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Parkinson & altzheimer----EXAM2 Flashcards

1
Q

PARKINSON’S DISEASE

A

• Affects > 1 million Americans, Age 40‐70, peak in 6th decade

• Male:Female ratio is 3:2
• Caucasians>Africans=Asians

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2
Q

Case Report‐Muhammad Ali

A

• Diagnosed in 1984 at the age of 42
• tremors, his speech was slurred, slow body movements.

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3
Q

Clinical features

Posi sym
Neg sym
Neuro sym

A

Tremor and rigidity‐ positive symptoms
Akinesia/ bradykinesia, postural instability‐ negative symptoms
Neuropsychiatric symptoms: Dementia-20% of patients
Depression
Sleep disorders Dopaminergic psychosis

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4
Q

Clinical Features

A
  • Symptoms usually begin on one side of body and progress to the other side
  • Disease is due to cell loss so it is not possible to cure it
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5
Q

Risk factors

A

• Aging (older than 60 years) • Male sex
• Oxidative stress
• Genetics
• Environment
• Head trauma
• Most cases are idiopathic

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6
Q

Therapeutics

Non pharmacologic- exercise, physical therapy
Pharmacologic-
Surgical-

A
  • Pharmacologic‐ anticholinergics, amantadine, carbidopa/levodopa, selegiline, dopamine agonists, COMT inhibitors
  • Surgical‐ pallidotomy, thalamotomy, deep‐brain stimulation, transplantation of dopamine‐producing cells
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7
Q

Dopamine Metabolism

A 
L‐Tyrosine
      (Tyrosine hydroxylase)
L‐Dopa ->COMT ->3OMD
       ( dopa de carboxylate)
Dopamine-> MAO
       (Dopamine hydroxylase)
NE
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8
Q

MAO‐B inhibitors

Selegiline, Rasagilline

A
  • Selective at normal doses‐ irreversible‐ blocks breakdown of dopamine allowing a dose reductions of levodopa up to 1⁄2
  • Renewal of MAO‐B is slow so the drug effect can last for weeks
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9
Q

MAO‐B inhibitors

Drug interaction

A

• Prolong effect of L‐Dopa,also increases peak concentration and ADR’s of levodopa
• Marketed for producing extension of L‐dopa effects
• ADR’s insomnia and jitteriness
• May interact with fluoxetine,TCA and meperidine
• D/C 2weeks prior to surgery with general anesthesia

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10
Q

Amantadine‐ an antiviral agent

A

• Relieves mild signs and symptoms‐ short term‐ especially effective against tremor
• MOA‐ NMDA antagonist? Anticholinergic? –
• may promote dopamine release from peripheral stores, blocks dopamine reuptake, stimulates dopamine receptors

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11
Q

Amantadine

ADR‐ dry mouth, sedation, vivid dreams (due to anticholinergic properties?)

A

• Depression, hallucinations, anxiety, dizziness, psychosis, confusion
• Mottling of skin (livedo reticularis) frequent and reversible
• Do not use in seizure patients or those with CHF
• Avoid HCTZ, triamterene, amiloride, anticholinergics or CNS stimulants

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12
Q

Anticholinergics

A

• Benztropine (Cogentin)
• Trihexyphenidyl (Artane)
• Procyclidine (Kemadrin)
• Biperidine (Akineton)
• Diphenhydramine (Benadryl)

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13
Q

Anticholinergics

A

• Effective for rigidity, dystonia and tremor
• Not helpful for bradykinesis
• Older patients sensitive to ADR (dry mouth, urinary retention, confusion)
• If doesn’t work, try another

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14
Q

Dopamine Agonists

A

-Ergoline Agonists-
• Bromocriptine‐sole remaining agent

-Non‐ErgolineAgonists -
• Ropinirole
• Pramipexole
• Apomorphine

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15
Q

Dopamine Agonists

A

• Enhance dopaminergic transmission by binding to post‐synaptic dopamine receptors
• These don’t increase dopamine concentrations
• Prolongs effective treatment period in those with deteriorating L‐Dopa response

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16
Q

ADR: Dopamine Agonists

Diarrhea: onset after 2‐12 weeks; caution with lower gastrointestinal disease or an increased risk of dehydration.

• Hallucinations: may improve with reduction in levodopa therapy.

A

• Impulse control disorders: Dopaminergic agents have been associated with compulsive behaviors and/or loss of impulse control. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some.
• Hepatotoxicity: fatal liver injury associated with use of too alone

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17
Q

ADR: Dopamine Agonists

• Neuroleptic malignant syndrome: Concomitant use of tolcapone and nonselective MAO inhibitors should be avoided.
• Orthostatic hypotension: use with caution in hypotension (cardiovascular disease or cerebrovascular disease).

A

• Pleural/retroperitoneal fibrosis: Dopaminergic agents from the ergot class have been associated with fibrotic complications, such as retroperitoneal fibrosis, pulmonary infiltrates or effusion and pleural thickening.
• Rhabdomyolysis: Severe rhabdomyolysis has been reported with use

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18
Q

Bromocriptine

A

• Ergot‐ May be nice 1st line drug
• Lower incidence of response fluctuations and dyskinesias than L‐Dopa
• Can be given with carbidopa/levodopa, or to refractory patients
• Optimal therapy is probably a combination of both drugs

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19
Q

Bromocriptine

A

• ADR ‐ anorexia, N, V, orthostatic hypotension, digital vasospasm, cardiac arrhythmia, dyskinesias, pleural fibrosis, confusion, hallucinations, delusion

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20
Q

Ropinirole

A

• Non‐ergot dopamine agonist
• Use early in course either as monotherapy or with levodopa
• Decreased risk of developing dyskinesias than levodopa alone
• Also approved for restless legs syndrome

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21
Q

Ropinirole

A

• ADR‐ syncope, hypotension, hallucinations nausea
• Drug interactions‐ omeprazole, estrogen, cipro will increase levels

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22
Q

Pramipexole

A

• Highly potent at D2, D3 and D4 receptor
• Virtually no systemic metabolism
• Use in combination with levodopa‐ can reduce levodopa dose 30%
• Also useful for restless legs syndrome

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23
Q

Restless Legs Syndrome

A

• Irresistible urge or need to move the limbs, usually starts in the legs
• Etiology is not understood‐ may involve dopamine system.

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24
Q

Apomorphine (Apokyn(R))

A

• Non‐ergot Dopamine Agonist
• For acute treatment of severe rigidity or inability to move (rescue therapy)
• Most patients need an antiemetic‐ Drug of choice is trimethobenzamide (Tigan(R))
• If combined with ondansetron and others hypotension and LOC can result

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25
Tolcapone/ Entacapone
• Catechol‐o‐methyltransferase inhibitor • Inhibits a pathway of levodopa metabolism, reducing levodopa clearance, increasing response time with levodopa / carbidopa • Adjunctive therapy to levodopa‐ increases brain penetration • Acts in the periphery; does not enter CNS well
26
Tolcapone/ Entacapone
• ADR‐ diarrhea, nausea, upset stomach, cramps, hypotension, dyskinesias, urine discoloration • Monitor ‐ LFT’s with tolcapone • Do not use with MAOI’s, catecholamines, methyldopa
27
Levodopa
• Cornerstone of therapy for Parkinson’s • DOES NOT STOP PROGRESSION of the disease • Best results if given early in the course (lowers mortality).
28
Levodopa
• Metabolized in the periphery by aromatic L‐ amino acid decarboxylase (AADC) • This dopamine results in adverse effects‐ nausea, vomiting, hypotension, arrhythmias
29
Carbidopa
• An AADC inhibitor • Allows more levodopa to cross the blood brain barrier • Used in ratio with levodopa (C:L=1:4 or 1:10)
30
Levodopa‐Clinical use
• Best results if given early in the course (lowers mortality). Adjust dose to reduce adverse effects or to continue benefit if the patient becomes unresponsive to the therapy • 1/3 of patients respond well, 1/3 of patients less well, 1/3 of patients can’t tolerate or don’t respond
31
Levodopa‐Clinical use
• Response to the drug decreases after 3‐4 years anyway • Treats all symptoms; best at relieving bradykinesia • Interactions‐ – Decrease L‐dopa effect‐ phenytoin, phenothiazine, BP control agents – B6 increases peripheral conversion
32
Levodopa‐ Adverse effects
• Gastrointestinal‐ without carbidopa 80% will show anorexia, nausea, vomiting, 20% with carbidopa – Take after meals, divide doses, antacids – Emetic center is also affected by peripherally produced dopamine. Do not give phenothiazines which exacerbate disease
33
Levodopa‐ Adverse effects
• Cardiovascular‐ arrythmias, orthostatic hypotension, increased BP with non‐ selective MAOI or sympathomimetics • Dyskinesias 80%‐ Chorea, tremor, dystonia, myoclonus, tics – Difficult to treat if L‐Dopa continued
34
Levodopa‐ Adverse effects
• Behavioral effects‐ depression, agitation, sleep disorders, mood changes hallucinations • Mydriasis • Blood dyscrasias • Aggravate gout
35
Levodopa‐ Dosing/ drug holidays
• Response to drug con fluctuate during the day. May need to – 1. take more often in smaller doses – 2. add bromocriptine, selegiline, or entacapone – 3.decrease dietary protein with biggest protein intake in the evening
36
Levodopa‐ Dosing/ drug holidays
• Drug holidays do not usually increase sensitivity to drug • Can decrease neuro and behavioral ADR • Practice has fallen out of favor‐ can be dangerous in severe patients
37
Antipsychotic Agents
• Sometimes needed in patient management • Most common agents – Clozapine – Quetiapine – Risperidone
38
ALZHEIMER’S DISEASE
A type of progressive dementia for which current treatments are palliative. They may slow progression of the symptoms for a time but do not affect the underlying illness. Patients gradually lose sense of time, date, year, become unable to operate simple appliances, and day to day tasks are beyond their comprehension.
39
Symptoms of AD • Cognitive‐ memory loss, aphasia, agnosia, disorientation, impairments in abstract thinking, apraxia
• Behavioral‐ easy distractibility; demanding, stubborn, or uncooperative conduct; losing, hoarding or hiding things; wandering, repetitive speech or action, agitation, sleep disturbances • Mood Changes‐apathy, anger, paranoia, delusions, depression, irritability, aggression, hallucinations
40
Risk factors for AD
• Age:>65~6%,>85~35% • Down’s syndrome • Family history • Head injury • Stroke
41
Other causes of Dementia
• Vascular disease• Parkinson’sdisease • Majordepression• Normalpressurehydrocephalus •Metabolicdisorders• Chronicdrugintoxication • Hypothyroidism • Alcoholism • Infectiousdiseases
42
AD destroys neurons in the cortex and limbic structures of the CNS‐ area associated with higher learning, memory, reasoning, behavior and emotional control. There are 4 major alterations in these brain structures
1. Cortical atrophy 2. Degeneration of cholinergic and other neurons 3. Presence of neurofibrillary tangles 4. Accumulation of neuritic plaques
43
Treatment Theories
• AChE‐ acetylcholinesterase inhibitors‐ approved for treatment of mild to moderate AD. • NMDA‐ N‐methyl‐D‐aspartate‐ only agent is memantine‐ for treatment of moderate to severe AD
44
Tacrine‐Cognex(R)
• Acetylcholinesterase and butyrylcholinesterase inhibitor • For mild to moderate disease‐ improves memory and cognition • Adverse effects‐ Nausea, vomiting, diarrhea, agitation, anorexia • Hepatotoxicity (~30%) tends to occur in first 8 weeks of therapy
45
Tacrine
• Must be given every 6 hours • Active metabolite • Increase dose over 12‐18 weeks to minimize ADR • Give on an empty stomach • Cimetidine decreases clearance by 30%
46
Donepezil‐Aricept(R)
• Centrally active acetylcholinesterase inhibitor‐ low peripheral activity • High degree of selectivity for CNS ACH esterase‐ essentially no Butyrylcholinesterase • Reversible, noncompetitive
47
Donepezil
• Given once daily; soon available in transdermal patch • No liver toxicity • Once thought to improve actual progression of disease; 2004 study showed 2 years of slowed progression but no difference in time to disability or institutionalization
48
Carbamates
• Rivastigmine‐ 10 fold greater affinity for brain AChE than peripheral • Low oral bioavailability; also available in a patch • Longer DOA than physostigmine • ADR‐ nausea, vomiting, diarrhea, headache, dizziness
49
Galantamine (Reminyl®)
• Reversible, competitive AChE inhibitor • Some improvement in mild to moderate disease • Very potent on brain AChE • ADR: GI, agitation, insomnia
50
Memantine (Namenda(R))
• First FDA treatment for Moderate to severe AD • N‐methyl‐D‐aspartate (NMDA) antagonist • Can be used alone or with an AChE inhibitor • ADR: Fatigue, somnolence, hallucinations, headache, hypertension, cough, constipation
51
Other pharmacotherapy
• Estrogen replacement therapy may be neuroprotective. Does not appear to improve cognition and functioning • Gingko is not well studied. – 2012 study showed no benefit – interacts with antiplatelet drugs – GI side effects
52
Behavior and Mood Therapy
• Behavior and mood disturbances are very common in AD patients • For agitation or psychosis atypical antipsychotics are used (risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) • Antidepressants can also be helpful
53
Dopamine ant
Selegile, rasagiline Amantadine Anticholinergic
54
Selegiline | Rasagiline
``` MAO-B inhibitor Renewal-slow (last long) Inc dopa Inc levodopa Irreversible-blocks breakdown of dopa-> dec dopa life time ```
55
Dopamine ant Use of Seleiline, rasagiline
Mao-b inhi-> renewal takes slow-> last long Prolong dopa effect Selective Irreversible
56
Dopamin ant Selegiline, rasagiline AD
Inc AD of levodopa Insomnia Jitteriness
57
Selegiline, rasagiline_ drug interaction
Fluoxetine TCA Meperidine D/c 2wks priot to surgery
58
Amantadine Use
Promote dopamine release from peripheral stores Block dopamine reuptake Stimulate dopamine receptors Short term use- more effective
59
Amantadine AD
``` Anticholonergic effect(dry, sedation, vivid dream) Depression Mottling skin (livedo reticularis) ```
60
Amantadine- drug interaction
Not give to CHF, Seizure Avoids- HCTZ, triamterence, amiloride, anticholinergics, CNS stimulants

Pharm (19 decks)

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