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PHARMACOLOGY > CHAPTER 8: NEURODEGENERATIVE DISEASES > Flashcards

CHAPTER 8: NEURODEGENERATIVE DISEASES Flashcards

1
Q

What does CNS consist of?

A

brain and spinal cord, meninges, BBB, blood supply to the brain

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2
Q

what are the CNS functions?

A

sensory, motor, intellect/emotion

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3
Q

common neurotransmitters?

A

ACh, NE, glutamate, glycine, dopamine, serotonin, Gamma-aminobutyric acid (GABA)

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4
Q

excitatory vs. inhibitory neurotransmission/pathway

A
  • both bind to post synaptic receptor, transiently open ion channels, and alter the post synpatic POTENTIAL

excitatory DEpolarizes, inhibitory HYPERpolarizes post synaptic membrane

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5
Q

why are some pathways meant to be inhibitory?

A

because certain pathways must remain inhibitory to be kept NORMAL

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6
Q

Excitatory post synaptic potentials (EPSP) are generated by:

A
  • release of neurotransmitters, inc permeability on Na+ ions
  • influx Na+, weak depol, and move post syn potential TOWARDS firing threshold
  • inc stimulation of excitatory neurons, depol PASSES threshold, and generates “all or none” AP
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7
Q

Inhibitory post synaptic potentials (IPSP) are generated by:

A
  • stimulating inhibitory neurons, releasing neurotransmitters like GABA or GLYCINE—> transient inc permeability for SPECIFIC IONS

GABA induces hyperpol

  • influx Cl-, efflux, K+—> weak hyperpolarization, move post syn potential AWAY from firing threshold (less firing)
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8
Q

which specific ions are moving in excitatory vs inhibitory

A

excitatory: Na+ influx
inhibitory: Cl- influx, K+ efflux

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9
Q

Neurodegenerative Diseases: list and explain what it is

A

Parkinson’s (PD), Alzheimer’s (AD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS)

  • PROGRESSIVE loss of selective neurons in discrete brain areas
  • cause characteristic disorders of movement and cognition
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10
Q

PARKINSON’S DISEASE: what is it? age range? cure?

A
  • progressive chronic neurological disorder
  • develop in ANY age– most in middl age/past 60
  • NO CURE
    therapy aims to manage the symptoms/signs not necessarily slow down progression (not possible)
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11
Q

PARKINSON’S: signs and symptoms

A
  • lack of coordination
  • rhythmic tremors
  • rigidity/weakness
  • trouble maintaining position/posture
  • bradykinesia—> slow movement
  • difficutly walking
  • drooling/affect speech
  • mask-like expressions
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12
Q

PARKINSON’S: mechanism

A
  • destruction of dopaminergic neurons in SUBSTANTIA NIGRA—> reduces dopamine actions in CORPUS STRIATUM

cells in substantia nigra are destroyed, results in degeneration of nerve terminals that secerete dopamine
dopamine depletion—-> blocks the autoinhibition of ACh and releases MORE in corpus—-> triggers chain of abnormal signaling resulting in motor impairment

SIMPLE: dopamine neurons destroyed, not able to inhibit ACh firing, starts firing like crazy and results in motor impairment

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13
Q

secondary parkinsonism

A

drugs blocking dopamine receptors in brain may produce Parkinsonism SYMPTOMS
- drugs should be used cautiously in PD patients

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14
Q

Substantia Nigra and Corpus Stratum importance

A
  • these are parts of basal ganglia system that are involved in motor control
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15
Q

Drugs used in PARKINSON’S, categories?

A

Levodopa w carbidopa
selegiline, rasagiline, safinamide
entacapone and tolcapone
amantadine

MAO-B selective Inhibitors, COMT Inhibitors, Dopamine Agonists, Antimuscarinic Agents

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16
Q

Therapeutic Strategies of treating PARKINSON’S

A

need to try and reestablish correct dopamine/ACh balance by:
- restoring dopamine in basal ganglia
- antagonizing excitatory effect of cholinergic neurons

restore balance in this CIRCUIT

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17
Q

GOALS of treating PARKINSON’S

A

drug therapy is aimed at achieving a balance between stimulating cholinergic effects and inhibitory effects of dopamine in basal ganglia

18
Q

type 1 drugs vs. type 2 drugs

A

type 1: for inhibition
- inc dopamine conc
- inc dopamine release
- stimulate dopamine receptors

type 2: stimulation
- anticholinergic drugs block stimulant (of cholinergic neurons)

19
Q

LEVODOPA and CARBIDOPA: MOA

(combination therapy)

A

levodopa: restore dopaminergic neurotransmission in the neostriatum, ENHANCE synth of dopamine in surviving neurons of susbstantia nigra

carbidopa: diminish metabolism of levodopa in periphery, inc levodopa availability to CNS (gets in through transporter AADC)

20
Q

neurotransmission L-dopa and carbidopa

A

PERIPHERY: Carbidopa stops DDC (dopa decarboxylase) inhibits levodopa metabolism, L-dopa turns into DOPA, and crosses BBB into neuron to be turned into dopamine

CNS: tyrosine converted by TH (tyrosine hydroxylase) into L-dopa, AADC (amino acid decarboxylase) makes that into Dopamine

21
Q

administered levodopa vs. levodopa plus carbidopa

A

administered levodopa will undergo metabolism in peripheral tissues and GI tract, cause undesirable side effects and result in LOST LEVODOPA (less drug to go to CNS)

levo+carbidopa decreases metabolism in periphery/GI, less side effects, and MORE levodopa to go into CNS (cross BBB)

22
Q

what does carbidopa do for levodopa?

A

it blocks the DECARBOXYLASE ENZYME that is trying to metabolize levodopa

LEts CARry the drug to the brain!

23
Q

LEVODOPA and CARBIDOPA: indications and therapeutic effects, withdrawal?

A
  • treat PD
    effects:
  • dec rigidity, tremor, and other symptoms

WITHDRAWAL MUST BE GRADUAL

24
Q

LEVODOPA and CARBIDOPA: absorption/metabolism

A
  • SHORT half-life (1-2 hrs), fluctuates in plasma conc.
  • motor fluctuations–> PT may suddenly lose normal mobility, experience tremors, cramps, immobility
25
Q

when is it best to take levodopa and carbidopa?

A

on an empty stomach, if you take it after eating there are amino acids present trying to break down/metabolize your food and the DRUG! this will let less drug go to the brain!

eating=harder for L-dopa to get to brain

26
Q

LEVODOPA and CARBIDOPA: peripheral and CNS effects

A

PERIPHERAL
- anorexia
- nausea, vomiting
- tachycardia, ventricular extrasystole (DA action on heart)
- possible develop of hypotension
- mydriasis–> adrenergic action

CNS
- visual/auditory hallucinations
- dyskinesia–> abnormal involun movements (overactivity of dopamine in basal ganglia)
- mood changes, depression, psychosis (activation dopamine receptors), anxiety

27
Q

why don’t we just use dopamine to treat PD?

A

it does NOT cross the BBB, so we use L-dopa and transporters.
dopamine interferes with ADRENERGIC RECEPTORS as well

28
Q

LEVODOPA and CARBIDOPA: interactions

A
  • vitamin B6–> inc peripheral breakdown levodopa
  • co-administration L-dopa and nonselective MAOIs—> hypertensive crisis (enhanced catecholamine production)
  • psychotic PT—> worsens symptoms (build up central catecholamines)
  • cardiac PT: monitor for arrhythmia

CONTRAINDICATE: antipsychotic drugs (potently block DA receptors/augment PD symptoms)

29
Q

MAO INHIBITORS:
what are the differences between MAO-A and MAO-B? (not the inhibition)

A

MAO type A–> metabolism of NE and 5-HT

MAO type B–> metabolism of DA

30
Q

MAOB Selective Inhibitors: SELEGILINE

A

LOW DOSE: REVERSIBLE selective inhibitor MAOB
HIGH DOSE: lose selectivity
- inc dopamine in brain
- metabolize to methamphetamine and amphetamine–> may produce insomnia

31
Q

MAOB Selective Inhibitors: RASAGILINE

A
  • IRREVERSIBLE, selective MAOB inhibitor
  • MORE POTENT THAT SELEGILINE
  • inc dopamine in brain
    NOT metabolized to amph and meth
32
Q

MAOB Selective Inhibitors: SAFINAMIDE

A

REVERSIBLE, selective MAO B inhibitor
- inc dopamine in brain
NOT metabolized to amph and meth

33
Q

COMT Inhibitors: entacapone and tolcapone
- MOA

A
  • selectively and reversibly inhibit COMT
34
Q

Entacapone and Tolcapone: therapeutic effects

A
  • inhibit COMT–> dec plasma conc of 3-O-methyldopa—> INC uptake L-dopa—> inc conc brain dopamine

-reduce wearing off symptoms in levi-carbi pts

REMEMBER L-dopa and 3OMD compete for entry into BBB, so we want to dec 3OMD and allow more L-dopa in

35
Q

explain how COMT inhibitors work step by step

A

when carbidopa inhibits peripheral DDC (the thing that metabolizes) L dopa, 3-O-methyldopa is created which competes L-dopa for active transport into CNS

inhibiting COMT, decreases conc 3-O-methyldopa and allows inc central uptake L-dopa into brain and therefore inc dopamine in brain!

36
Q

Entacapone and Tolcapone: adverse effects

A
  • diarrhea
  • nausea
  • anorexia
  • postural/orthostatic hypotension
  • dyskinsesias
  • hallucinations
  • sleep disorders
  • suddenly developed hepatic necrosis w TOLCAPONE
    entacapone doesn’t exhibit this toxicity, largely replaced tolcapone
37
Q

Dopamine Agonists: bromocriptine, ropinirole, pramipexole, rotigotine, apomorphine
- routes of administration

A

bromocriptine (oral), ropinirole (oral), pramipexole (oral), rotigotine (transdermal), apomorphine (injectable for severe/advanced stages)

38
Q

Dopamine Agonists: MOA

A

type 1: STIMULATE dopamine receptors

    • longer duration of action than L-dopa
  • effective in PT exhibiting fluctuations in response to L-dopa
  • initial therapy associated w/less risk dyskinesias/motor fluctuations compared to L-dopa

fluctuations in L-dopa, wear off effect, its difficult to maintain a constant level of dopamine so the effect fluctuate throughout the day

39
Q

Dopamine Agonists: adverse effects

A
  • sedation
  • nausea
  • confusion
  • hallucinations
  • hypotension
40
Q

Antiviral: Amantadine
- therapeutic effects and adverse effects

A

-accidentally discovered to help PD treatment

therapeutic:
- inc dopamine release
- block cholinergic receptors
- inhibit NMDA (type of glutamate receptor)

ADVERSE:
- restlessness, agitation, confusion, hallucinations
HIGH DOSES: acute toxic psychosis, orthostat hypotension, urinary retention, peripheral edema, dry mouth

41
Q

Antimuscarinic Agents : benztropine, trihexyphenidyl, biperiden, procyclidine

  • main purpose
  • therapeutic effects
  • adverse effects
  • contraindications
A

INHIBIT PSNS
muss less efficacious than L-dopa, only play ADJUVANT ROLE
therapeutic:
- block cholinergic transmission, correct imbalance of DA/ACh activity

adverse:
- mood change, confusion, xerostomia, constipation, visual problems, GI peristalsis interference

contraindications:
- PT w/ glaucoma, prostatic hyperplasia, pyloric stenosis

PHARMACOLOGY (29 decks)

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