adverse drug reactions ,deepika

8/13/2019 Adverse Drug Reactions ,Deepika

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Adverse Drug Reactions

DR.DEEPIKA SHARMA

(PERIO-1styr PG)


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Introduction Drugs currently represent an important therapeutic

strategy and are widely used, especially in the hospitalsetting. However, there are inherent risks in theirpharmacological action or related to their use, which can

lead to the development of adverse drug reactions (ADRs). Numerous drugs can adversely affect the oral cavity and

dentition.

It may be necessary to discontinue an agent if the oraleffects are severe enough. While adverse effects tomedications can affect anyone, it is important to recognizethat elderly patients, or those with nutritional deficiencies,may be at increased risk for developing iatrogenic oral

problems.


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In order for the physician, pharmacist or dentist toproperly assess and manage a patient, a completemedication history must be conducted.

Drugs have the potential to affect the oral cavity in anumber like xerostomia, intraoral hemorrhage,

candida albicans (oral thrush), gingival hyperplasia,taste changes, tooth discoloration, stomatitis, andulceration or necrosis etc.

It is important that healthcare professionals

understand the impact and severity that medicationscan have on the oral health of their patients.


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Definition

Adverse Drug Reaction (ADR) a response to amedicine which is noxious and unintended, and whichoccurs at doses normally used by man for theprophylaxis, diagnosis, or therapy of disease or for the

modification of a physiological function.(WHO 1972) An adverse drug reaction is defined as any

untoward medical occurrence that may present duringtreatment with a medicine but which does not

necessarily have a causal relationship with thistreatment.

(Edwards IR, Aronson JK. Adverse drugreactions: definitions, diagnosis, and

management. Lancet 2000)


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Classification Of AdverseDrug Reactions


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Type A (Augmented)An extension of the normal pharmacological actions and effects of asubstance. They are predictable and dose related. (Pirmohamedand Park 2003).

Type B (Bizarre)These are relatively uncommon, cannot be predicted from the knownpharmacology of the drug and are not dose related.

Type C (Chronic)These relate to the cumulative toxic effects of a drug used over time.The adverse effects increase gradually.

Type D (Delayed)

These are rare and only become evident some time after thetreatment has been completed.

Type E (End of use)These relate to the effects of abrupt withdrawal of a drug that isbeing received long term.


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Mechanisms Of Adverse Drug

ReactionsA. HUMORALType-I(anaphylactic)reactions-IgE antibodies are produced whichget fixed to the mast cells.On exposure to the drug AG:AB reactiontakes place on mast cell surface releasing mediators likehistamine,5-HT, prostaglandins,etc.resulting inurticaria,itching,angioedema,asthma, rhinitis or anaphylactic shock.

Type -II(cytolytic)reactions -drug +component of a specific tissuecell act as an AG.The resulting antibodies(IgG,IgM) bind to targetcells;on reexposure AG:AB reaction takes place on the surface of

these cells,complement is activated & cytolysis occurs,eg.thrombocytopenia,agranulocytosis,aplastic anemia,hemolysis,organ damage.


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Type-III(retarded, arthus)reactions -these aremediated by circulating antibodies. AG:AB complexes

bind complement and precipitate on vascularendothelium giving rise to a destructive inflammatoryresponse.Manifestations are rashes,fever ,lymphadenopathy etc.

These reactions usually subsides in 1-2 weeks.B. CELL MEDIATED-

Type-IV(delayed hypersensitivity )reactions-These are mediated through production of sensitized T-

lymphocytes carrying receptors for the AG.On contact withAG,these T cells produce lymphokines which attractsgranulocytes & generates an inflammatory response;eg.dermatitis,some rashes,fever ,photosensitization.

The reaction generally takes >12 hrs to develop.


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Effects Of Adverse Drugreactions In Oral cavity


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Adverse Effects Of Drugs On Tooth

Development The anti-epileptic drug phenytoin is reported to cause abnormalitiesin the roots of the teeth (Girgis SS et al in 1980).

Defects include shortening of the root, root resorption, and anincreased deposition of cementum. The mechanism of phenytoin-induced root abnormalities is uncertain, but may be related to the

drug inhibiting vitamin D metabolism or parathyroid hormoneproduction(Harris M in 1974).

Local anesthetic drugs such as lidocaine and prilocaine are cytotoxicto the enamel organ and will interfere with amelogenesis (HansonJW et in 1976).It has been suggested that the pressures usedduring intraligamentary injections can force anesthetic agents into

any underlying tooth germs that may be present (Brannstrom M in1982).

The respiratory stimulant doxapram has been reported to producepremature appearance of the tooth buds (Tay-Uyboco J in 1991).The mechanism of this unwanted effect remains uncertain.


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Xerostomia

More than 400 medications claim xerostomia as a side effect. The synergistic effects of medications have been recognizedand are increasingly common in elderly patients takingpolypharmacy.

General drug classes that are strongly associated withxerostomia include antidepressants and antipsychotics,antihypertensives, antihistamines, and anticholinergics.

Medications that produce xerostomia, also may increase theincidence of root surface caries.


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Patients with xerostomia may complain of generalized mouthsoreness, dry mouth, painful or burning tongue, reduceddenture retention, taste changes, difficulty in chewing, andproblems with talking and swallowing.

Xerostomia is managed symptomatically by increasing thepatients water intake, using saliva substitutes, and orallubricants,saliva stimulants. Agents such as citric acid, and

cholinergic agents such as pilocarpine and bethanecol canalso be used to stimulate the flow of saliva.


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Drug-Induced Pain And Swelling OfThe Salivary Glands

Several case reports have identified a range of drugs that cancause pain and swelling of the salivary glands. These includethe pyrazolone derivatives, phenylbutazone andoxyphenbutazone,, chlorhexidine, and doxycycline.

Parotid swelling is a rare unwanted effect arising from

chlorhexidine mouth-rinsing. The condition appears tosubside spontaneously within a few days after discontinuinguse. The clinical features have the appearance of mechanicalobstruction of the parotid duct. It is suggested that over-vigorous mouth rinsing may create a negative pressure in theparotid and the aspiration of chlorhexidine into the gland.Patients should be advised to be less vigorous with theirmouth rinsing so as to avoid this unwanted effect.

A case report has suggested that doxycycline can induce aparotitis (Pan VC in 1991). The mechanism is unclear and itmay be the result of edema and spasm of smooth muscles in

the parotid gland or of a hypersensitivity reaction.


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Intraoral Hemorrhage

Intraoral hemorrhage can be associated withnumerous factors such as thrombocytopenia,defective vascular integrity, or alterations incoagulation.

Numerous agents have been implicated to causethrombocytopenia including sulfonamides, quinine,quinidine, thiazide diuretics, methyldopa,antineoplastic agents, heparin, phenytoin.

Numerous antibiotics such as cephalosporins,penicillin, and tetracyclines have also been associatedwith intraoral hemorrhage


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Dysguesia (taste changes)

There are more than 200 drugs in the that have thepotential to cause changes in taste sensations.

Numerous drugs can cause taste changes includingclarithromycin, captopril, enalapril,metronidazole,

chlorhexidine, diltiazem, etc. Patients may have complaints of a bitter, metallic,

unpleasant or altered taste, medication taste,complete loss of taste, and decreased taste sensation.


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The mechanisms by which drugs affect the tastesensations vary. There are three mechanisms

involved in medication taste disorders. First, there is the influence of saliva on taste, i.e. the

drug itself may be secreted into the saliva, producing

dyguesia. Another potential mechanism is the effect of drugmetabolite which could possibly interact with tastebuds or saliva.

Finally, drugs may directly damage the taste buds.There may be age-related effects on taste that canenhance medication taste disorders.


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Toxic Epidermal Necrolysis

Toxic epidermal necrolysis or Lyells syndromerepresents the most severe variant of the diseasespectrum that comprises erythema multiforme andStevensJohnson syndrome.

The most frequently affected mucosal membrane isthe oropharynx, followed by the eyes and genitalia.

Oral cavity involvement is characterized bywidespread painful blistering and ulceration.

As with StevensJohnson syndrome, the main drugsimplicated include sulfonamides, anti-epileptics,oxicam, corticosteroids.


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Mucous Membrane Pemphigoid

Mucous membrane pemphigoid is one of a number ofblister-producing autoimmune mucocutaneous diseases.It is the variant most likely to occur in the mouth.

Clinically, lesions appear as relatively sturdy vesicles orbullae that break down into shallow ulcerations.

Its pathogenesis relates to antibodies that attack theattachment fibrils.

A variety of drugs like Amoxicillin,Ibuprofen,Penicillin,Salicylic acid, Isoniazid, Clonidine,Sulphonamides, have been cited as the causal agents inmucous membrane pemphigoid .

Drug-induced mucous membrane pemphigoid tends tooccur in younger patients. Resolution of the lesionsoccurs following withdrawal of the causative agent.


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Pemphigus Vulgaris

Pemphigus is a potentially life-threatening,vesiculobullous disorder of the skin and mucousmembrane. The oral cavity is the only site ofinvolvement in 50% of cases of pemphigus and is the

initial site of presentation in almost 75% of cases. It is characterized by extensive flaccid blisters and

mucocutaneous erosions. Patients with pemphigus produce IgG antibodies and

desmoglein (a transmembrane glycoprotein thatmediates cell adhesion).Drugs have been implicated inthe induction of pemphigus are Cephalexin ,Diclofenac, penicillin, Rifampicin ,Captopril.


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Lichen planus

Oral lichen planus is a chronic inflammatory oral mucosal disease

of unknown cause. Clinical appearance is described by "6 P's" of lichen planus: planar

(flat-topped), purple, polygonal, pruritic, papules, and plaques The term lichenoid drug eruptions can be used in two senses. First, drug eruptions similar to or identical to lichen planus and

second, drug eruptions that do not necessarily appear like lichenplanus clinically but that have histological features very like thiscondition.

In addition to systemic medication, lichenoid reactions can beassociated with dental materials like amalgam, especially mercuricchloride.For some patients replacing their amalgam restoration

may result in an improvement of their oral lesions. However, itshould be recognized that composite restorations have also beenimplicated in oral lichenoid reactions and so completereplacement of amalgam restorations, as a possible treatment, isnot always justified.


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Oral lichenoid reaction

Oral lichenoid reaction


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Effect of Bisphosphonates onAlveolar Bone

Bisphosphonates were introduced in the mid-1990s, asan alternative to hormone replacement therapies forosteoporosis and to treat osteolytic tumors.

Bisphosphonates bind to and accumulate in bone, and

remain there for months after therapy is discontinued.Bisphosphonates inhibit osteoclast attachment to bone,induce apoptosis of osteoclasts, and inhibitdifferentiation of bone marrow precursor cells into

osteoclasts. They may also contribute to the inhibition ofbone resorption and increase in bone mass.

Alendronate and risedronate are oral preparations usedto treat osteoporosis..


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Oral Candidiasis Candidiasis is the most common oral opportunistic

infection seen in dental practices. Patients usually present with creamy, white plaques on

the tongue and buccal mucosa. When scraped thelesions leave a red, painful ulcerated surface exposed.

Immunocompromised patients such as AIDS and cancerpatients may be more susceptible to oral infectionssince they have defects in cell-mediated immunity.

Broad spectrum antibiotics, antineoplastic agents

(cancer chemotherapy), corticosteroids, andimmunosuppressive agents used to prevent rejection oftransplant organs are all drugs which have the potentialto produce oral candidiasis.

Nystatin suspensions or clotrimazole troches areextremely effective in treating oral candidiasis.


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Gingival Hyperplasia

Patients may present to the dentist with gingivalenlargement if they have been taking agents such asphenytoin, nifedipine, or cyclosporin.

Gingival hyperplasia occurs when there is an increased

production and growth of normal gingival cells.Itoccurs in roughly 50% of patients taking phenytoin forthe chronic management of epileptic seizures. Withintwo or three months of taking phenytoin, gingival

enlargement presents as a painless enlargement ofinterdental papillae.

Phenytoin can produce gingival enlargement which issevere enough to completely cover the teeth.


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phenytoin induced gingival hyperplasia


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The exact mechanism by which phenytoin induces hyperplasiais not completely understood. However, phenytoin may

increase the expression of the gene for platelet derived growthfactor B (PDGF-B). When gingival macrophages are exposedto phenytoin they secrete increased amounts of PDGF whichmay increase the proliferation of gingival cells and alveolarbone cells.

Patients who are started on a strict program of oral hygienewithin ten days of initiation of therapy may be able tominimize the occurrence of gingival enlargement. Phenytoin-induced gingival hyperplasia can also be treated surgically.

Patients using phenyton are at risk for gingival hyperplasia,and should be supplemented with 1 mg folic acid 1-3 times aday to decrease this side effect.


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Approximately 5% of patients taking the calciumchannel blocker nifedipine will present with gingivalenlargement. Nifedipine induces gingivalovergrowth when numerous inflammatory cellsreplace the collagen of connective tissues.

Nifedipine produces alterations of the intracellularcalcium levels in gingival cells and can produce localinflammatory factors to elicit gingival enlargement.


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Tooth Discoloration Numerous drugs are noted to have the capability to

produce tooth discoloration.

One of the most highly profiled drugs to cause toothdiscoloration in young adults is tetracycline.

However, other agents such as minocycline,isoproterenol, iron salts, ciprofloxacin,chlorhexidine, and methacycline all have reportedlycaused tooth discoloration.

Tetracycline and oxytetracycline cause a yellowdiscoloration, whereas chlortetracycline produces agray-brown discoloration.


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Minocycline is often given to adult patients andadolescents to control acne. Minocycline produces

pigmentation changes of permanent teeth when itchelates with iron to form insoluble complexes. Oraliron solutions can cause superficial discoloration ofteeth.

Ciprofloxacin given intravenously to infants forKlebsiella pneumonia causes a greenish discolorationwhich could not be removed was noted when infantsteeth developed.

chlorhexidine tooth staining occurs in fifty percent ofpatients after a few days of use. The most commonside effect of oral chlorhexidine mouth rinse is theformation of yellow-brown stains which can beremoved by professional cleaning.


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Stomatitis

The most common cause of nonspecific stomatitis isthe use of antineoplastic agents. Agents which havethe potential to cause stomatitis include, thiopeta,procarbazine, dactinomycin, methotrexate, and

fluorouracil. Mild forms of stomatitis can be managed by cleansing

the oral cavity with a soft tooth brush and rinsing witha saline solution. Mouth rinses such as Kaopectate

have been successful in decreasing the patientsdiscomfort.


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Oral Ulceration and Necrosis

Ulceration and necrosis of the oral mucosa occurswhen patients use medications that are not intendedfor topical therapeutic use or they are takingmedications incorrectly.

The classic aspirin burn is a good example of whatcan happen when patients try to self medicate.

Drugs capable of producing stomatitis can potentiallyproduce reactions that are severe and lead to

ulcerations. Drugs capable of causing ulceration ormucosal necrosis include aspirin, phenylbutazone,indomethecin, silver nitrate,etc.


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Anaphylactic shockA type of distributive shock that results from widespread systemic allergic

reaction to an antigen

Hypersensitive reaction

Life threatening

Clinical Presentation- Cutaneous manifestations Urticaria Erythema Pruritis Angioedema

Respiratory compromise

Stridor Wheezing Bronchorrhea Respiratory distress

Circulatory collapse Tachycardia Vasodilation

hypotension


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Management- The resuscitation council of UK has recommended the

following measures: Put the patient in reclining position,administer oxygenat high flow rate and perform cardiopulmonaryresusciation if required.

Inject adrenaline 0.5 mg (0.5 ml of 1 in 1000solution)i.m ; repeat every 5-10 min in case the patientdoesnt improve or improvement is transient.

Administer a H1 antihistaminic (chlorpheniramine 10-

20mg) i.m /slow i.v. i.v glucocorticoid (hydrocortisone sod. Succinate 100-200mg) should be added in severe/recurrent cases .itacts slowly but is specially valuable for prolongedreactions and in asthmatics.


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Aspirin burn


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Points To Consider For TheEvaluation Of A Suspected Adverse

Drug Reaction


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1. The temporal relationship (time toonset)

There should be a plausible temporalrelationship between exposure and the onset of

the suspected ADR, taking into considerationthe pharmacological characteristics of thesuspected drug. For short-term reactions, e.g.flushing with nifedipine, the relevant time to

onset is the time between the last dose and theonset of the reaction. For long-term reactions,e.g. hepatitis with methotrexate, the relevantperiod is the time from the beginning of the

therapy and ADR onset.


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2. Existing information about theADR The event described had been previously reported as an ADR in

clinical trials, post-marketing studies, case reports. If the eventis not documented anywhere else, it does not necessarily meanthat it cannot occur with the suspected drug.

3. Pharmacological plausibility Most type A reactions are pharmacodynamic andpharmacokinetic plausible, though easy to diagnose.However, the recognition of type B reaction might bedifficult if previous reports on that particular ADR are not

available.

4. Exclusion of other causes Alternative causes (other than the suspected drug) such as

patients underlying disease or other drugs cannot explainthe reaction


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5. Dechallenge or dose reduction

Recovery or condition improvement after stopping the drug orafter the dose reduction is supportive for a causal relationship,particularly when the timing of the recovery/conditionimprovement is consistent with the pharmacologicalcharacteristics of the drug; some ADRs might be irreversible.

6. Rechallenge or dose increase The recurrence of the ADR after dose increase or rechallenge is

a strong indicator of causality. Rechallenge is justifiable only ifthe benefit to the patient outweighs the risks of the reactions

recurrence, as in some cases the reaction (especially type Breactions) may be more severe or even fatal on repeatedexposure.


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7. Drug interactions

If a drug interaction is suspected in causing the ADR,plausible temporal relationship with the introductionor withdrawal of the interacting drug is an importantconsideration in causality assessment.


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Adverse drug effects associated withspecific medications

Adverse drugeffect

Drug name

Abortion,uterinehaemorrhage

Misoprostol (cytotec),a labor-inducing drug

Bleeding ofintestine

Aspirine therapy

Deafness andkidney failure

Gentamicine(an antibiotic)

Death, followingsedation

Propofol(Diprivan)

glaucoma Corticosteroid-based eye drops

Hair loss &anemia

chemotherapy


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Adverse drug effect Drug name

headache Spinal anesthesia

insomnia Stimulants,Ritalin

Liver failure Paracetamol

seizures Withdrawal from benzodiazepine

hypertension Ephedrine users

parkinsonism MPTP a meperidine related drugconsidered highly neurotpxic

teratogen Phenytoin ,tetracycline,thalidomideetc.


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Management Of Adverse DrugReactions

Rapid action is sometimes important because of theserious nature of a suspected ADR, for exampleanaphylactic shock. Emergency treatment and

withdrawal of all medicines is occasionally essential,in which case cautious reintroduction of essentialmedicines should be considered.

A problem immediately arises if one or more of themedicines is essential to the patient. If the culprit isfairly clear, a benefit-risk decision needs to be takenabout the need for the drug the severity of the

reaction, and its potential for treatment.


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If several medicines could be causative, the non-essentialmedicines should be withdrawn first, preferably one at a time,

depending on the severity of the reaction.

If the reaction is likely to be dose related, dose reductionshould be considered.

Many prescribers unnecessarily withhold a drug wheninteractions are suspected, rather than adjusting the dose. Thepatient should be observed during withdrawal.


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If the patient is not doing well after withdrawal of the first drug,the next most likely culprit should be considered, and the

process repeated. On the other hand, the patient may besuffering through being deprived of the medicine withheld. Inthat case, either another suitable drug should be substituted ,orthe same drug should be tried at a lower dosage.

The latter approach should be tried if more than one drug waswithheld, for instance if an interaction was suspected or if theseriousness of the reaction made it wise to withhold severalpossible drugs. Reintroduce apparently essential medicines oneat a time, starting with the one least likely to be the culprit.


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If the patient cannot manage without a medicine thathas caused an adverse reaction, provide symptomatic

relief while continuing the essential treatment. Forexample, severe nausea and vomiting are routinelytreated symptomatically in patients receiving anti-cancer drugs. However, when treating an adversedrug reaction, it is important not to introduce moremedicines than are essential. Always have a cleartherapeutic objective in mind, do not treat for longer

than is necessary, and review the patient regularlyand look for ways to simplify management.


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References:-

Essentials of pharmacology for dentistry(2005,K DTRIPATHI).

Oral and dental adverse drug reactions.ROBIN A.SEYMOUR & MEENAKSHI RUDRALINGHAM.

Periodontology 2000, Vol. 46, 2008, 926. Adverse Drug Interactions.Daniel E. Becker. AmericanDental Society of Anesthesiology ,2011

Edwards IR, Aronson JK. Adverse drug reactions:definitions, diagnosis, and management. Lancet 2000

Harris M, Goldhaber P. Root abnormalities in epilepticsand the inhibition of parathyroid hormone induced boneresorption by diphenyl hydantoin in tissue culture. ArchOral Biol 1974: 19: 981984.

adverse drug reactions ,deepika

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