Pharm: L13: Parkinson's and Alzheimer's Disease

Question 1

1. Parkinson’s is believed to be due to the DEGENERATION of Dopamine Neurons that project from _____ to the ______?

Answer 1

1. Substantia Nigra to the Corpus Striatum (Nigrostriatal Pathway)

Question 2

Primary Symptoms

1. They occur once what % of Striatal DA is lost?
2. What are the 4 PRIMARY SYMPTOMS?

Answer 2

1. about 70%

2. Bradykinesia, Difficult to Balance, Difficult to Walk, and Tremors and Stiffness

Question 3

Secondary Symptoms

1. What 4 secondary symptoms are there?

Answer 3

1. Dementia, Depression, Difficulty Speaking, and Postural Deformity

Question 4

Parkinsonian Symptoms

1. These can occur from what issues?
2. What Dopamine AGONIST used to treat upset stomach can cause Parkinsonian like Symptoms?

Answer 4

1. Brain tumors, repeated head Trauma, Prolonged use of Antipsychotic Drugs, and w/Manganese and Carbon Monoxide Poisoning.
2. METACLOPRAMIDE

Question 5

1. What are the 3 Possible Etiologies of parkinsons?
2. It’s due to the degeneration of Dopamine neurons in what area of the Substantia Nigra?
   a. This leads to what 2 things occurring?
   b. This Culminates in what type of output?
   c. And what type of Input?
   d. What’s the end result?
3. What are LEWY Bodies?

Answer 5

1. Idiopathic, Parkin (alpha-synuclein gene) and MPTP.
2. in the PARS COMPACTA
   a. Overactivity in INDIRECT PATHWAY and Underactivity in the DIRECT PATHWAY

b. Increased Glutamatergic Output from the SUBTHALAMIC NUCLEUS
c. Increased GABA Input into the Thalamus
d. Decreased Glutamate Input into the Cortex
3. THey are INTRACELLULAR Aggregation of a-Synuclein and other Proteins

Question 6

DA Synthesis and Metabolism

1. Tyrosine is converted to what which leads to what?
   a. After DA is released into the Synaptic cleft, how does is get taken up again?
   b. DA is metabolized by what Enzyme in the Nerve Terminal?
   c. In the Periphery, DA is also metabolized by what 2 things?

Answer 6

1. to l-Dopa –> Dopamine (via Dopa Decarboxylase)
   a. via DA Transporter (DAT)
   b. MAO-B
   c. MAO-A and COMT

Question 7

Interactions of DA and ACh

1. DA in SN loss leads to an imbalance b/w DA and ACh, leading to what?
   a. DA pathways normally inhibit what?
   b. Whereas ACh does what?
   c. Loss of DA thus leads to what?

Answer 7

1. Leads to an imbalance b/w DA and ACh, so ACh will now be dominant.
   a. GABA output from the Striatum.
   b. Stimulates GABA output from the Striatum
   c. to Overactivity of Inhibitory GABA neurons.

Question 8

Dopaminergic Neurotransmission and Therapeutic Targets in PD

1. There are 4 areas that can affected. What are they?

Answer 8

1. Increase brain DA levels
2. Inhibit DA metabolism in the brain (MAO and COMT)
3. Stimulate brain DA D2 Receptors
4. Decrease Cholinergic Activity

Question 9

L-DOPA

1. Purpose?
2. 2 Peripheral Effects?
3. Clinical Uses
   a. Improves PD symptoms for how many years?
   b. What happens to the EFFECTIVENESS of l-Dopa over time?
   c. Will it slow progression?
   d. Does it help in DRUG-INDUCED PARKINSONISM?
4. Pharmacokinetics
   a. how is it taken?
   b. Dosage levels?
   c. % that gets into the CNS?

Answer 9

1. Increase DA Levels (“Replacement” Therapy)
2. Nausea and Vomiting (due to having to take it ORALLY and it is metabolized quickly in the Periphery
3. a. about 3-4 years
   b. It will GO DOWN
   c. NO.
   d. NO
4. a. Orally
   b. HIGH
   c. 1-3% gets into the CNS

Question 10

Carbidopa

1. What is it?
   a. Can it cross the BBB?
   b. What does it do?
   c. This leads to what?

Answer 10

1. DOPA DECARBOXYLASE INHIBITOR
   a. No.
   b. Inhibits formation of DA from l-dopa in the periphery. NO EFFECT on SYNTHESIS of DA in the Brain.
   c. Increased l-Dopa gets into the BRAIN!!

Question 11

L-Dopa/Carbidopa (Sinemet)

1. What does the 2 of these taken together do?
2. Pharm: How is it taken?
3. Side Effects
   a. Increase as what happens?
   b. GI issues? WHAT SHOULD be avoided?
   c. What DEVELOP WITH TIME? More common with what?
   d. Behavioral: What things? How do you treat?

Answer 11

1. Inhibits l-dopa conversion to DA in the Periphery, but not the brain. Decreases dose of l-dopa needed. Decreases peripheral Effects; Nausea
2. Orally
3. a. As Disease Progresses
   b. Nausea/Emesis; Avoid ANTIEMETICS that block DA D2 receptors (Prochlorperazine) (Divide doses to help decrease GI Effects)

c. DYSKINESIAS; More common w/L-Dopa/Carbidopa combo.
d. Depression, anxiety, agitation,etc. TREAT with ATYPICAL ANTIPSYCHOTICS!

Question 12

Parkinson’s: On-Off Phenomenon

1. What is it?
   a. What can we do about it?
   b. What drug is used as a “RESCUE”?

Answer 12

1. Fluctuations. On = Improved MOBILITY w/Dyskinesias and OFF = AKINESIA due to FALLING DRUG LEVELS
   a. Increase dose frequency, Add another drug,
   b. APOMORPHINE (DA Receptor Antagonist!!)

Question 13

L-Dopa; Drug Interactions/CIs

1. Interactions: with what type of drug?
   a. What can it do?
2. CIs
   a. Mentally?
   b. to the EYE?
   c. HEART?
   d. GI System?
   e. What else?

Answer 13

1. MONOAMINE OXIDASE INHIBITORS
   a. can cause a HYPERTENSIVE CRISIS (need to wait 2 wks after stopping MAOI before giving l-Dopa)
2. a. PSYCHOSIS (increases DA)
   b. CLOSED-ANGLE GLAUCOMA (increases intraocular pressure)
   c. CARDIAC DISEASE (with it, CARBIDOPA decreases Peripheral effects but Risk is SMALL)
   d. ACTIVE PEPTIC ULCER: l-dopa can increase GI Bleeding

e. MALIGNANT MELANOMA: l-dopa is a Precursor of Melanin

Question 14

MAOIs

1. What do they Inhibit?
2. What is the Drug called?
3. What MAO does it inhibit?
4. What does it DECREASE?
5. Does it Affect Peripheral Metabolism of DA?
6. PHARM: How is it taken?
7. Adverse Effects?
   a. DO NOT COMBINE with WHAT!?

Answer 14

1. DA Metabolism
2. Selegiline
3. MAO-B, NOT MAO-A
4. Decreases Striatal Metabolism of DA
5. No!
6. Oral (2x’s/day; Breakfast and Lunch)
7. INSOMNIA

SEVERE HYPERTENSION if combined w/MAOIs (PHENELZINE)

Can increase side effects of L-DOPA in late stages

a. DONT COMBINE with MEPERIDNE (can cause stupor, rigidity, agitation, possible Serotonin Syndrome: Dont combine with TCAs or SSRIs)

Question 15

COMT Inhibitors

1. What drug is it?
2. What does it do?!
3. Used in COMBINATION with what?
4. INCREASES what?
5. SIDE EFFECTS? (URINE is the big one)

Answer 15

1. Entacapone (metabolizes DA and L-Dopa)
2. INHIBITS COMT and L-Dopa METABOLISM in the PERIPHERY ONLY!
3. with L-Dopa/Carbidopa
4. the AMT of L-DOPA Available for UPTAKE into the BRAIN
5. confusion, nausea, hypotension, abdominal pain. (ORANGE COLOR IN URINE!!)

Question 16

DA RECEPTOR AGONISTS

1. What do they do?
   a. What ones mainly?
2. What 4 DRUGS are there? (BARP)?

Answer 16

1. Stimulate DA Receptors
   a. DA D2 receptors (they continue to be EFFECTIVE as the DISEASE PROGRESSES due to direct action on receptors)
2. Bromocriptine; Apomorphine; Ropinirole; Pramipexole

Question 17

DA RECEPTOR AGONISTS

1. Bromocriptine: What is it?
   a. What can it cause?
2. Apomorphine
   a. Used for temporary relief during what part of l-dopa therapy?
   b. Half LIFE?
   c. Side Effects?
   d. AVOID what?
3. Ropinirole
   a. What is it?
   b. Best used when?
   c. DOC for what symptom?
4. Pramipexole: Issue with it?

Answer 17

1. 1. Ergot derivatives.
      a. ERYTHROMELALGIA
2. a. during OFF-PERIODS in Patients
   b. VERY SHORT (10 min)
   c. NAUSEA. AVOID ANTIEMETICS that target 5HT system (severe hypertension, loss of consciousness) and those that BLOCK DA D2 Receptors (Proclorperazine)
3. New DA D2 Agonists.
   a. Pure DA D2 Agonist
   b. MONOTHERAPY in Mild PD; Soothing response to L-dopa in Late PD.

c. for RESTLESS LEG SYNDROME
4. FDA warning for possible heart failure (sept 2012)
* Pramipexole and Ropinirole can both CAUSE a RARE SIDE EFFECT that will cause SUDDEN SLEEP DURING THE DAY!!!

Question 18

DA Agonists: SIDE EFFECTS

1. GI
2. Cardiovascular
3. Dyskinesia
4. Mental Disturbances
5. Erythromelalgia
6. Prolactin

Answer 18

1. ANOREXIA, NAUSEA, VOMITING
2. POSTURAL HYPOTENSION (at start of Tx); CARDIAC ARRYTHMIAS (if so..discontinue Tx)
3. Like L-dopa…reduce Dose of Dopaminergic Drugs
4. Confusion, Hallucinations, Delusions
5. BROMOCRIPTINE (Side effect of ERGOT DERIVATIVES): Red, tender, swollen feet. Disappears w/in a few days of discontinuing Bromocriptine
6. DA Agonists will decrease release

Question 19

Anticholinergics

1. What drug?
2. What does it do?
3. What does it Improve?
   a. Has LITTLE EFFECT on what?
4. What stages is it used in?
5. Side effects?

Answer 19

1. Benztropine
2. Muscarinic Receptor Antagonists: RESTORES DA/ACh BALANCE in STRIATUM
3. RIGIDITY and TREMOR
   a. on BRADYKINESIA
4. Early and Late Stages; ADJUNCT to DA THERAPY
5. Constipation, Urinary Retention, Blurred Vision, Sedation, Confusion…when discontinuing, do it gradually.
   * TCAs or Antihistamines INCREASE EFFECTS

Question 20

1. What are the 5 Risk factors of DEMENTIA?

Answer 20

1. Age
2. Genetics (small)
3. Gender (Females)
4. Lack of Education
5. Head Injury

Question 21

Alzheimer’s Disease

1. What are NEURITIC PLAQUES?
2. What are NEUROFIBRILLARY TANGES?

Answer 21

1. B-Amyloids: Dense deposits outside and around the nerve cells in the brain.
2. TAU PROTEINS found w/in the twisted strands of fiber.

Question 22

Alzheimer’s Disease

1. Mild Symptoms?

Answer 22

1. Confusion, Memory Loss; Disorientation, changes in personality and judgement

Question 23

Alzheimer’s Disease

1. Moderate Symptoms

Answer 23

1. Hard doing daily activities; Anxiety, suspiciousness, agitation, sleep disturbances, hard to Recognize family and friends

Question 24

Alzheimer’s Disease

1. Severe Symptoms

Answer 24

1. Loss of Speech, appetite, weight loss, and loss of bladder and bowel control

Question 25

Alzheimer's Disease: Neurochemical Changes 1. Degeneration of what NEURONS? 2. What HORMONES are REDUCED up to 90%?

Answer 25

1. of CHOLINERGIC NEURONS from NUCLEUS BASALIS of MEYNERT: they project to the CEREBRAL CORTEX and HIPPOCAMPUS (Hallmark of AD) 2. ACh

Question 26

AD: ACE Inhibitors 1. What 2 drugs? (DR) 2. What do they inhibit? 3. What do they increase? 4. METABOLIZED by what? 5. What PERIPHERAL CHOLINERGIC SIDE EFFECTS are there? * Currently the DRUGS that are FDA Approved to treat AD

Answer 26

1. Donepezil and Rivastigmine 2. Metabolism of ACh 3. the Amt of ACh in the nerve terminal 4. by CYP450s 5. GI, Nausea, Vomiting, Diarrhea, STOMACH CRAMPS MOST COMMON * WELL ABSORBED and readily Penetrates the CNS

Question 27

AD: ACE Inhibitors 1. How often are they taken? 2. What do they do to the brain? 3. What about the disease progression? 4. Delays what?

Answer 27

1. once a day 2. Increases brain activity and Improves Cognitive Symptoms 3. May Slow progression of the disease 4. Transition from Mild Cognitive Impairment to AD

Question 28

AD: NMDA Antagonist 1. What drug? 2. What does it do? 3. Used in what AD cases? 4. What does it compete for? 5. MONITOR in PATIENTS with what problem? 6. Side Effects? 7. CI with what?

Answer 28

1. MEMANTINE 2. Non-competitive Antagonist: BLOCKS PATHOLOGICAL ACTIVATION of NMDA RECEPTORS 3. MORE SEVERE AD cases. 4. Renal Secretion with many drugs 5. with RENAL IMPAIRMENT 6. Agitation, insomnia, urinary incontinence, UTI, and Diarrhea 7. with MEPERIDINE * May increase Side effects of L-Dopa