Adverse Reactions of Drugs Targeting Epilepsy, Parkinson

and Alzheimer's disease

Hamid R. SadeghniaDepartment of Pharmacology

School of Medicine, MUMS

Outline

Adverse Drug Reactions (ADRs)

ADRs of anti-epileptic drugs

ADRs of anti-parkinsonian drugs

ADRs of drugs targeting Alzheimer's disease

ADRs: any unexpected, unintended, undesired, or excessive response to a medicine that occurs at doses usually used for prophylaxis, diagnosis, or therapy of disease

ADRs

Anticonvulsants• Carbamazepine

(Tegretol)• Clobazam (Urbanyl)• Clonazepam (Klonopin)• Diazepam (Valium)• Ethosuximide (Zarontin)• Gabapentin (Neurontin)• Lamotrigine (Lamictal)• Levetiracetam (Keppra)

• Oxcarbazepine (Trileptal)• Phenobarbital (Luminal)• Phenytoin (Dilantin)• Primidone (Mysoline)• Topiramate (Topamax)• Valproic Acid (Depakene)• Zonisamide (Zonegran)

I. CNS Effects:drowsiness, somnolence, fatigue, ataxia,

headache, restlessness, nystagmus, blurred vision, diplopia, dizziness, vertigo and paresthesia

The most frequently occurring adverse effectsDose relatedMost noticeable during initial therapy

General Statement

II. GI Effects:nausea and vomiting, gastric distress, dysphagia, loss of taste, constipation, diarrhea, anorexia hiccups

General Statement

III. Dermatologic Effects:skin rash, urticaria, exfoliative dermatitis, toxic epidermal necrosis, Stevens-Johnson syndrome, systemic lupus erythematosus (SLE),

Appear to be hypersensitivity reactions

General Statement

IV. Hematologic Effects:folate deficiency and megaloblastic anemiabone marrow depression

aplastic anemia macrocytic anemia, leukopenia, Thrombocytopenia, agranulocytosis

Appear to be idiosyncratic reactions

General Statement

V. Hepatic Effects:Hepatitis and jaundiceHypersensitivity reactions

VI. Renal Effects:fatal nephrotic syndromes (oxazolidinediones,

Succinimides)

VII. hypocalcemia, rickets or osteomalaciasupplemental vitamin D (4000 units/week)

General Statement

Common: drowsiness, dizziness, ataxia, confusion, nausea, vomiting, rash, blurred vision, nystagmus

Hyponatremia and water intoxication– Antidiuretic effects ( Plasma level of ADH)

Idiosyncratic reactions: – Bone marrow depression (aplastic anemia

agranulocytosis, etc.)– Stevens–Johnson syndrome, toxic epidermal necrolysis– hepatitis

Carbamazepin (Tegretol)

Pregnancy: Category D

Common: anterograde amnesia, disorientation, drowsiness, fatigue, incoordination, drug dependence

Serious: respiratory depression, bone marrow depression, hypotension, rigidity, hepatitis

Clobazam (Urbanyl) Clonazepam (Klonopin)Diazepam (Valium)

Pregnancy: Category C

GI distress • pain, nausea, vomiting, anorexia

CNS effects • drowsiness, lethargy, euphoria, dizziness,

headache, and hiccupUrticaria, skin rashes, including Stevens-

Johnson syndrome, SLEblood disorders

• leucopenia, agranulocytosis, thrombocytopenia and aplastic anaemia

Ethosuximide (Zarontin)

Pregnancy: Category C

Commons:Anorexia, weight loss, nausea and vomiting,

rash, insomnia, headache, dizziness, somnolence, and diplopia

Serious:aplastic anemia severe hepatitis

FELBAMATE (Felbatrol)

Pregnancy: Category D

Common: • dizziness (15%), ataxia (12%), fatigue,

somnolence, weight gainSerious:

• depression, leukopenia, bronchospasm, nystagmus, diplopia, personality changes, poor coordination

Gabapentin (Neurontin)

Pregnancy: Category C

Dizziness Ataxia Headache Diplopia, blurred vision Nausea, vomiting Somnolence Skin rash “Stevens-Johnson”, toxic epidermal necrolysis Blood dyscrasias (neutropenia, etc)

Lamotrigine (Lamictal)

Pregnancy: Category C

Asthenia, Dizziness Somnolence Nervousness Ataxia, Headache, Amnesia, Depression, Psychotic adverse reactions

Levetiracetam (Keppra)

Pregnancy: Category C

• Like CBZ with improved toxicity profile:• Hyponatremia (more commonly than CBZ)• Dizziness, ataxia, nystagmus, and diplopia• Less hypersensitivity reactions

(erythematous skin rashes, etc.)• Less idiosyncratic blood dyscrasias (aplastic

anemia, agranulocytosis, etc.)• Less hepatotoxicity

Oxcarbazepine (Trileptal)

Pregnancy: Category C

• Common: lethargy, drowsiness, sedation, CNS excitation

• Serious: – hypoventilation, – apnea, – hypotension, – confusion, – psychiatric disturbance,– arrhythmias

Phenobarbital (Luminal)

Pregnancy: Category D

• Ataxia, confusion, diplopia and nystagmus• Hirsutism • Gingival hyperplasia• Folate deficiency and megaloblastic anemia • Idiosyncratic reactions

• severe dermatitis (skin rash, SLE, SJS, etc.)• bone marrow depression (agranulocytosis, etc.)

Phenytoin (Dilantin)

Pregnancy: Category D

• Common: drowsiness, diplopia, nausea, vomiting, ataxia, sedation, headache, GI problems

• Serious: – leukopenia, – megaloblastic anemia responsive to folate,– lupus-like syndrome

Primidone (Mysoline)

Pregnancy: Category D

• Ataxia • Fatigue• Dizziness• Cognitive slowing• Paresthesias• Confusion• Reduced sweating with hyperthermia • Impaired speech

Topiramate (Topamax)

Pregnancy: Category C

• Common: – Nausea, vomiting, abdominal cramping,

dyspepsia, diarrhea, anorexia.

• Serious: – Hepatotoxicity (fatal), – Thrombocytopenia, – Erythema multiforme,– Pancreatitis

Valproic acid (Depakene)

Pregnancy: Category D

• Atrial fibrillation; ventricular extrasystoles • Agitation; Ataxia; confusion; paresthesia;

depression• Somnolence, speech abnormalities• Agranulocytosis; anemia; thrombocytopenia• Rash; Stevens-Johnson syndrome, toxic

epidermal necrolysis

Zonisamide (Zonegran)

Pregnancy: Category D

Antiparkinson drugs

• Anticholinergics– Biperiden– Trihexyphenidyl– Diphenhydramin

e

• Dopaminergic Agents• Amantadine• Bromocriptine• Levodopa C,

Levodopa B• Pramipexole• Ropirinole• Selegiline

Anticholinergics

• Common: – Dry mouth, blurred vision, constipation,

urinary retention, drowsiness, dry skin, hyperthermia, IOP

• Serious: – forgetfulness, hallucinations, sedation,

depression, anxiety, arrhythmia

Pregnancy: Category C

Amantadine (Symmetrel)

• Common: – dizziness, – insomnia

• Serious: – CHF, – seizures, hallucinations, depression, psychosis,– bone marrow depression,– renal toxicity

Pregnancy: Category C

BROMOCRIPTINE (Parlodel)

• Common: – decreased BP (28%), – headache (10%), dizziness,– Nausea, vomiting

• Serious: – Seizures, CVA, depression, hallucinations – prolonged hypotension, MI– liver toxicity– pulmonary fibrosis

Pregnancy: Category B

Levodopa C (Sinemet) Levodopa B (Madopar)• Common: – Nausea, vomiting, cardiac arrhythmias, postural

hypotension, anxiety, insomnia, somnolence, vivid dreams

• Serious: – Aggression, paranoid delusions, hallucinations,

delirium, severe depression, dyskinesias (involuntary choreiform movements)

end-of-dose “wearing off ” and “peak-dose dyskinesias.”

Pregnancy: Category C

Pramipexole (Sifrol)Ropirinole (Requip)• Common: – nausea, vomiting, confusion, hallucinations,

lightheadedness, postural hypotension, sedation, vivid dreams

• Serious: – compulsive behaviors, psychosis, sleep attacks,

depression– dyskinesias Pregnancy: Category C

Selegiline (L-Deprenyl)

• Common: – nausea (20%), dizziness, abdominal pain (8%),

dry mouth (66%),

• Serious: – arrhythmias, confusion, psychosis, depression,

hallucinations, agitation, tremor, orthostatic hypotension

Pregnancy: Category C

Selegiline (L-Deprenyl)

• Food & drug interactions: – Food containing tyramine– SSRIs– SNRIs– TCAs– Opioid analgesics (Tramadol, etc.)– Sympathomimetic amines (amphetamines, etc.)– Carbamazepine and Oxcarbamazepine

Alzheimer's Disease

PHARMACOTHERAPY OF COGNITIVE SYMPTOMS

• Cholinesterase inhibitors (In mild–moderate disease)

– Donepezil (Aricept)

– Galantamine (Remenyl)

– Rivastigmine (Excelon)

• Antiglutamatergic agents (In moderate to severe disease)

Memantin (Namenda)

Cholinesterase inhibitors

• GI symptoms (nausea, vomiting, and diarrhea, Peptic ulcers/GI bleeding, anorexia)

• urinary incontinence,• dizziness, headache, insomnia, confusion,

depression, seizures• syncope, bradycardia, • salivation, sweating• Exacerbation of asthma

Pregnancy: Category B

Memantin (Namenda)

Well tolerated• Constipation, • Vomiting,• Somnolence,• Confusion, dizziness, • Hallucinations, headache,• Coughing,• Hypertension

Pregnancy: Category B

Egb 761 (Ginkgo Biloba extract)

Antioxidant, anti-inflammatory and neuroprotective effects

nausea, stomach upset headache insomnia Hemorrhage (effects on platelet

adhesion, anti-PAF activity)

Thank you very much Thank you very much for your attentionfor your attention