Dopamine receptor agonists

Basic and clinical pharmacology of dopamine receptor agonists

1. Dopaminereceptor
agonists
Domina Petric, MD

2. Dopaminereceptor agonists
•Thesedrugsdo notrequireenzymatic
conversionto anactivemetabolite.
•Theyhaveno potentiallytoxic
metabolites.
•Theydo notcompetewithother
substancesfor activetransport intothe
bloodandacrosstheblood-brainbarrier.
•Drugsselectivelyaffectingcertain
dopaminereceptorsmayhavemore
limitedadverseeffectsthanlevodopa.

3. Dopaminereceptor agonists
•Dopamineagonistshaveanimportant
role as first-linetherapyfor Parkinson´s
disease.
•Theiruse is associatedwitha lower
incidenceoftheresponsefluctuations
anddyskinesiasthatoccurwithlong-term
levodopatherapy.
•Dopaminergictherapymaybebest
initiatedwitha dopamineagonist.

4. Dopaminereceptor agonists
•Thedoseofthedopamineagonistis
builtupgraduallydependingon
responseandtolerance.
•Dopamineagonistsmaybegivento
patientswithparkinsonismwhoare
takinglevodopaandhaveend-of-dose
akinesia, or on-offphenomenon, or are
becomingresistantto treatmentwith
levodopa.

5. Dopaminereceptor agonists
Theresponseto a
dopamineagonistis
generallydisappointingin
patientswhohavenever
respondedto levodopa.

6. Bromocriptine
•Bromocriptineis D2 agonist.
•Itis nowrarelyusedfor
parkinsonism.
•Theusualdailydoseof
bromocriptinefor parkinsonism
variesbetween7,5 and30 mg.
•To minimizeadverseeffects, thedose
is builtupslowlyover2 or 3 months.

7. Pergolide
Pergolidedirectlystimulates
bothD1 andD2receptors.
Itis notusedfor parkinsonismany
more becauseitsuse hasbeen
associatedwiththedevelopmentof
valvularheartdisease.

8. Pramipexole
•Itis effectiveas monotherapyfor mild
parkinsonism.
•Itis alsohelpfulinpatientswith
advanceddisease, permittingthe
doseoflevodopato bereducedand
smoothingoutresponsefluctuations.
•Pramipexolemayameliorateaffective
symptoms.

9. Pramipexole
•Possibleneuroprotectiveeffect: abilityof
pramipexoleto scavengehydrogen
peroxideandenhanceneurotrophic
activityinmesencephalicdopaminergic
cellcultures.
•Pramipexoleis rapidlyabsorbedafteroral
administration, reachingpeakplasma
concentrationsinabout2 hours.
•Itis excretedlargelyunchangedinthe
urine.

10. Pramipexole
•Startingdoseis 0,125 mg threetimes
daily.
•Doseis doubledafter1 weekand
againafteranotherweek.
•Furtherincrementsinthedailydose
are by0,75 mg at weeklyintervals.
•Most patientsrequirebetween0,5
and1,5 mg threetimesdaily.

11. Pramipexole
•Renalinsufficiencymay
necessitatedosageadjustment.
•Extended-releasepreparationis
takenoncedaily.
•Thispreparationis more
convenientfor patientsandavoids
swingsinbloodlevelsofthedrug
overtheday.

12. Ropinirole
•Itis a relativelypure D2 receptor agonist.
•Itis effectiveas monotherapyinpatients
withmilddisease.
•Itis alsohelpfulinpatientswithmore
advanceddiseaseusinglevodopafor
smoothingtheresponsefluctuations.
•Start doseis 0,25 mg threetimesdaily.
•Thetotal dailydoseis increasedby0,75 mg at
weeklyintervalsuntilthefourthweek, afterthat
incrementis by1,5 mg.

13. Ropinirole
In most cases dosage between 2 and
8 mg three times daily is necessary.
Ropinirole is metabolized by
CYP1A2.
A prolonged-releasepreparation
takenoncedailyis available.

14. Rotigotine
•Thedopamineagonistrotigotine
is delivereddailythrougha skin
patch: more continuous
dopaminergicstimulationthan
oralmedicationinearlydisease.
•Itsefficacyinmore advanced
diseaseis lessclear.

15. Adverseeffects
Dopaminereceptor agonists

16. Gastrointestinaleffects
•Anorexia, nauseaandvomitingmay
occurwhena dopamineagonistis
introduced.
•Theseside effectscanbeminimizedby
takingthemedicationwithmeals.
•Constipation, dyspepsiaandsymptoms
ofrefluxesophagitismayalsooccur.
•Bleedingfrompepticulceration!

17. Cardiovasculareffects
•Posturalhypotensionmayoccur,
particularlyat theinitiationoftherapy.
•Painlessdigitalvasospasmis a dose-
relatedcomplicationoflong-term
treatmentwiththeergot derivatives
(bromocriptine, pergolide).
•Cardiacarrhythmias: indicationfor
discontinuingtreatment.
•Peripheraledema.
•Cardiacvalvulopathywithpergolide.

18. Dyskinesias
Abnormalmovements
similarto thoseintroduced
bylevodopamayoccurand
are reversedbyreducingthe
total doseofdopaminergic
drug beingtaken.

19. Mentaldisturbances
•Confusion, hallucinations, delusionsand
otherpsychiatricreactionsare more
commonandseverewithdopamine
receptor agoniststhanwithlevodopa.
•Disordersofimpulse controlmayleadto
compulsivegambling, shopping, betting,
sexualactivityandotherbehaviors.
•Thesebehaviorsclearon withdrawalof
theoffendingmedication.

20. Miscellaneous
•Ergot-deriveddopamineagonists
(bromocriptine, pergolide): headache,
nasalcongestion, increasedarousal,
pulmonaryinfiltrates, pleuraland
retroperitonealfibrosis, erythromelalgia.
•Pergolide: cardiacvalvulopathies.
•Erythromelalgiaconsistsofred, tender,
painful, swollenfeetand, occasionally,
hands, at timesassociatedwitharthralgia.

21. www.erythromelalgia.org

22. Miscellaneous
Inrareinstances, an
uncontrollabletendencyto fall
asleepat inappropriatetimes
hasoccured, particularlyin
patientsreceivingpramipexole
or ropinirole.

23. Contraindications
•Dopamineagonistsare
contraindicatedinpatientswitha
historyofpsychoticillnessor
recentmyocardialinfarction, or
withactivepepticulceration.
•Theergot-derivedagonistsare
bestavoidedinpatientswith
peripheralvasculardisease.

24. Apomorphine
Dopamineagonist

25. Apomorphine
•Apomorphineis a potentdopamine
agonist.
•Subcutaneousinjectionofapomorphine
hydrochloride(Apokyn) is effectivefor the
temporaryrelief(rescue) ofoff-periodsof
akinesiainpatientson optimized
dopaminergictherapy.
•Itis rapidlytakenupinthebloodand
thenthebrain.

26. Apomorphine
•Clinicalbenefitbeginswithin10
minutesofinjectionandpersistsfor up
to 2 hours.
•Theoptimaldoseis identifiedby
administeringincreasingtest doses
untiladequatebenefitis achievedor a
maximumof10 mg is reached.
•Most patientsrequirea doseof3-6 mg,
but no more thanthreetimesdaily!

27. Apomorphine
•Nauseaat theinitiationofapomorphine
treatment: pretreatmentwiththe
antiemetictrimethobenzamide(300 mg
threetimesdaily) for 3 daysandthenfor
at least1 monthafter.
•Otheradverseeffects: dyskinesias,
drowsiness, chestpain, sweating,
hypotension, bruisingat the
injectionsite.

28. Literature
•Katzung, Masters, Trevor.
Basicandclinical
pharmacology.
•www.erythromelalgia.org