescaline, a hallucinogen epinephrine-related substance, and myristicin, a component of nutmeg

Phencyclidine developed as an anaesthetic but unsuitable due to sever psychiatric side effect include agitation, delirium, and psychosis

 Anticholinergics psychosis caused by almost all anticholinergic drugs, and plant alkaloids such as jimsonweed and angel's trumpet

Phenothiazines such as thioridazine and chlorpromazine may cause an anticholinergic syndrome when taken in excess or concomitantly with mescaline or phencyclidine
Other drugs with anticholinergic action include antidepressants, antihistamines, anti spasmodics, antiparkinsonian agents, ophthalmic solutions, and belladonna alkaloids such as atropine, sleeping medications, antihistamines, and preparations for colds

Menifestation with confusion, psychomotor agitation, auditory and visual hallucinations, and impairment of short term memory

 There are primary and secondary mechanisms of seizure Primary mechanisms : Substance that directly affect the CNS Examples include stimulants, isoniazid, theophylline etc. Medication withdrawal causes primary seizures as in alcohol withdrawal seizures (e.g. excessive stimulation of primed NMDA Receptors) Secondary seizures impaired substrate availability or utilization. Opiates causes hypoxia, blockade of oxygen utilization (e.g. CO, cyanide), reduced oxygen carriage capacity (e.g. Methemoglobinemia, anaemia), cerebral oedema, lack of energy (uncoupling of oxidative phosphorylation salicylate or dinitrophenol), or disturbances of glucose and electrolyte metabolism.

 In a recent article Thundiyil et al examined 386 cases of drug induced seizure reported

Buproprion was the leading cause (23%), followed by Diphenhydramine (8.3%), Tricyclic antidepressants (7.7%), Tramadol 7.5%, Amphetamines (6.9%,), Isoniazid (5.9%) and Venlafaxine (5.9%) Specific drugs Cocaine and other stimulants Antidepressants : Amoxapine Lithium, Anticholinergic Agents : Diphenhydramine Isoniazid toxicity causes seizures and severe metabolic acidosis. Theophylline

 Drug that blocks the action of dopamine is likely to cause parkinsonism Drugs used to treat schizophrenia and other psychotic disorders The atypical neuroleptics Clozapine, Quetiapine. Lesser extent Olanzapine, Risperidone have a lower incidence of extrapyramidal side effects Calcium channel blocking drugs Responsible agents are cinnarizine and flunarizine Other Drugs produced DIP. Amiodarone, Fluphenazine, Lithium, Methyldopa, Metoclopramide, Tranylcypromine, Prochlorperazine.

 Aim of the present study was to investigate changes in the plasma CGRP concentration and platelet serotonin content during the immediate headache and the delayed genuine migraine attack provoked by nitroglycerin. Basal CGRP concentration was significantly higher and platelet 5-HT content tended to be lower in Migraine patients Recently, found that CGRP-antagonist BIBN4096BS is able to inhibit vasodilatation induced by trigeminal ganglion stimulation

Caffeine and other stimulant also produced migraine

Cardiovascular Drugs: ACEIs: treatment of hypertension, especially in the presence of left ventricular dysfunction and CHF It produced Dry cough due to accumulation of bredykiknine. Bradykinin causes vasodilation and capillary leakage leading to side effects

Beta-Blockers: Small doses of beta-blockers can cause bronchospasm, with manifesting symptoms such as shortness of breath and wheezing
Amioderone: Dysrhythmia frequently treated with antiarrhythmic drug therapy Long-term use cause pulmonary complications like pneumonitis and acute respiratory distress syndrome (ARDS)

Anti-inflammatory agents: Patients commonly take NSAIDs & Aspirin for pain, without even consulting a doctor or a pharmacist

Aspirin and NSAIDs may precipitate asthmatic attacks in approximately 8% of asthma sufferers and these attacks can occasionally proceed to be potentially fatal
Patients with chronic rhinitis and nasal polyps are at greatest risk After aspirin, patients exhibit various symptoms such as rhinorrhea, dyspnoea and cough

Symptoms remains for 20 min to 3 hours after ingestion of the drugs

Lead to bronchospasm and angioedema with overproduction of leukotrienes leads to asthmatic reaction

Chemotherapeutic drugs:

Bleomycin : Bleomycin is deposited in the skin and lungs Chronic lung damage secondary to the use of bleomycin is rare though it can progress to o pulmonary fibrosis and death in a minority of patients The role of Interleukin-4 in the development of lung fibrosis is as yet unclear Doses of bleomycin <300mg, the incidence of pneumonitis is 3-5% whilst dose >500mg the incidence is 20% Mitomycin-C : Incidence of pulmonary toxicity with Mitomycin-C is about 5% and this includes bronchospasm, acute pneumonitis, haemolytic-uremic-like syndrome, acute lung injury, chronic interstitial pneumonitis, and pleural disease

Hypnotics and Sedatives:

Benzodiazepines can cause dependence the over use of this class of drugs Respiratory depression with diazepam may be detectable at doses of 14mg/adult

Resulting increase in CO2 is slight, & leads to decreased tidal volume.

Barbiturates are thought to induce respiratory depression by desensitization of the medulla to hypercapnia and These agents inhibit the respiratory rate and affect the depth and volume of inspiration

o Antimicrobial drugs Nitrofurantoin: commonly UTI infections, may cause Pulmonary disease with eosinophilia Initially the patient presents with fever, dyspnoea, cough and pulmonary infiltrates, and there is often marked peripheral blood eosinophilia

Sulphonamides and sulpha containing drugs Combination in co-trimoxazole, are known to cause pulmonary eosinophilia, and fibrosing alveolitis
Tetracyclines: Minocycline can cause pulmonary eosinophilia, Characterised by pulmonary infiltrates on the chest Xray Symptoms such as dyspnoea, eosinophilia in blood and BAL fluids, may cause respiratory failure

Illicit drugs: Chronic heavy marijuana use may predispose people to COPD Heroin is a derivative of morphine and can cause slow breathing by stimulation of receptors Reduction of oxygen in brain increase pCO2 with high doses, it can also depress the brains response to hypoxia This results in severe respiratory depression progressing to apnoea Therefore, fatal heroin overdose is nearly always caused by respiratory arrest Cocaine may cause wheezing which occurs from exacerbated asthma or hypersensitivity pneumonitis. Cocaine use may also lead to non-cardiogenic pulmonary oedema or to diffuse alveolar hemorrhage Long-term users of crack, a chemical derivative of cocaine, can suffer from bronchitis and other breathing problems

oMiscellaneous: Bromocriptine, a dopamine receptors agonist, can cause pulmonary fibrosis and pleural disease as well as nasal congestion. Venlafaxine a 5HT and NA reuptake inhibitor, may potentially cause pneumonitis Doxazosin, an -adrenoceptor blocking drug, may cause rhinitis Candersartan an angiotensin-II receptor antagonist, is URTI and influenzalike symptoms including rhinitis and pharyngitis

 Example of Drugs induced lung diseases Usual Interstitial Pneumonitis (UIP) Eosinophilic Pneumonia (EP) Hypersensitivity Pneumonitis (HSP) Bronchiolitis Obliterans (BO) Pulmonary Edema +/- Diffuse Alveolar Damage (DAD) Diffuse Alveolar Hemorrhage (DAH)

 Usual Interstitial Pneumonitis Cytotoxic agent (e.g. methotrexate, bleomycin) Repeated cycles of therapy causes direct injury or immune-mediated acute lung injury Loss of type 1 pneumocytes, decreased gas exchange and fibroblastic proliferation in the alveolar walls Risk of Pulm HTN, Lung Cancer and active inflammation

Eosinophilic Pneumonia Drugs: cytotoxic agents, penicillamine, sulfasalazine, nitrofurantoin, NSAIDS, ampicillin, cocaine Elevated levels of alveolar eosinophil Accumulation of eosinophils and macrophages within the alveolar spaces Releas of attractants (eg IL-5)

 Hypersensitivity Pneumonitis HSP may also be referred to as external allergic alveolitis Drugs: cytotoxic agents, penicillamine, nitrofurantoin, sulfa, NSAIDS Hyperreactive immune-mediated response to extrinsic antigen (eg drug) Acute dyspnea +/- chronic fibrosis involves immune complex and delayed-type hypersensitivity response

Bronchiolitis Obliterans (BO) Reactive inflammatory process of lower respiratory tract with granulation tissue obstructing the terminal bronchioles Drugs: cytotoxic agents, penicillamine, sulfasalazine Epithelial necrosis causes excessive granulation of tissue Luminal obstruction production of collateral air drift towards remaining bronchioles hyperinflation vasoconstriction (creating an emphysema-like effect) risk of hypoxia and pulmonary hypertension

 Pulmonary Edema Non-cardiogenic intra-alveolar edema Can be mild or severe, with more severe cases involving diffuse alveolar damage (DAD), and rarely ARDS Drugs: Many cytotoxic agents, cardiovascular drugs, renal drugs, neuropsychiatric, analgesics, recreational, etc Increased capillary permeability +/- alveolar epithelial damage (ie DAD) edema and hyaline membrane formation resolution or organization/fibrosis Diffuse Alveolar Hemorrhage (DAH) Drugs: cytoxic agents, anticoagulants, thrombolytics, antiplatelets, nitrofurantoin, propothiouracil, phenytoin, penicillamine Hemorrhage from the pulmonary microcirculation Which opposed to bleeds originating from bronchial circulation

Lupus Syndrome Procainamide, ethosuximide, hydralazine, penicillin, isoniazid, phenylbutazone Autoimmune disorder Drug-induced lupus syndrome is pleural involvement . Symptoms of acute pleuritis are common, and pleural effusions and fibrosis have been reported

Drug-induced Aplastic anaemia, Haemolytic anaemia, Thrombocytopenia, and Agranulocytosis reported

Antibacterials chloramphenico l, cotrimoxazole, Sulphonamides

Antiinflammatory agents: fenbufen, diclofenac, gold, indometacin, penicillamine, piroxicam

Antithyroid Antimalarials drugs pyrimethamine carbimazole, propylthiouracil

Antiepileptics lamotrigine, phenytoin, valproic acid, carbamazepine

Antidepressants Antihypertensiv and es antipsychotics lisinopril chlorpromazine, dosulepin

Antidiabetics chlorpropamide, tolbutamide Other acetazolamide

 Granulocytes and a neutrophil count of less than 0.5x109/l agranulocytosis

Drug-induced agranulocytosis can be caused by direct bone marrow toxicity or by immune mediated reaction
The antithyroid drugs carbimazole (Neo-Mercazole) an propylthiouracil carry a relatively high risk of haematological dysfunctions Fatalities caused by carbimazole and propylthiouracil reported to the Yellow Card scheme result from agranulocytosis and neutropenia including agranulocytosis

 The atypical antipsychotic clozapine is a known cause of agranulocytosis. It is associated with a 2-3 % incidence of neutropenia and a case fatality rate of between 4 and 16 % Its use is restricted to patients enrolled in strict blood-monitoring programmes Other psychotropic drugs and antidepressants have also been associated with agranulocytosis Chlorpromazine is associated with a delayed-onset agranulocytosis, with severe cases occurring in 0.1% of patients taking standard doses

PRCA is characterised by anaemia with a marked reduction in reticulocytes, and leads to weakness, pallor and lethargy in patients.

Around 5 % of cases are drug induced and many of the drugs associated with aplastic anaemia can cause PRCA.
Phenytoin, azathioprine, and isoniazid have been implicated in several case reports

 Severe reductions in platelet count to less than 150x109/l are indicative of thrombocytopenia Less serious signs, such as petechiae and purpura, can also give way to more severe haemorrhage in the GI and genitourinary tracts Cerebral haemorrhage is a common cause of death

Drug-induced thrombocytopenia can either be due to direct effects on the bone marrow, or through an autoimmune mechanism
Best-known drug associated with thrombocytopenia is heparin, which can cause mild to moderate thrombocytopenia (platelet count 50-150x109 /l)

 Heparin should be immediately discontinued Reaction involves a complex immune reaction The diagnosis is made by one or more clinical events and antibody detection Heparin, which can cause to thrombotic events such as myocardial infarction (MI) and strokes GP IIb/IIIa inhibitors, like abciximab, also associated with thrombocytopenia -lactam antibiotics have been associated with a seven-fold increase in risk for thrombocytopenia, by either an immune mediated mechanism or bone marrow suppression Other drugs have been associated with thrombocytopenia, including co-trimoxazole, acetazolamide, chlorpropamide, furosemide, diazepam, methyldopa, sodium valproate, thiazide diuretics, tolbutamide and trimethoprim

 Drug-associated haemolytic anaemia is thought to occur in approximately one in a million people, with four distinct mechanisms proposed for the majority of cases: Iimmune complex formation, Hapten formation, Autoantibody production and, in G6PD deficiency, Oxidative red cell damage Immune complexes seem to be the major cause, with quinine, quinidine, rifampicin, methotrexate, sulphonylureas and antihistamines among those associated

 Penicillin has been associated with hapten formation around 3% of patients receiving high doses will develop a positive antiglobulin test, of which a small proportion will develop haemolytic anaemia. A positive Coombs test can distinguish immune reactions from other causes of haemolytic anaemia.

Haemolysis caused by G6PD deficiency is dose dependent and increases with cumulative doses
Drugs with a definite risk of haemolysis include nitrofurantoin, primaquine, quinolones and sulphonamides.

 Use of methysergide and ergotamine for migraine prophylaxis Appetite suppressants fenfluramine and dexfenfluramine Dopamine agonists pergolide and cabergoline, Recently, the recreational drug ecstasy Migraine prophylaxis: ergot alkaloids & Methysergide Patients taking methysergide developed cardiac murmurs of mitral insufficiency or aortic insufficiency, or both during treatment Physicians initially thought that only left-sided valves were affected, but autopsy studies & reports showed tricuspid valve involvement. So other druds used in migrrin prophylaxis like blockers (propranolol), Antidepressants (amitriptyline), Anticonvulsants (sodium valproate, topiramate) are recommended for migraine prophylaxis

 Obesity: appetite suppressants Fenfluramine and phentermine have been used as adjuncts for the treatment of obesity Fenfluramine is a racemic mixture of two isomers (levofenfluramine and dexfenfluramine) In which the dexfenfluramine isomer stimulates serotonin release from cellular stores in neurons and platelets Activation of the 5-HT2B receptor by norfenfluramine (the active metabolite of dexfenfluramine) is thought to be the main mechanism in the development of fenfluramine induced valvular heart disease On the basis of these reports, fenfluramine and dexfenfluramine were voluntarily withdrawn from the market. Who has used appetite suppressants and developed mild or greater aortic regurgitation, or moderate or greater mitral regurgitation

 Parkinsons disease: dopamine agonists Studies of echocardiographic prevalence have shown moderate to severe valvular heart disease in 031% of patients taking pergolide and in 069% of those receiving cabergoline (table 2). To draw further conclusions, a detailed analysis of these studies is needed because of the variations in duration of exposure, peak dose, cumulative dose, and the limitations of different study designs Recreational drug use: ecstasy An amphetamine-based drug, is a psychoactive stimulant used for recreational purposes. Development of significant valvular regurgitation in eight (28%) people who took ecstasy compared with none in the control group

 Anthracyclines, Daunorubicin and doxorubicin are among the most frequently used anthracyclines The anthracyclines are anticancer antibiotics act by inhibition of the nucleic acid synthesis by binding to both strands of the DNA Cardiotoxicity is considered to be an adverse effect of all anthracyclines, although epirubicine may cause less cardiotoxicity Formation of free oxygen radicals, disturbance of the mitochondrial energy metabolism and intracellular calcium overloading are considered mechanisms in the pathogenesis of anthracycline-induced cardiotoxicity Based on the dose-dependency of the anthracycline-induced impairment of left ventricular function Characterized by heart failure, cardiac arrhythmias might be the first manifestation in some patients Mitoxantrone is structurally related to doxorubicin and has also been associated with the development of left ventricular impairment

Cyclophosphamide is an alkylating agent that causes cytotoxicity by its biologically active metabolites Cardiotoxicity of cyclophosphamide is thought to be due to toxic endothelial damage followed by extravasation of toxic metabolites with resultant myocyte damage and interstitial hemorrhage and edema In patients who develop severe progressive CHF, this complication may lead to death within a few weeks. Paclitaxel used in the treatment of advanced ovarian and breast cancer Paclitaxel promotes the polymerization of tubulin. Microtubules formed in the presence of paclitaxel are extraordinarily stable and dysfunctional. These dysfunctional microtubules interfere with normal cell division and interphase processes and may eventually lead to cellular death.

NSAIDs NSAIDs act by interference with PG biosynthesis by inhibiting enzyme COX In patients with an impaired left ventricular function, PGs play an important role in the maintenance of cardiovascular and renal homeostasis PGs have a vasodilatory effect on the afferent arteriole Oppose the effects of angiotensin II on the systemic circulation and decrease total body sodium and water. COX-1 is mainly responsible for the synthesis of PGE2 and PGI2 in kidney and stomach To prevent the potentially adverse effects on renal function, so-called renal-sparing NSAIDs have been introduced, such as sulindac, nabumetone and meloxicam.

 Antiarrhythmics The cardiodepressant adverse effects of antiarrhythmic drugs can mainly be attributed to their negative inotropic properties. In patients with preexistent left ventricular impairment, antiarrhythmics can induce or exacerbate CHF The degree of negative inotropy may vary from drug to drug. Class III antiarrhythmics, however, are usually considered as lacking these negative inotropic properties. Pathophysiologically, the negative inotropic effects of antiarrhythmic drugs are mediated by alterations of the intracellular calcium content Beta-adrenoceptor antagonists The negative chronotropic and negative inotropic properties of these drugs can easily induce CHF Topical administration of beta-blockers in patients with glaucoma has been associated with the occurrence of CHF in some case reports

Others drugs which have same effects like Antiarrythemic ad blockers Calcium channel blocking agents Anesthetics Immunomodulating drugs 3 types of interferon: interferon- , interferon and interferon-, are used for clinical indications Cardiac adverse effects of the interferons are cardiac arrhythmias, cardiomyopathy and symptoms of ischemic heart disease IL-2, approved for the treatment of metastatic renal cell carcinoma Production of cytokines may have a central role in the development of IL-2 induced cardiac dysfunction Cytokines may inhibit the accumulation of cellular cAMP which may blunt myocardial contractility

 Types of drugs induced Arrhythemia Sinus tachycardia Atrial tachycardia Atrial fibrillation/flutter Ventricular fibrillation Polymorphic ventricular tachycardia with QT-prolongation (Torsade de Pointes) Monomorphic ventricular tachycardia Bradyarrhythmias

This toxicity is occur due to blockage of delayed rectifier K+ channel

Antiarrhythmics Class Ia, Ic, III, digoxin Antiinfectives & Antifungals Macrolides, Fluoroquinolones, Azoles Antihistamines Terfenadine, Astemizole, Loratadine Antipsychotics & Antidepressants Phenothiazines, Atypical Antipsychotics Tricyclics, Tetracyclics, SSRIs Gastrointestinal agents Cisapride, Domperidone, Dolasetron

Monomorphic VT may degenerate into ventricular fibrillation and sudden cardiac death

Examples: Drugs (Sodium channel blocking activity) Antiarrhythmics class Ic e.g. Flecainide, Propafenone Tricyclic anidepressants e.g. Amitriptyline, Imipramine High risk in patients with structural heart disease or receiving drugs at high dose e.g. overdose

Heart rate < 60 bpm Sinus node dysfunction Atrial arrhythmias with conduction block Conduction block Drugs -blockers, calcium channel blockers, digoxin, antiarrhythmics

 A) Hemodynamic kidney injury: i) NSAID and drugs that inhibit renin angiotensin system GFR normaly depend on renal perfusion pressure and on tonus of the afferent and efferent arteriole Regulated by vasodilatory maintained by the afferent arteriole dilatation, prostaglandins and by the efferent arteriole vasoconstriction mediated partly by angiotensin II Conditions where renal blood flow is impaired, such as CHF, liver cirrhosis, dehydration and chronic kidney disease vasodilatory prostaglandins help to maintain renal blood flow and glomerular filtration Non-selective COX inhibitors impair synthesis of Vasodilatory prostaglandins in the kidney and are associated with development of intrarenal vasoconstriction and renal function impairment.

 Other forms of kidney injury by the NSAID are acute tubulointerstitial nephritis, chronic interstitial nephritis and glomerulopathy Other drugs cause kidney injury by intrarenal vasoconstriction are vasopressors, calcineurin inhibitors (cyclosporine and tacrolimus) and amphotericin-1B. ii) Contrast-induced nephropathy: CIN is a form of acute kidney injury that occurs after i.v administration of iodine-based radiocontrast agents for radiologic examinations Risk for CIN are diabetics, volume-depleted patients, older patients and patients with pre-existant kidney injury. Acute worsening of glomerular Acute worsening of GFR occurs within several days of radiologic procedure (usually after 48-72 hrs).

 After several days renal function returns to baseline level However, sometimes hemodialysis is needed to bridge period to recovery Even small decrements in kidney function have been linked to increased mortality in patients with CIN B) Intrinsic kidney injury: i) Tubulointerstitial injury caused by two mechanisms: 1) Acute hypersensitive interstitial nephritis Idiosyncratic phenomenon, caused by the allergic reaction to variety of drugs -lactam antibiotics (penicillins and cephalosporins), quinolone antibiotics (ciprofloxacin), NSAID, proton pump inhibitors (e.g. omeprazole), sulfonamides, allopurinol, etc. T and B lymphocytes, with frequently prominent eosinophils is found in renal tissue obtained by biopsy

2) Acute tubular necrosis Induced by prototype class of drug, Aminoglycoside antibiotics, these drugs are freely filtrable by the glomerulus Nephrotoxic potential is dependent on the number of cationic groups on the molecule Aminoglycosides bind to acidic phospholipids and megalin on the apical membrane of proximal tubule cells, and after uptake into the cells by endocytosis they accumulate in lysosomes causing their rupture Other drugs like, platinum derivatives, amphotericin B, foscarnet, cidofovir and statins (by causing rhabdomyolysis and myoglobinuria).

ii) Osmotic nephrosis ON is a form of acute kidney injury caused by a high-dose i.v Ig Osmotic diuretics such as mannitol and plasma expanders, such as hydroxiethylstarch Characterized by isometric vacuolization of proximal tubules Proximal tubule cell injury occurs after uptake of either osmotic agent itself, or its vehicle (such as sucrose in case of i.v Ig) with consequent tubule cell swelling and injury

 Analgesic nephropathy: Relatively frequent cause of chronic kidney disease Characterised by the chronic interstitial nephritis, often with papillary necrosis 1st manifestation : decreased GFR and decreased urinary concentration capability Unless analgesic abuse is stopped, renal injury is progressive and leads to ESKD Responsible agents are analgesics in combinations Phenacetin + Acetylsalicilic acid, Codeine + Caffeine Metabolite of phenacetin, Acetaminophen, which is a very frequently used analgesic also associated with nephrotoxicity Mechanisms : oxidative stress and chronic inhibition of synthesis of vasodilatory PG with consequent chronic renal ischemic injury.

B) Intrarenal obstruction : It is mainly due to antiviral drug precipitation, mainly Acyclovir Crystaline nephropathy has also been a complication of antiretroviral drugs such as indinavir or tenofovir, especially in patients with high urinary pH values (pH >6). Toxicity of these drugs is potentiated by concomitant use of sulfometoxazole, Methotrexate is ppts in kidney tubul in high dose, in the setting of dehydration and/or low urine pH (pH < 7). Crystal-induced tubule obstruction is accompanied with crystaluria

Drug-induced Gastrointestinal Disorders

Impairment of gastrointestinal defences: NSAIDs inhibiting PG synthesis Increased incidence of Salmonella and Campylobacter enteritis with acid-suppressing agents because the main physiological role of stomach acid is to sterilize ingested food before passage to the intestine Direct injury to the G.I.T: Oesophageal: potassium preparations, Gastroduodenal ulcers: cytotoxic drugs, Ulceration and colitis: Oral gold Alteration in colonic bacterial flora: Use of cephalosporins and Helicobacter pylori eradication therapy is a growing problem

 Heartburn: Drugs that relax the lower oesophageal sphincter are particularly likely to cause problems because of the increased acid exposure of the oesophagus (often without mucosal injury) e.g. Anticholinergic agents (e.g. Procyclidine, Benzhexol) Tricyclic antidepressants, and Phenothiazines Monilial oesophagitis : of dyspepsia (heartburn or odynophagia painful swallowing) in patients taking corticosteroids. It also occurs in patients taking immunosuppressive drugs. Mucosal injury and strictures Emepromium bromide, TC, KCl, certain bisphosphonates and quinidine are recognized as being toxic If patients swallow their pills in a reclining position pre-existing oesophageal disease or left atrial enlargement

 NSAID: Induced dyspepsia is common in patients infected with H. pylori. Cause of gastric and duodenal ulcers NSAID-associated ulcers are important because of the 3 to 5 fold increase the risk of ulcer bleeding, perforation and death. NSAIDs are used widely in the elderly, particularly in women.

 Dyspepsia occurs with the nonaspirin salicylates (e.g. mesalazine) used in inflammatory bowel disease Erythromycin, which causes epigastric pain and general cramp as a consequence of its motilin-like prokinetic activity Reserpine, cytotoxic agents, oral gold and pivampicillin have been associated with peptic ulceration, Recently, Ca+ antagonists have been implicated in peptic ulcer bleeding Corticosteroids no risk of ulceration, except in patients taking NSAIDs Nausea and vomiting: Stimulating the CTZ in the area postrema. Chemotherapeutic agents probably cause nausea and vomiting by stimulating serotonin release From enterochromaffin cells within the gut which activates the vagus.

Drugs such as potassium chloride, iron preparations and NSAIDs probably act via direct gastric irritation Pancreatitis Alcohol is a common cause of pancreatitis. The main culprits are: diuretics (thiazides, frusemide), sulphonamides, azathioprine, 6mercaptopurine, corticosteroids, L-asparaginase (about 7% of recipients) Constipation Reduced bowel frequency also occurs with 5-HT antidepressants (e.g. fluoxetine) and locally acting antispasmodics (e.g. mebeverine, peppermint oil). Codeine-containing analgesics are available over the counter; some patients establish a self-defeating cycle, using them for constipation-induced abdominal pain. Aluminium-containing antacids

sucralfate and Gaviscon also commonly constipate, as does iron (though this can also cause diarrhoea). Drug-induced megacolon from enteric neurotoxicity caused by vincristine or (possibly) laxatives is an uncommon but important cause of drug-induced constipation Diarrhoea Antibiotics, which disturb the colonic flora and tend to select C. Difficile -blockers: act by antagonizing antiperistaltic adrenergic stimulation Bile acids, direct irritant action in the colon Misoprostol, which stimulates intestinal secretion and motility Magnesium-containing antacids recent study accounted for 4% of patients referred for evaluation of diarrhoea.

 Malabsorption Many drugs (e.g. colchicine, methotrexate, biguanides, laxatives, salicylates) can cause malabsorption, though this is usually of little clinical significance. Sulphasalazine and phenytoin commonly cause folate malabsorption. Colitis mefenamic acid :directly injurious to epithelial cells Oral gold (auranofin): Penicillamine Antibiotics NSAIDs seldom cause diarrhoea and none has been conclusively shown to be a primary cause of colitis

DILD generally has low incidence of occurrence, but can have serious outcomes (10 - 52% of cases of FHF which is 75 - 90% fatal) Serum enzymes can be grouped into two categories: Those reflective of damage/necrosis (AST/(SGOT), ALT/(SGPT), LDH). Those reflective of cholestasis (Alk Phos (AP), GGT), 5-Nucleotidase (5-NT), Leucine Aminopeptidase (LAP) )

Drug CYP

Reactive metabolite

(Low Amounts)

(High Amounts) Extensive covalent binding

Protein

Immune reactions

Direct toxicity

Drugs

Betaoxidation
Mitochondria
Steatosis

Respiration

Cell dysfunction Cell death Lactic acidosis

ACUTE HEPATITIS Cytolytic hepatitis Mixed hepatitis Cholestatic hepatitis + cholangi(oli)tis Bland cholestasis Steatosis

Subacute or chronic hepatitis

Vanishing bile duct syndrome

Steatohepatitis Sinusoidal dilation, Peliosis VOD ( SOS ), Budd-Chiari Hepatic adenoma, HCC

Anti-TB drugs: INH without other anti-TB drugs with other non-TB drugs INH + rifampin + pyrazinamide INH + ethambutol rifampin + pyrazinamide Sulfa-related drugs : Septra, sulfadiazine, sulfasalazine Other antibiotics: Augmentin, nitrofurantoin, doxycycline, itraconazole ciprofloxacin,

Phenytoin ; Valproate ; PTU ; Disulfiram Statins : including Baychol Bromfenac (Duract): Troglitazone (Rezulin): Herbals and/or dietary HAART Halothane/Isoflurane:

Major cause for drug withdrawal or prescribing restrictions

Recent cases: Ximelagatran, Troglitazone Bromofenac, Felbamate Pemoline, Tolcapone Trovafloxacin

Hy's law is a prognostic indicator that a pure drug-induced liver injury (DILI) leading to jaundice, without a hepatic transplant, has a case fatality rate of 10% to 50%. The law is based on observations by Hy Zimmerman, a major scholar of drug-induced liver injury.
Hys Law cases have the following three components The drug causes hepatocellular injury, generally shown by more frequent 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control agent or placebo. Among subjects showing such AT elevations, often with ATs much greater than 3xULN, some subjects also show elevation of serum TBL to >2xULN, without initial findings of cholestasis (serum alkaline phosphatase (ALP) activity >2xULN). No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C, preexisting or acute liver disease, or another drug capable of causing the observed injury.

 Essential of medical pharmacology, By K.D.Tripathi, A textbook of Clinical Pharmacy Practice , by Parthasarthi G

Pharmacotherapy A pathophysiologic Approch, By joseph T. Diprio Robet L talbert,P.P1297-1312

http://www.ifcc.org http://xa.yimg.com/kq/groups www.asia.cmpmedica.com/cmpmedica www.ncbi.nlm.nih.gov/pmc/articles www.invitroplus.mcgill.ca www.merckmanuals.com www.worstpills.org/public/page.cfm www.fpnotebook.com/id/pharm/DrgIndcdFvr.htm