Adverse Reactions of Drugs Targeting Epilepsy, Parkinson and Alzheimer's disease Hamid R. Sadeghnia Department 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 effects  Dose related  Most 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 anemia  bone marrow depression  aplastic anemia  macrocytic anemia,  leukopenia,  Thrombocytopenia,  agranulocytosis Appear to be idiosyncratic reactions General Statement

V.Hepatic Effects:  Hepatitis and jaundice  Hypersensitivity reactions VI.Renal Effects:  fatal nephrotic syndromes (oxazolidinediones, Succinimides) VII. hypocalcemia, rickets or osteomalacia  supplemental 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)

 Common: anterograde amnesia, disorientation, drowsiness, fatigue, incoordination, drug dependence  Serious: respiratory depression, bone marrow depression, hypotension, rigidity, hepatitis Clobazam (Urbanyl) Clonazepam (Klonopin) Diazepam (Valium)

 GI distress pain, nausea, vomiting, anorexia  CNS effects drowsiness, lethargy, euphoria, dizziness, headache, and hiccup  Urticaria, skin rashes, including Stevens- Johnson syndrome, SLE  blood disorders leucopenia, agranulocytosis, thrombocytopenia and aplastic anaemia Ethosuximide (Zarontin)

 Commons:  Anorexia, weight loss, nausea and vomiting, rash, insomnia, headache, dizziness, somnolence, and diplopia  Serious :  aplastic anemia  severe hepatitis FELBAMATE (Felbatrol)

 Common: dizziness (15%), ataxia (12%), fatigue, somnolence, weight gain  Serious: depression, leukopenia, bronchospasm, nystagmus, diplopia, personality changes, poor coordination Gabapentin (Neurontin)

 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 – Diphenhydramine 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

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.”

Pramipexole (Sifrol) Ropirinole (Requip) Common: – nausea, vomiting, confusion, hallucinations, lightheadedness, postural hypotension, sedation, vivid dreams Serious: – compulsive behaviors, psychosis, sleep attacks, depression – dyskinesias

Selegiline (L-Deprenyl) Common: – nausea (20%), dizziness, abdominal pain (8%), dry mouth (66%), Serious: – arrhythmias, confusion, psychosis, depression, hallucinations, agitation, tremor, orthostatic hypotension

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 for your attention