Parkinson's Disease Drugs

Question 1

What are some motor symptoms of parkinsons?

Answer 1

Tremor, rigidity, bradykinesia (slowness of movement)

postural instability, speech, swallowing difficulty

Question 2

What are some non-motor symptoms of parkinsons?

Answer 2

Constipation, restlessness, paraesthesia,

autonomic symptoms: dry mouth, urinary retention, erectile dysfunction, dec libido

Cold/hot intolerance

Question 3

What are 5 theoretical ways to treat parkinsons?

Answer 3

give DA precursor

DA2 receptor agonist

MAOI + something

Release more DA

Remove Ach

Question 4

Why does parkinsons occur?

Answer 4

There is an imbalance between DA and Ach, favouring Ach.

Causes excessive cholinergic activity = muscle rigidity, tremor

Question 5

List the DA agonist types

Answer 5

Dopamine precursor w/ dopa-decarboxylase inhibitors (DDCi)

DA-R agonist

MAO-B inhibitor

COMT inhibitor

Apomorphine

Drugs that release DA

Question 6

What are the three dopaminergic pathways?

Answer 6

Nigrostriatal pathway = motor control

Mesolimbic/mesocortical pathways (emotion/drug-induced reward)= midbrain to limbic system, inc nucleus accumbens and cortex

Tuberhypophyseal neurons (reg pituitary sec)= from hypothalamus to pituitary gland

Question 7

What is levodopa?

Answer 7

Gold standard parkinsons treatment, favourable benefit to adverse effect profile (esp. in elderly w/ cognitive impairment)

Improve 2-3 wks, some need it for >6 months for therapeutic effect

Question 8

What is the role of DOPA decarboxylase>

Answer 8

Responsible for the conversion of DOPA to dopamine in periphery

Question 9

What is the role of COMT?

Answer 9

COMT is responsible for the breakdown of catecholamines due to the targeting of catechol groups

An important catechol = dopamine, noradrenaline, adrenaline

Question 10

Why is levodopa given with a DDCi?

Answer 10

When levodope is given orally, DDC and MAO in gut convert (90%) L-DOPA to dopamine and metabolites—> only 10% of original dose (now active) gets into blood

In periphery (tissue plasma) —> DDC and COMT –> Convert further 90% of L-DOPA in DA and metabolites

BB = the presence of DDC will convert the remaining 1% of L-DOPA in DA, which will result in minimal DA binding to CNS DA receptors

Question 11

List some ADRs associated with Levodopa

Answer 11

Anxiety, agitation, confusion, delusions (D2 hyperstim), hallucinations, depression, somnolence, nightmares

CV = hypotension (DA vasodilator), tachycardia, arrythmia (DA also hits B1)

GI = constipation, severe nausea, vomiting, anorexia, peptic ulcers

Other = dyskinesia, hypersexuality, unpredictable loss of mobility, lactation inhibit

Question 12

What affect does DA have on prolactin and growth hormone?

Answer 12

A D2 block results in inc prolactin and dec GH

Inc DA –> inc GH, dec prolactin

Question 13

How do D2 agonist effect impulse control?

Answer 13

2-3 fold inc in risk of impulse control disorders (Addiction)

Compulsive buying, pathologic gambling, binge-eating, compulsive sexual behaviour

Question 14

What syndrome occurs with abrupt withdrawal of L-DOPA?

Answer 14

Neuroleptic malignant syndrome

Symp = fever, muscle rigidity, rhabdomyolysis, profuse sweating, tachycardia, tachypnoea, agitation

Question 15

Explain some drug interactions associated with L-DOPA

Answer 15

Dopamine antagonists = antipsychotics (typicals)

Antihypertensive = DA is a vasodilator

MAO-A inhibitor = non-selective metabolite of monoamines

Ferrous sulphate = dec GI absorption

Anticonvulsants

Question 16

How do antiepileptics work?

Answer 16

Block VGNaC in use dependent manner

Inc GABA

Inhibit glutamate and aspartate

Question 17

What happens with prolonged L-DOPA therapy? (>2 yrs)

Answer 17

“On-off syndrome” = fluctuations of being symptom free “on” to full-blown parkinsons “off” during therapy (mins to hrs)

Question 18

Why does on-off syndrome occur?

Answer 18

Dec in delivery of DA centrally

Alteration in sensitivity of DA-R

Variation in amount and rate of drug absorption

DA metabolite interference

Question 19

What is the ‘waring off’ effect with long-term L-DOPA use?

Answer 19

L-DOPA’s duration of action shortens and patients become less responsive

Question 20

List the relevant DDCi

Answer 20

carbidopa

Question 21

Discuss DA-R agonists

Answer 21

Direct stimulate DA-R

differing affinities for DA-R

improve bradykinesia, rigidity

less effective than L-DOPA = due to fast adaption

Question 22

List the ergot derivative DA-R agonists

Answer 22

Bromocriptine
Pergolide
Cabergoline

Question 23

List the non-ergot derivative DA-R agonists

Answer 23

pramipexole
Rotigotine
Ropinorole

Question 24

Which DA-R agonists carry a risk of fibrotic cardiac vulvopathy

Answer 24

pergolide or cabergoline

This is not seen in non-ergot derivates

Question 25

Which DA-R agonist is associated with pulmonary fibrosis?

Answer 25

bromocriptine

Question 26

Which DA-R is used to inhibit lactation?

Answer 26

Cabergoline = dec prolactin due to DA stimulus

Question 27

Discuss Apomorphine

Answer 27

Used as anti-parkinsons drug = DA agonist, not structurally related to ergot alkaloids

Its a morphine derivative w/ little analgesic activity

A potent D2 agonist = extreme N/V and hypotension

Used in severely disabled by motor fluctations in L-DOPA

Question 28

Which drugs irreversibly inhibit MAO-B?

Answer 28

Selegiline

rasagiline = more potent (5x more potent)

Question 29

What is the MOA of rasagiline and selegiline?

Answer 29

irreversibly inhibit MOA-B –> indirect dopamine agonism

also blocks DA reuptake, antioxidant

Question 30

Which drugs interact with Selegiline?

Answer 30

MAOi, SSRI (fluoxetine, sertraline), TCA’s, St Johns wort, linezolid, sumatriptan, pethidine –> inc mania risk, serotonin toxicity

^ need to discontinue selegiline for 2-5 wks before use

L-DOPA = reduce dose due to additive effect

Tyramine rich foods = tyramine reaction, less severe than with MAO-A inhibitors, relatively specific to NA, 5HT and drugs

Question 31

Name the relevant COMT inhibitor and its MOA

Answer 31

Entacapone = inc lvls of DA and NA

C/I = hepatic failure

Question 32

Is entacapone used alone?

Answer 32

No, entacapone is usually an adjunct to L-DOPA-carbidopa therapy, should dec L-DOP dose by 10-30%

Question 33

Name the M-R antagonists used to treat parkinsons

Answer 33

Centrally acting:

Benztropine, benzhexol, biperiden, orphenadrine

Question 34

List the ADRs of the M-R antagonists used in parkinsons

Answer 34

Atropine ADRs

dry mouth, constipation, urinary retention, blurred vision

cognitive impairment, hallucinations, memory loss

Question 35

Which drugs can cause parkinsons?

Answer 35

Anything that takes DA

High risk = Antipsychotics, methyldopa, metoclopramide, tetrabenazine

Intermediate risk = verapamil (Take Ca2+ away –> affect C-type Ca2+ channels –> impair movement), valporate (VGNa+C block), lithium (mimic Na+, dec DA)

Question 36

What is the MOA of local anaesthetics?

Answer 36

Use dependent block of voltage gated Na+ channels –> drug gains more access readily when channel opens

Depth of block inc with action of potential freq

Question 37

What is the difference between Ester LAs and Amide LAs?

Answer 37

Ester local anaesthetics = cocaine, procaine, tetracaine (too much cause arrythmias and death)

Amide local anaesthetics = Cinchocaine, lidocaine, prilocaine, bupivavaine, benzocaine

Difference = amide LAs have longer half life due to CYP450 metabolism whilst ester LAs undergo metabolism by esterases which are found more abundantly

Question 38

In which order do LAs block conduction?

Answer 38

Nociceptive/sympathetic transmission blocked first

small myelinated fibred > non-myelinated fibres > large myelinated fibres

less effective in acidic tissue

Question 39

When considering the MOA of LAs, what is the loss of nerve function orders?

Answer 39

1) pain = fires the fastest
2) temp
3) touch
4) proprioception
5) skeletal muscle tone

as you up the dose`