Antiparkinson Drugs

A 62-year-old man presents with an intermittent

tremor in his left hand and some vague
discomfort in the left arm. Physical examination
shows a minimal rest tremor in the left hand that
disappears with use of the limb, mild rigidity at
the left wrist and
elbow, slowness of finger tapping with the left
hand, and decreased arm swing on the
left while walking.
How should he be evaluated and treated?
Nutt JG and Wooten GF. N Engl J Med 2005;353:1021-7

Lang AE and Lozano AM. N Engl J Med 1998; 339:1044-1053

Muhammad Ali and Parkinson

3
 Prevalence
• 1.5 million in USA and 120,000 in the UK – accounts
for about 10% of all acute hospital admissions
• Effects 2 in 1,000 people; aged 80+ incidence is 1 in
50.
• Mainly affects adults in later life
• Slightly more common in men, Afro-Caribbean's and
people from the Indian subcontinent
• Affects the quality of life of about 500,000 (family,
carers etc)
 Causes
• Unclear, but is a number of factors:
– Environmental – toxins
– Free Radicals – there is a increase in post-mortem
brain sections
– Aging – age related decline in dopamine
production
– Genetic – possible, no single gene identified
• Etiologi:
❖ Parkinsonisme pasca ensefalitis
❖ Parkinsonisme akibat obat
❖ Parkinsonisme idiopatik
The Sites of Neurodegeneration and Neurochemical Pathways Involved in Parkinson's Disease.

Lang AE, Lozano AM. N Engl J Med 1998;339:1044-1053.

 Parkinson’s Disease
• A degenerative and progressive disorder
• Associated with neurological consequences of
decreased dopamine levels produced by the basal
ganglia (substantia nigra)
• Dopamine is a neurotransmitter found in the neural
synapses in the brain
• Normally, neurones from the SN supply dopamine to
the corpus striatum (controls unconscious muscle
control)
• Initiates movement, speech and self-expression
• Balance, posture, muscle tone and involuntary
movement depends on the roles of dopamine
(inhibitory) and acetylcholine (Ach: excitatory)
• If dopamine missing, Ach produces more of an effect
on muscles

• Basis to exploit by drugs:

– Restore dopamine function
– Inhibit Ach within corpus striatum
Consequences of dopamine reductions
• Tremors – hands and head develop involuntary
movements when at rest; pin-rolling sign (finger and
thumb)
• Muscle rigidity – arthritis-like stiffness, difficulty in
bending or moving limbs; poker face
• Bradykinesia – problems chewing, swallowing or
speaking; difficulty in initiating movements and
controlling fine movements; walking becomes
difficult (shuffle feet)
• Postural instability – humped over appearance,
prone to falls
 Additional symptomatology
• Anxiety
• Depression
• Sleep disturbance
• Dementia
• Disturbance of ANS (difficulty in urinating)
 Clinical Presentation
• Altered body image (depression) • Excessive sweating (impaired
• Poor balance thermoregulation)
• Bradykinesia (slow movement) • Fastinating gait
• Bradyphrenia (slowness of • Hallucinations (visual)
thought) • Postural hypotension
• Constipation • Restless leg syndrome (leg aches,
• Dribbling/drooling tingle, or burn)
• Dyskinesias (involuntary • Rigidity
movements) • Sleep disturbance
• Dysphagia (difficulty swallowing • Slurring/slowing of speech
• Dystonia (pain spasms) • Tremor

Ref: Noble C (2000) Parkinson’s Disease – the challenge. Nursing Standard, 15 (12), 43-51
Clinical Presentation (Lonis Herzberg)
 Medication Rational
• Replace depleted levels of dopamine
• Stimulate the nerve receptors enabling
neurotransmission
• Increase the effect of dopamine on nerve
receptors (agonist)
• Counteract the imbalance of Ach and
Dopamine
• The Drugs:
– Dopaminergic drugs (improving dopamine
functioning)
• Levodopa
• Dopamine receptor agonists
• Amantadine
• Selective monoamine oxidase B inhibitors
• Catechol-O-methyltransferase inhibitors
– Antimuscarinic drugs (Ach inhibitors)
 Levodopa
• Can not administer dopamine directly, as it does not cross the
blood brain barrier
• A natural amino acid that the brain converts into dopamine
(replacement therapy) used since the 1960’s
• Levodopa alone (Dopar, larodopa): Oral 100, 250, 500 mg
• To make it slow release, combined with(an enzyme
decarboxilase inhibitor) :
- benserazide to create co-beneldopa or co-careldopa:
50/100 mg per day
- Carbidopa (Sinemet) : 10/100 mg, 25/100 mg, 25/250 mg
per day
- Carbidopa/Levodopa/entacapone (Stalevo): 12.5 mg/50
mg/200 mg
• 30-60 minute s before meal
Decarboksilase

D1
 Pharmacokinetics
▪ Absorbed by the small intestine by an active
transport system
only 20-30% oral dose reached the circulation
▪ Decarboxylation occurs in peripheral tissues
(gut wall, liver and kidney
• decrease amount available for distribution (1% of an
oral dose CNS)
• Extracerebral dopamine amounts causing unwanted
effects (benserazide reduce the peripheral dopamine
production)
▪ Short half-life
 Adverse effects
– As a result of the amount of peripheral dopamine levels
• Nausea, vomiting
• Postural hypotension
– As a result of the amount of CNS dopamine levels
• Dyskinetic involuntary movements (face & neck)
• Hallucinations and confusion: counteracting by antipsycotic low
affinity for dopamine D2 (Clozapine, risperidone)
– Long term effects (1-5 years)
▪ Wearing-off: gejala parkinson timbul sebelum dosis berikutnya
▪ Fenomena pasang surut (On-Off): flukutuasi efek obat dalam waktu
singkat, beberapa jam membaik lalu memburuk mendadak
▪ Pembekuan gerakan (freezing): secara mendadak pasien yang
sedang berjalan tidak bisa melangkah, atau langkahnya
pendek-pendek sekali
 Drug Interactions
+ Decarboxylase inhibitors:
1. Increased the levodopa through the CNS,
reduced the dose ~ 75%
2. Easier to reach the effective dose
3. Reduced the peripheral dopamine side effects
(nausea, vomite, hypotension)
4. Easier to control the symptom
5. The pyridoxine side effects can be avoided
 Dopamine receptor agonists
merangsang reseptor dopaminergik sentral

• Apopmorphine (APO-go):
– SC administration
– Rescue therapy (temporary relief) of off-periods of
akinesia – rapid onset (10 min) with a short duration
of action (~ 2 houirs) maximum dose 10 mg
– Side efffect: NAUSEA, others dyskinesia, drowsiness

• Bromocriptine (Parlodel)...D2 agonist; Pergolide

(Celance)...D1&D2, associated with valvular heart
disease (NOT USED)
• Ropinirole (Requip)
 Pramipreksol
• Agonis dopamin non-ergot, afinitas pada reseptor D3
• Efektif monoterapi pada parkinson ringan, pada
parkinson berat berguna untuk menurunkan dosis
levodopa
• Bersifat neuroprotektif dan meningkatkan aktifitas
neurotropik
• Obat cepat diabsorbsi, puncak plasma dalam 2 jam,
ekskresi terutama dalam bentuk utuh
• Dosis diawali 0.125 mg/8 jam, doubled setelah 1
minggu, dan sama untuk berikutnya
• Adverse effects:
– Use gradual dose titration
– Dyskinesia
– Hallucinations and confusion (apomorfin)
– Peripheral vasospasm (Raynaunds)
– Respiratory depression (Apomorphine)
 Amantadine (Symmetrel)
• Originally an antiviral drug, now used as conjunctive therapy for
dyskinesis effects produced by Levodopa
• MoA:
– stimulates/promotes the release of dopamine stored in the
synaptic terminals
– Reduces reuptake of released dopamine by pre-synaptic
neuron
• Pharmacokinetics:
– Well absorbed, long half-life, excreted unchanged by the
kidney
• Adverse effects:
– Not many
– Ankle oedema, postural hypotension, nervousness,
insomnia, hallucinations (high dose)
 Other Disease Modifying Drugs
• Selective monoamine oxidase B inhibitors (selegiline
– Trade name Eldepryl/Zelapar):
– MoA: prolongs the effects of levodopa as MAO-B degrades
dopamine
– Pharmacokinetics: completely absorption, short half-life
– Adverse effects: nausea, vomitus, Constipation; dry
mouth, sore throat; transient dizziness; insomnia,
confusion and hallucinations
– Early stage – prescribed on it is own to delay need for
levodopa and there is good evidence for its slowing down
of PD progression
• Catechol-O-methyltransferase inhibitors - COMT
(entacapone, Trade name Comtess)
– MoA: inhibits the breakdown of levodopa
– Pharmacokinetics: variability of absorption, extensive
first-pass metabolism, short half-life
– Adverse effects: dyskinesias, hallucinations; nausea,
vomitus and abdominal pain
– New combination – Levodopa/carbidopa/entacapone
(Stalevo) as 1 tablet (50, 100, 150mg)
• Antimuscarinic/Anticholinergic Drugs: (may improve
tremor and rigidity of parkinsonism)
– Trihexyphenidyl (Broflex, Artane, Agitane); Benztropine
(Cogentin); Orphanadrine (Disipal); Procycline (Kemadrin,
Arpicolin)
– Less common drugs but they affect Ach based interactions
– MoA: blocking cholingeric (Ach) receptors to restore
balance
– Pharmacokinetics: fairly well absorbed, extensive hepatic
metabolism, intermediate to long half-lifes
– Adverse effects: dry mouth and confusion
Disease Modifying Drugs Overview
 Symptom Management Drugs

• PD is multidimensional, therefore there are a

number of clinical presentations that require
supplementary agents
– Drug-Drug reactions is the problem
– Major area is depression
 Antidepressants
• Amitriptyline (Tryptizol), imipramine (Tofranil),
Nortriptyline (Allegron), Iofepramine (Gamanil)
• MoA: block re-uptake of noradrenaline and
serotonin => Sedative actions, can help with drooling
and loss of appetite
• Adverse effects: sleepiness, dry mouth, increased
hunger, cardiac arrhythmias and changes in BP
• Can interfere with the effects of levodopa!
 Other Drugs to Avoid

Generic Name Brand Name Prescribed for

Prochlorperazine Stemetil N +V, Dizziness
Prephenazine Triptafen Depression
Flupentixol Fluanxol/Depixol Confusion,
Hallucinations
Chlorpromazine Largactil “
Pimozide Orap “
Sulpiride Dolmatil “
ANTIEPILEPTIC DRUGS
 Epilepsy
Chronic CNS disorders → recurrent seizures.

Seizures are sudden, transitory, and

uncontrolled episodes of brain dysfunction
resulting from abnormal discharge of
neuronal cells with associated motor,
sensory or behavioral changes.
 Causes for Acute Seizures

• Trauma • High fever

• Encephalitis • Hypoglycemia
• Drugs
• Extreme acidosis
• Birth trauma
• Extreme alkalosis
• Withdrawal from
depressants • Hyponatremia
• Tumor • Hypocalcemia
• Idiopathic
 Neuronal Substrates of Epilepsy

The Synapse

ions

The Brain The Ion Channels/Receptors

 Classification of Epileptic Seizures
I. Partial (focal) Seizures
A. Simple Partial Seizures
B. Complex Partial Seizures

II. Generalized Seizures

C. Generalized Tonic-Clonic Seizures
D. Absence Seizures
E. Tonic Seizures
F. Atonic Seizures
G. Clonic Seizures
H. Myoclonic Seizures
I. Infantile Spasms
 II. Generalized Seizures
In Generalized seizures,
both hemispheres
are widely involved
from the outset.

Manifestations of the
seizure are
determined by the
cortical site at which
the seizure arises.

Present in 40% of all

epileptic
Syndromes.
 II. Generalized Seizures
A. Generalized Tonic-Clonic Seizures

Major convulsions, usually with two phases:

1) Tonic phase
2) Clonic phase

Convulsions:
– motor manifestations
– may or may not be present during seizures
– excessive neuronal discharge

Convulsions appear in Simple Partial and Complex Partial Seizures if the

focal neuronal discharge includes motor centers; they occur in all
Generalized Tonic-Clonic Seizures regardless of the site of origin.
Atonic, Akinetic, and Absence Seizures are non-convulsive
 II. Generalized Seizures
B. Absence Seizures (Petit Mal)
• Brief and abrupt loss of consciousness,
vacant stare.
• Sometimes with no motor manifestation
• Minor muscular twitching restricted to
eyelids (eyelid flutter) and face.
• Typical 2.5 – 3.5 Hz spike-and-wave
discharge.
• Usually of short duration (5-10 sec), but
may occur dozens of times a day.
• No loss of postural control.
Treatment of Seizures
 Treatment of Seizures
Goals:
• Block repetitive neuronal firing.
• Block synchronization of neuronal
discharges.
• Block propagation of seizure.

Minimize side effects with the simplest

drug regimen.
MONOTHERAPY IS RECOMMENDED IN MOST CASES
 Treatment of Seizures
Strategies:
1. Modification of ion conductances.

2. Increase inhibitory (GABAergic)

transmission.

3. Decrease excitatory (glutamatergic)

activity.
 Antiseizure drugs
Mechanisms of action
1. Inhibit glutamate neurotransmission
Felbamate, topiramate and valproate
2. Enhancement of GABA actions
-increase GABA actions at receptor
(benzodiazepines, phenobarbital)
-vigabatrin inhibits GABA transaminase
-tiagabin blocks GABA uptake

3. Inhibition of sodium channel function

-phenytoin, carbamazepine, valproic acid,
lamotrigine
4. Inhibition of Calcium T-type channels
(ethosuximide)
GABAergic SYNAPSE

• GABA agonists
• Barbiturates
• Benzodiazepines
• GABA re-uptake
inhibitors

Goal : ↑ GABA
Activity
 GLUTAMATERGIC SYNAPSE

• Excitatory Synapse.
• Permeable to Na+, Ca2+
Na+ and K+.
Ca2+ AGONISTS
• Magnesium ions block
GLU channel in resting state.
GLY
• Glycine (GLY) binding
enhances the ability of
GLU or NMDA to open
the channel.

Mg++ Goal: ↓ GLU Activity

K+
 Treatment of Seizures
1) Hydantoins: phenytoin
2) Barbiturates: phenobarbital
3) Oxazolidinediones: trimethadione
4) Succinimides: ethosuximide
5) Acetylureas: phenacemide
6) Other: carbamazepine, lamotrigine,
vigabatrin, etc.
7) Diet
8) Surgery, Vagus Nerve Stimulation
(VNS).
 Treatment of Seizures
PARTIAL SEIZURES ( Simple and Complex,
including secondarily generalized)
Drugs of choice: Carbamazepine
Phenytoin
Valproate
Alternatives: Lamotrigine, phenobarbital,
primidone, oxcarbamazepin
Add-on therapy: Gabapentin, topiramate,
tiagabine, levetiracetam, zonisamide.
 Treatment of Seizures
PRIMARY GENERALIZED TONIC-CLONIC
SEIZURES (Grand Mal)
Drugs of choice: Carbamazepine
Phenytoin
Valproate*

Alternatives: Lamotrigine,
phenobarbital, topiramate,
oxcartbazepine, primidone,
levetiracetam, phenobarbital.
 Drugs for Partial Seizures and Generalized
Tonic-Clonic Seizures

•Phenytoin – preferentially binds to and prolongs the inactive

state of voltage-sensitive Na channels
•Carbamazepine –tricyclic compound that blocks
voltage-sensitive Na channels and acts presynaptically to
decrease synaptic transmission.
Carbamazepine induces microsomal enzymes leading to an
increase in its own clearance after chronic use and several
important drug interactions
•Valproate – blocks voltage-sensitive Na channels and T-type
Ca2+ channels, increases GABA synthesis, decreases GABA
degradation, may decrease glutamate synthesis
 Adjuncts in the treatment of Partial
Seizures
• Felbamate – blocks glycine activation of NMDA
receptors and inhibit initiation of seizures

• Gabapentin – despite the fact that Gabapentin has a

similar structural relationship to GABA, it does not act
on the GABA receptor. Gabapentin may alter GABA
metabolism or alter reuptake by presynaptic GABA
transporters.
• Lamotrigine – blocks voltage-sensitive NA channels and
has another mechanism of action (inhibits the release of
excitatory amino acids such as glutamate?)

• Topiramate - blocks voltage-sensitive NA channels,

augments GABA activation of GABAA receptor, blocks
kainate and AMPA glutamate receptors
 Treatment of Seizures
GENERALIZED ABSENCE SEIZURES
Drugs of choice: Ethosuximide
Valproate*

Alternatives: Lamotrigine,
clonazepam, zonisamide, topiramate (?).

* First choice if primary generalized tonic-clonic seizure

is also present.
 Treatment of Seizures
ATYPICAL ABSENCE, MYOCLONIC,
ATONIC* SEIZURES
Drugs of choice: Valproate**
Lamotrigine***

Alternatives: Topiramate, clonazepam,

zonisamide, felbamate.

* Often refractory to medications.

**Not approved except if absence seizure is involved.
*** Not FDA approved for this indication.
 Treatment of Seizures
INFANTILE SPASMS

Drugs of choice: Corticotropin (IM) or

Corticosteroids (Prednisone)
Zonisamide

Alternatives: Clonazepam, nitrazepam,

vigabatrin, phenobarbital.
 Status Epilepticus
• seizures recur within a short period of
time
• last for at least 30 minutes
• can lead to systemic hypoxia, acidemia,
hyperpyrexia, cardiovascular collapse,
and renal shutdown.
• The most common, generalized tonic-clonic
status epilepticus is life-threatening and must
be treated immediately with concomitant
cardiovascular, respiratory and metabolic
management.
 Drugs for Status Epilepticus
1. Diazepam – GABA mediated Cl- flux
2. Phenytoin – voltage-sensitive Na channels
3. Phenobarbital –if necessary
4. General anesthesia
 DIAZEPAM (Valium) AND
LORAZEPAM (Ativan)

• Benzodiazepines.
• Will also be discussed with Sedative
hypnotics.
Toxicity • Given I.V.
•Sedation • Lorazepam may be longer acting.
•Children may • 1° for treating status epilepticus
manifest a • Have muscle relaxant activity.
paradoxical • Allosteric modulators of GABA
hyperactivity. receptors.
•Tolerance • Potentiates GABA function, by
increasing the frequency of channel
opening.
 Treatment of Status Epilepticus in Adults
Initial
• Diazepam, i.v. 5-10 mg (1-2 mg/min)
repeat dose (5-10 mg) every 20-30 min.
• Lorazepam, i.v. 2-6 mg (1 mg/min)
repeat dose (2-6 mg) every 20-30 min.
Follow-up
• Phenytoin, i.v. 15-20 mg/Kg (30-50 mg/min).
repeat dose (100-150 mg) every 30 min.
• Phenobarbital, i.v. 10-20 mg/Kg (25-30mg/min).
repeat dose (120-240 mg) every 20 min.
 Status epilepticus

0-5 min history, physical examination,

intubation?, ECG
5-10 min start 2 large bore IV saline, dextrose,
thiamine, lorazepam or diazapam IV
10-30 min Phenytoin or phenobarbital IV
30-60 min If seizures persist after phenytoin, use
phenobarbital or vice versa. Admit to
CCU, get EEG, consider thiopental,
propofol
 Drug interactions
• Many antiepileptic drugs interact with other
medications
• Carbamazepine and phenytoin induce
cytochrome P450 enzymes
• Phenytoin – plasma protein bound
• Valproate inhibits the metabolism of
phenobarbital, phenytoin, carbamazepine
and ethosuximide
 Side Effects
• Antiepileptic drugs frequently produce
CNS and gastrointestinal side effects

• Some antiepileptic drugs infrequently

cause severe hematologic or hepatic
toxicity

• Valproate and phenytoin cause birth

defects
 Management of Seizure Disorders
• Start therapy with low dose of single
drug
• Increase dose to attain serum
concentration
• If single drug is not effective, a second
drug may be added or substituted
• Discontinue drug use slowly
• Monitor serum levels to ensure adequate
dosage (toxicity, therapeutic failure or
non-compliance)
 Therapeutic choices
Seizure type 1st choice alternative or add-on
Tonic-clonic carbamazepine clobazam
phenytoin lamotrigine
valproic acid topiramate
Absence ethosuximide clobazam
valproic acid lamotrigine
topiramate
Partial (simple carbamazepine clobazam
or complex) phenytoin lamotrigine
valproic acid
phenobarbital
Pharmacokinetic Parameters
Thank you

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