IDT Exam 2 Drugs

Deutetrabenazine

(Austedo®) –

MOA: *Vesicular Monoamine Transporter (VMAT)  Inhibitors on monoamine oxidase containing neurons (dopamine, serotonin, norepinephrine, histamine)

Approved April 3, 2017 to treat hyperkinetic movement disorders associated with Huntington’s disease and tardive dyskinesia 

Tetrabenazine

(Xenazine®)

MOA: *Vesicular Monoamine Transporter (VMAT)  Inhibitors on monoamine oxidase containing neurons (dopamine, serotonin, norepinephrine, histamine)

Approved August 15, 2008 to treat chorea of Huntington’s disease 

Valbenazine

(Ingrezza®)

MOA:*Vesicular Monoamine Transporter (VMAT)  Inhibitors on monoamine oxidase containing neurons (dopamine, serotonin, norepinephrine, histamine)

Approved April 11, 2017 to treat tardive dyskinesia 

Benztropine

Muscarinic ACh R antag (anticholinergics)

ØTend to be used in early PD/ younger patients (< 70 yrs) to reduce tremors (not brady, rigid, gait)

ØAdverse effects: drowsiness, blurred vision, dry mouth, constipation, mental confusion,

ØContraindicated in older PD patients or those patients showing signs of mental impairment (would exacerbated by anticholinergic drugs)

Carbidopa/Levodopa & Carbidopa/Levodopa/Entacapone

Cinemet, Parcopa,

Fixed proportions 1:10, 1:4

Absorbed in duodenum by AA transport system - protein restriction diet can improve response

AE: GI (N/V/loss appetite) bc D2 chemoreceptor trigger zone→ tolerance in a few months, impuslive disorders, CV (ortho HoTN bc peri DA at D1 and B1, arrhythmias, ^NE), Dystonia/Dyskinesia, Dark urine

-Motor AE in50% pt; rapid, involun movement; diphasic, square-wave, peak-dose, off-period dyskinesia

Contra: Narrow angle glaucoma, non-sel MAOi (14 day sep)

-IR to ER not 1:1

-T1/2 1-2 hrs- TID dosing; 0.5-1h dosing (IR)

Inbrija

L-DOPA inhaler

-ONLY ADJUNCT for “off period”, not to replace L-DOPA therapy

Pramipexole

Mirapex

D2 agonist PO TID

-monotherapy for mild-mod PD; Adj to L-DOPA for motor flux

AE COMMON: NV, Ortho HoTN, Dyskinesia, Psych (hallu, confu, delirium, impulse, mani), somno

-Dosing adj for CrCl <50

Ropinirole

Requip

DA Agonist PO TID

-monotherapy for mild-mod PD; Adj to L-DOPA for motor flux

AE COMMON: NV, Ortho HoTN, Dyskinesia, Psych (hallu, confu, delirium, impulse, mani), somno

-Dose adj for CrCl <30

Rotigotine

Neupro

DA ag - transdermal patch (remove before MRI, rotate site q2wk)

-monotherapy for mild-mod PD; Adj to L-DOPA for motor flux

AE COMMON: NV, Ortho HoTN, Dyskinesia, Psych (hallu, confu, delirium, impulse, mani), somno

-No renal dosing adj

Apomorphine

Apokyn

DA ag

-monotherapy for mild-mod PD; Adj to L-DOPA for motor flux

-•Antiemetic therapy  with trimethobenzamide (Tigan®) is recommended 3 days prior to initiation

5HT-3 antagonist such as ondansetron should not be used due to risk of severe hypotension

-SQ injection - initial test dose under supervision + titration

AE COMMON: SEVERE NV, Ortho HoTN, Dyskinesia, Psych (hallu, confu, delirium, impulse, mani), somno

Tavapadon

Juvmo

Sel D1 + 5 agonist

-monotherapy for mild-mod PD; Adj to L-DOPA for motor flux

-extra “on” time for L-DOPA

-New!!

-CYP3A4 metab

AE: N, HA, Dizz, HoTN,;; LESS PSYCH Hallu, Drows, impulse contr <10%

Tolcapone

COMTi - ØInhibition of dopa decarboxylase produces compensatory activation/inc of COMT

Adverse effects: HEPATOTOXIC, diarrhea,   fatigue, sleep disorders,   anxiety, nausea, dizziness,   hallucination, confusion, Discolor body fluids

-Req LFT

Entacapone

Stavelo (w/ L-DOPA)

COMTi - ØInhibition of dopa decarboxylase produces compensatory activation/inc of COMT

-periphally active add-on to L-DOPA therapy

Adverse effects: diarrhea,   fatigue, sleep disorders,   anxiety, nausea, dizziness,   hallucination, confusion, Discolor body fluids

Opicapone

COMT i

-oral, peripherally active, high affinity (sub-picomolar Kd)→ Longer duration, indirect incr of L-DOPA

-more efficacy than ENT / TOL

ØAdverse effects: dyskinesias (can be related to L-DOPA boost rather than a direct action of OPC) , sleep disturbances, abnormal dreams, dizziness, Discolor body fluids

Selegiline

Eldepryl, Emsam, Zelpar

MAOB>A i

-Metabolized to amphetamine (no evid of abuse)

--many drug interactions, not preferred

-Contra: Linezolid Opioids Cyclobenz, St Johns Wort, SSRI, SNRI, TCA/Serotonin syndrome (14 d), Tyramine rich foods

AE:

Rasagiline

Azilect

MAOB>A i

-Monotherapy in early stages

-many drug interactions, not preferred

-Contra: Linezolid Opioids Cyclobenz, St Johns Wort, SSRI, SNRI, TCA/Serotonin syndrome (14 d), Tyramine rich foods

Safinamide

Xadago

REVERSIBLE MAOB>A i (1000x) + inh Glutamate rel

-improved “off time”

-many drug interactions, not preferred

-Contra: Linezolid Opioids Cyclobenz, St Johns Wort, SSRI, SNRI, TCA/Serotonin syndrome (14 d), Tyramine rich foods

•Use is contraindicated in severe hepatic impairment

AE: N, Dyskinesia, Impulse ctr, exacerbates psych dx

Istradefylline

Nourianz

A2AR antag (Adenosine R)

ØApproved August 2019 to treat “off” time as an add-on to L-DOPA therapy

ØFirst in class oral adenosine A_2A receptor antagonist for symptomatic anti-PD therapy !

ØActs on GABAergic striatal neurons where A_2A receptors oppose the actions of D2 dopamine receptors in the indirect pathway

ØNote: Caffeine is non-specific and causes tolerance – loss of motor stimulating effects that didn’t occur in animal models of istradefylline action

Metab by CYP3A4

Amantadine

Osmolex, Gocovri, Symmetrel

ØRepurposed anti-viral medication used in PD and MS (not used for flu now)

ØMuscarinic antagonist and weak noncompetitive NMDA antagonist

ØMost useful in treatment of L-DOPA induced dyskinesia (anti-dyskinesic agent) in advanced PD when other treatments start to fail

ØCan be used to treat mild symptoms delay L-Dopa therapy early PD

ØWarning: insomnia, dizziness, skin blotches, dry mouth

•Livedo reticularis: cutaneous reaction

ØLower dose if renal function is impaired

Droxidopa

Northera

ØPro-drug of NE. Approved for neurogenic orthostatic hypotension - monitor BP

ØSide effects: dizziness, nausea, confusion, exacerbation of heart problems

ØBlack box warning: increased risk of supine hypertension

ØInteraction: high dose Carbidopa (e.g. combination L-DOPA therapy) may block effectiveness.

ACh inh Indic + list

ØRivastigmine, Donepezil, Galantamine

(3) Depression (SSRIs and SRNIs) and Anxiety – select carefully

(4) Fatigue

(5) Pain, muscle cramps

(6) Sexual problems

(7) Insomnia

(8) Urinary problems and constipation