PHA: GENERAL LECTURE FIRST SHIFT

ANTICONVULSANTS, ANTI-PARKINSONISM AND OTHER LEC # 7

MOVEMENT DISORDER, DRUGS FOR ALZHEIMER’S DISEASE OCT 02, 2020
Dr. Dennis S. Flores

OUTLINE 2. Generalized Onset Seizures

§ Affect both sides or hemispheres of the brain at the same
I. Anticonvulsants C. Status Epilepticus
time
A. Seizures D. Acute Repetitive
§ Almost always have loss of consciousness
B. Drugs/Treatment Seizures (Seizure
a. Drugs Used for Focal Clusters) • International League Against Epilepsy Classification of
(Partial Onset E. Teratogenicity and Seizures
Seizures) Breastfeeding I. Focal Onset Seizures
b. Drugs Used for Focal F. Suicidality A. Focal Aware Seizure (Simple Partial Seizure)
Seizures and Certain G. Withdrawal B. Focal Impaired Awareness Seizure (Complex Partial
Generalized Seizures H. Drugs in Development Seizure)
Types II. Anti-Parkinsonism C. Focal-to-Bilateral Tonic-Clonic Seizure (Partial
c. Drugs Used for A. Parkinson’s Disease Seizure Secondarily Generalized or Grand Mal
Generalized Onset B. Drugs/Treatment Seizure)
Seizures C. Drug-Induced II. Generalized Onset Seizures
d. Drugs Used for Parkinsonism A. Generalized Tonic-Clonic Seizure (Primary
Generalized Absence D. Initiation of Therapy Generalized Tonic-Clonic Seizure or Grand Mal
Seizures E. Atypical Parkinsonism Seizure)
e. Drugs Used for Syndromes B. Generalized Absence Seizure (Petit Mal Seizure)
Myoclonic Seizures F. Other Movement C. Myoclonic Seizure
(Juvenile Myoclonic Disorders D. Atonic Seizure (Drop Seizure, Astatic Seizure)
Epilepsy) III. Drugs for Alzheimer’s E. Epileptic Spasms
f. Drugs used for Atonic Disease • Tonic-Clonic Convulsions
Seizures (LGS) A. Alzheimer’s Disease ® Person loses consciousness, falls, stiffens (tonic phase),
g. Drugs Used for B. Drugs/Treatment and jerks (clonic phase)
Infantile Spasms C. Five US FDA ® It usually lasts for less than 3 minutes but are followed by
(West’s Syndrome) Approved Drug confusion and tiredness of variable duration (postictal
h. Other Drugs Used in Treatment of period)
Management of Alzheimer’s Disease • Generalized Absence “Petit Mal” Seizures
Seizures and Epilepsy D. Future Treatment ® Brief episodes of unconsciousness (4-20 seconds, usually
IV. Review Questions <10 seconds) with no warning and immediate resumption
V. References of consciousness (no postictal period)
VI. Appendix ® Most commonly occur in children with childhood absence
epilepsy, a specific idiopathic generalized epilepsy
syndrome beginning between 4 to 10 years (usually 5-7
must know book previous trans
years)
® Most remit by age 12
I. ANTICONVULSANTS • Infantile Spasms (West’s Syndrome)
® Sudden flexion, extension, or mixed extension-flexion of
A. SEIZURES
predominantly proximal and truncal muscles
• Occurs when neurons become excessively active ® Limited forms, such as grimacing, head nodding, or subtle
• Can be viewed as a result of an imbalance between inhibitory eye movements, can occur
and excitatory processes in the brain that produce either too • Myoclonic Seizures
little inhibition or too much excitation ® Sudden, brief (<100 milliseconds), involuntary, single, or
• A sudden burst of electrical activity in the brain multiple contractions of muscles or muscle groups of
• Transitory alterations in behavior, sensation, or variable topography (axial, proximal limb, distal limb)
consciousness caused by an abnormal, synchronized electrical ® Myoclonus is less regularly repetitive and less sustained
discharge of the brain than in clonus
• EPILEPSY • Other Important Epilepsy Syndromes
® A chronic disorder of brain function characterized by ® Lennox-Gastaut Syndrome
recurrent and unpredictable occurrence of seizures ® Juvenile Myoclonic Epilepsy
® Fourth most common neurologic disorder after migraine, ® Dravet’s Syndrome
stroke, and Alzheimer’s disease PATHOGENESIS
CLASSIFICATION OF SEIZURES • Neurons communicate with each other through action potential
• Can be classified into two major groups, depending on where ® Action Potential
they begin in the brain: § Orchestrated by the sychronized opening and closing of
1. Focal Onset Seizures ion channels
§ Initially affect only a portion of the brain, typically one • Neurons are hyperactive (too little inhibition or too much
hemisphere only excitation)
§ May occur with or without impairment of awareness
§ Previously called “partial” or “partial onset” seizures

A-TWG1 Agreda, A., Alquitran, K., Antonil, J., Cac, C., Co, J. A- TEG11: Agnes, J., Agustin, M., Carpio, E., Chua, E., Bongco, B,
TWG EIC: Agapito, S. TEG EIC: Boligor, L.
 ® This limits the ability of the neurons to respond to further
stimulation
® Once GABAA dissociates from the GABAA receptor, it
becomes removed from the synaptic cleft by:
§ Reuptake by GABA Transporter 1 (GAT-1)
§ Degraded by GABA-transaminase (GABA-T)
§ Lecture: degraded by GABA-aminotransferase
• If there is too little GABA, it can allow neurons to be
hyperexcitable, leading to seizures
OVERVIEW OF ANTICONVULSANT DRUGS
Table 1. List of anticonvulsant drugs
Tonic-clonic & Absence Myoclonic Back-up and
partial seizures seizures seizures adjunctive
drugs
Felbamate
Gabapentin
Figure 1. Excitatory process
Lacosamide
• Excitatory Process (mediated by Glutamate) Carbamazepine Clonazepam Clonazepam Lamotrigine
® At rest, the inside is slightly more negative than the outside Lamotrigine Ethosuximide Lamotrigine Levetiracetam
® Action potential starts when voltage gated sodium channels Phenytoin Valproic Acid Valproic Acid Perampanel
open allowing positively charged sodium ions to rush into the Valproic Acid Phenobarbital
cell leading to membrane depolarization Retigabine
Rufinamide
® Membrane depolarization leads to the opening of high Tiagabine
voltage activated calcium channels allowing positively Topiramate
charged calcium ions to enter the neuron Vigabatrin
® Causes release of glutamate from the vesicles into the Zonisamide
synaptic cleft
® Glutamate will bind to two types of receptors in the • Main goals in therapeutic convention
postsynaptic neuron ® To lower neuronal hyperexcitability
§ AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic ® Enhance neuronal inhibition
acid) • Antiepileptic drugs may inhibit excessive firing by blocking
- Leads to opening of sodium channels channels, receptors, and enzymes
§ NMDA (N-methyl-D-aspartate)
Table 2. List of drugs that block channels and receptors
- Leads to opening of calcium channels
Carbamazepine Phenytoin
® Calcium may also enter the neuron through low voltage Na channels Oxcarbazepine Valproic Acid
activated calcium channels (T-type calcium channels) Lacosamide Topiramate
§ Respond to depolarization at or below the levels of resting Lamotrigine Zonisamide
membrane potential Ca channels Lamotrigine, Topiramate
• If there is too much glutamate, neurons can become Low voltage gated Valproic Acid, Zonisamide, Ethosuximide
hyperexcitable resulting to a seizure Ca channels
Alpha 2 delta 1 (An auxiliary subunit of high voltage Ca
protein channel)
(Auxiliary subunit of Gabapentin, Pregabalin
high voltage Ca
channel)
FREQUENCY of Benzodiazepines
opening of the • Diazepam, Lorazepam, Intramuscular
GABAA receptor Midazolam, Clonazepam, Nitrazepam
chloride channel
DURATION of
opening of the Barbiturates
GABAA receptor
chloride channel
AMPA receptor Topiramate
NMDA receptor Felbamate
SV2A protein (Found on vesicles) Levetiracetam
(Found on vesicles)
GAT-1 Tiagabine
GABA-1 Vigabatrine
Figure 2. Inhibitory Process KEEP IN MIND
• Inhibitory Process (mediated by GABA) • Many of the antiepileptic drugs act on multiple targets
® Inhibitory neurons prevent too much release of glutamate by Sodium Calcium Channel
releasing the neurotransmitter GABA (gamma-aminobutyric Channel
acid) Lamotrigine ✓ ✓
® GABAA binds to GABAA receptors on the post-excitatory Topiramate ✓ ✓
neuron (High voltage
® Facilitates opening of chloride channels to allow negatively gated)
charged chloride ions to enter, causing the membrane Valproic Acid ✓ ✓
potential to be more negative inside relative to the outside Zonisamide ✓ ✓
(hyperpolarized state) (Low voltage gated)

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• Valproic Acid and Zonisamide
® Mechanism of action is still not known (based on Katzung)
Figure 3. Drugs inhibiting specific channels, receptors, and enzymes
• Antiseizure drugs protect against seizures by interacting with one
or more molecular targets in the brain.
• The ultimate effect of these interactions is to inhibit the local
generation of seizure discharges by:
® Reducing the ability of neurons to fire action potentials at high
rate
® Reducing neuronal synchronization
• Antiseizure drugs inhibit the spread of epileptic activity to nearby
and distant sites by:
® Strengthening the inhibitory surround mediated by GABAergic
interneurons
® Reducing glutamate-mediated excitatory neurotransmission
• Specific actions of antiseizure drugs on their targets:
® Modulation of voltage-gated sodium, calcium, or potassium
channels
® Enhancement of fast GABA-mediated synaptic inhibition
® Modification of synaptic release processes
® Diminution of fast glutamate-mediated excitation
KEY POINTS TO REMEMBER IN CHOOSING AN
ANTICONVULSANT
• There is no proven algorithm for selecting an antiepileptic drug
• Multiple factors must be considered during the selection
process:
® Type of epilepsy being treated (e.g. focal vs. generalized,
specific syndrome, or if a clear first-line treatment exists)
® Patient factors that narrow possible treatment options (i.e.
comorbid medical problems, concurrent medications,
pregnancy, financial constraints)
® Medication factors (i.e. tolerability and rational
polypharmacy), and nonpharmacological adjuncts
• Understanding drug risks and benefits is key
• The goal is to provide the best chance for seizure freedom
with the lowest risk for potential side effects (i.e. tolerability)
B. DRUGS/TREATMENT
a. DRUGS USED FOR FOCAL (PARTIAL ONSET SEIZURES)
CARBAMAZEPINE
• Drug of choice for trigeminal neuralgia
• Mood stabilizer used to treat bipolar disorder (mania)
• The chemical structure of carbamazepine is similar to
Imipramine (a tricyclic antidepressant)
® However, carbamazepine is NOT used as an
antidepressant because it does NOT inhibit monoamine
(serotonin and norepinephrine) transporters with high
affinity
PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease
Figure 4. Structure of carbamazepine (left) and imipramine (right)
• Clinical Uses
® Focal and focal-to-bilateral tonic-clonic seizures
® Generalized tonic-clonic seizures in idiopathic generalized
epilepsies (anecdotal)
® Must be used with CAUTION as it can exacerbate absence
and myoclonic seizures
® Also effective for treatment of glossopharyngeal neuralgia
• Nearly 100% oral bioavailability
• Half-life: 36 hours after a single dose; drops to 8-12 hours in
continuous therapy
• Metabolism
® Liver; catalyzed by CYP3A4 and CYP2D6
® Main metabolite: carbamazepine-10,11 epoxide
§ Antiseizure activity; neurotoxicity
• Pharmacokinetics
® Autoinduction leads to
§ Decrease in steady state concentration of carbamazepine
§ Increase in the rate of metabolism of primidone,
phenytoin, ethosuximide, valproic acid and clonazepam
Figure 5. Effect of carbamazepine on serum levels of certain drugs
• Drug interactions
® Other antiseizure drugs, notably phenytoin and
phenobarbital, may decrease steady state concentrations of
carbamazepine through enzyme induction
Figure 6. Effect of phenytoin and phenobarbital on carbamazepine serum levels
® Some antiseizure drugs such as valproic acid may inhibit
carbamazepine clearance and increase steady-state
carbamazepine blood levels
Figure 7. Effect of valproic acid on carbamazepine serum levels
• Do NOT confuse autoinduction with drug interactions
because they may have contrasting effects on the serum
concentration of carbamazepine
• Adverse Effects
® Mild GI discomfort, dizziness, blurring of vision, diplopia,
ataxia; sedation (in high doses), and weight gain (rare)
® Benign leukopenia in many
® Rash and hyponatremia (most common reasons for
discontinuation)
® Stevens-Johnson syndrome is rare, but the risk is
significantly higher in patients with the HLA-B*1502 allele
§ Asians
- 10-fold higher incidence of carbamazepine-induced
Stevens-Johnson syndrome
3 of 17
 - Recommended that Asians should be tested before ® Used for IV administration and treatment of status epilepticus
using carbamazepine ® Lower incidence of purple glove syndrome
OXACARBAZEPINE • Pharmacokinetics
® Extensively bound to albumin (90%)
• A 10-keto analog of carbamazepine
§ Due to high protein binding, it has a low volume of
• Less potent than carbamazepine
distribution
• Mechanism of action is same as carbamazepine
® Prone to displacement by a variety of factors:
• Does not form the epoxide metabolite § Hyperbilirubinemia
• Fewer hypersensitivity reactions but hyponatremia is more § Drugs such as warfarin, valproic acid, phenylbutazone,
common sulfonamides
• Induces hepatic enzymes to a lesser extent - These drugs would compete with phenytoin for binding
Table 3. Difference between carbamazepine and oxcarbazepine to plasma proteins leading to toxicity
CARBAMAZEPINE OXCARBAZEPINE ® Patients with low plasma albumin (i.e. liver disease,
Potency More potent Less potent nephrotic syndrome) can result in abnormally high free
Mechanism of Blocks voltage-gated sodium channels concentrations and toxicity
Action ® Increased proportions of free drug also seen in neonates
Carbamazepine- Cannot form an epoxide and elderly à more prone to toxicity
Metabolism 10,11 epoxide metabolite
® Valproic acid inhibits phenytoin metabolism and increases
10-hydroxy metabolite (MHD –
monohydroxy derivative)
free phenytoin
More Fewer
Hypersensitivity **Cross-reactivity with
reactions carbamazepine does not
always occur
Figure 8. Effect of valproic acid on phenytoin serum levels
Induction of More Lesser extent
hepatic enzymes Less drug interactions • Metabolized by CYP2C9 and CYP2C19 to inactivate
Similar More adverse effects of metabolites that are excreted in the urine
Adverse effects oxcarbazepine are similar to ® Only a small proportion of the dose is excreted unchanged
those of carbamazepine • As blood levels rise within the therapeutic range, the maximum
Hyponatremia more common capacity of the liver to metabolize the drug is approached
• **If one has hypersensitivity reaction with carbamazepine, it (Saturation Kinetics)
does NOT follow a hypersensitivity reaction with oxcarbazepine ® Even small increases in dose may be associated with large
changes in phenytoin serum concentrations
LACOSAMIDE
® The half-life of the drug increases markedly
• Clinical Uses ® Steady state is not achieved in routine fashion (since the
® For treatment of focal onset seizures in patients 17 years or plasma level continues to rise)
older ® Patients quickly develop symptoms of toxicity
• Pharmacokinetics • A major enzyme-inducing antiseizure drug like
® Oral form is rapidly and completely absorbed in adults, carbamazepine, phenobarbital, and primidone
without food effect • Stimulates the rate of metabolism of many co-administered
® Bioavailability is nearly 100% antiseizure drugs, including valproic acid, tiagabine,
® Elimination half-life of 13 hours ethosuximide, lamotrigine, topiramate, oxcarbazepine and
® No active metabolites with minimal protein binding MHDs, zonisamide, felbamate, and many benzodiazepines
® Does not induce or inhibit cytochrome P450 isoenzymes • Adverse Effects
• Adverse effects ® Diplopia and ataxia
® Dizziness, headache, nausea, diplopia § Most common dose-related adverse effects
• Oral solution contains aspartame (source of phenylalanine); § Requires dosage adjustment
could be harmful to patients with phenylketonuria ® Nystagmus and loss of smooth extraocular pursuit
PHENYTOIN movements
® Sedation (at higher levels)
• Oldest non-sedating drug used for treatment of epilepsy ® Gingival hyperplasia and hirsutism occur to some degree
• It is prescribed for: in most patients
® Prevention of focal seizures and generalized tonic-clonic ® Long term use:
seizures § Coarsening of facial features
® For the acute treatment of status epilepticus § Mild peripheral neuropathy (diminished deep tendon
• May worsen other seizure types in primary generalized reflexes in the lower extremities)
epilepsies, including: § Abnormalities in vitamin D metabolism, leading to
® Absence epilepsy osteomalacia
® Juvenile myoclonic epilepsy ® A skin rash may indicate hypersensitivity of the patient to the
® Dravet’s syndrome drug
§ Previously known as severe myoclonic epilepsy of infancy Fever, skin lesions, lymphadenopathy, hematologic conditions
§ Type of epilepsy with seizures often triggered by hot (agranulocytosis) are rare
temperatures or fever TIAGABINE
• Available as IV preparation; IM administration is NOT • Clinical Uses
recommended (because some drug would precipitate in the
® Adjunctive treatment of focal seizures (NOT a primary
muscle) treatment) with or without secondary generalization
• “Purple glove syndrome” • Pharmacokinetics
® Purplish-black discoloration accompanied by edema and ® “Since it is rarely used, it is just nice to know its
pain which occurs distally to injection site pharmacokinetics”
• Fosphenytoin
® 90-100% bioavailable ( 80-100% bioavailable), has linear
® water-soluble prodrug of phenytoin
kinetics
® Rapidly converted to phenytoin in plasma
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 ® Highly protein bound • Adverse Effects
® Half-life of 5-8 hours and decreases in the presence of ® Dose-related
enzyme inducers § The higher the dose, the higher adverse effects
® Food decreases peak plasma concentration, the drug should ® Dizziness, somnolence, blurred vision, confusion,
be taken with food dysarthria
® Hepatic impairment causes a slight decrease in clearance ® Urinary symptoms, including retention, hesitation, and
and may necessitate a lower dose dysuria
® Oxidized in the liver by CYP3A § Due to effects of the drug on KCNQ potassium channels
® Elimination is primary in the feces (60-65%) and urine (25%) in the detrusor smooth muscle
• Adverse Effects ® Generally mild and usually do not require drug
® Apparent lack of efficacy limit the use of this drug discontinuation
® Minor adverse effects ® Causes pigment discoloration of the retina and skin
§ Nervousness, dizziness, tremor, difficulty concentrating, ® Blue pigmentation, primarily on the skin and lips, but also on
and depression and psychosis (rare) the palate, sclera, and conjunctiva
® Excessive confusion, somnolence, ataxia ® Retinal pigment abnormalities can occur independent of skin
§ May require discontinuation changes
® Can cause seizures in some patients ® Macular abnormalities, decreased visual acuity (reported, but
§ Notably those taking the drug for other indications lack documentation)
® Rash is an uncommon idiosyncratic adverse effect ® Used in cases where other antiseizure drugs are not
adequate or not tolerated
GABAPENTIN AND PREGABALIN
• Known as gabapentinoids b. DRUGS USED FOR FOCAL SEIZURES AND CERTAIN
• Clinical Uses GENERALIZED SEIZURE TYPES
® Treatment of focal seizures LAMOTRIGINE
§ Less effective than other antiseizure drugs for the • Well tolerated, but can produce a potentially fatal rash (Stevens-
treatment of focal seizures Johnson syndrome)
® No evidence of efficacy in generalized seizures ® Similar to carbamazepine
® Frequently used in the treatment of: • Has the same adverse effects as other sodium channel
§ Neuropathic pain conditions (including postherpetic blockers but causes insomnia instead of sedation
neuralgia and diabetic neuropathy) • Has fewer adverse cognitive effects than carbamazepine or
§ Anxiety disorders topiramate
§ Fibromyalgia (Pregabalin) • Clinical Uses
• Pharmacokinetics ® Improves depression in patients with epilepsy and reduces
® Not metabolized and do not induce hepatic enzymes risk of relapse in bipolar disorder
® Eliminated unchanged in the urine ® Add-on therapy/monotherapy for focal seizures
® Absorbed by the L-amino acid transport system ® Widely prescribed due to its excellent tolerability
® Gabapentin: oral bioavailability decreases with increasing ® Less effective than valproate and ethosuximide for
dose due to saturation of the transport system in the absence seizures but has fewer fetal risks than
small intestine valproate
® Pregabalin: exhibits linear absorption within therapeutic ® Effective in the treatment of focal seizures, generalized
dose range tonic-clonic seizures (in idiopathic generalized epilepsy),
§ Used at lower doses than gabapentin so it does NOT and generalized absence epilepsy
saturate the transport system • Pharmacokinetics
§ May be absorbed by mechanisms other than the L-amino ® Only 55% protein bound
acid transport system ® Has linear kinetics; metabolized primarily by
® Gabapentinoids are not bound to plasma proteins glucuronidation in the liver to the inactive 2-N-glucuronide,
• Adverse Effects which is excreted in the urine
® Gabapentin and Pregabalin are generally well tolerated ® Combination of lamotrigine and valproate is believed to be
® Somnolence, dizziness, ataxia, headache, and tremor efficacious, but valproate causes a two-fold increase in the
® Gabapentin may aggravate absence and myoclonic seizures half-life of lamotrigine.
® Weight gain and peripheral edema • Adverse Effects
® These happen at initiation of therapy, but resolve with ® Dizziness, headache, diplopia, nausea, insomnia,
continued dosing somnolence, skin rash (greater risk for pediatric patients)
RETIGABINE (EZOGABINE) LEVETIRACETAM
• A Potassium Channel opener • Broad-spectrum antiseizure drug
® Third line treatment for focal seizures (not commonly used) • One of the most commonly prescribed drugs for epilepsy
• Its use is limited to those who have failed to respond to other because of:
agents ® Favorable adverse effect profile
• Mechanism of Action ® Broad therapeutic window
® Allosteric opener of KCNQ2-5 (Kv7.2-Kv7.5) voltage-gated ® Favorable pharmacokinetic properties
potassium channels, inhibiting the release of various ® Lack of drug-drug interactions
neurotransmitters, including glutamate • Clinical Uses
• Pharmacokinetics ® Effective in the treatment of focal seizures in adults and
® Absorption is not affected by food, and kinetics are linear children, primary generalized tonic-clonic seizures, and
® Major metabolic pathways are N-glucuronidation and N- myoclonic seizures of juvenile myoclonic epilepsy
acetylation • Pharmacokinetics
® Neither inhibits nor induces the major CYP enzymes involved ® Oral absorption is rapid and nearly complete, with peak
in drug metabolism plasma concentrations in 1.3 hours
® Has linear kinetics and less than 10% protein binding
® Plasma half-life is 6-8 hours, may be longer in elderly
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 ®2/3 is excreted unchanged in urine and remainder as
inactive deaminated metabolite 2-pyrrolidine-N-butyric acid
® Metabolism occurs in blood; no metabolism in liver
® Minimal drug interactions
• Adverse Effects
® Somnolence, asthenia, ataxia, infection (colds), and
dizziness
® Less common but more serious - behavioral and mood
changes such as irritability, aggression, agitation, anger,
anxiety, apathy, depression, and emotional lability Figure 9. Effect of felbamate on phenytoin, valproic acid, and carbamazepine
epoxide serum levels
PHENOBARBITAL
• Clinical Uses c. DRUGS USED FOR GENERALIZED ONSET SEIZURES
® Useful in the treatment of focal seizures, generalized tonic- VALPROIC ACID
clonic seizures, and myoclonic seizures of juvenile
• One of the most versatile and effective antiseizure drugs
myoclonic epilepsy but is not a drug of first choice
® First-line broad spectrum antiseizure drug
• May worsen absence seizures and infantile spasms
• Clinical Uses
• Long term administration leads to physical dependence such
that seizure threshold is reduced upon withdrawal ® Used as mood stabilizer in bipolar disorder and as
prophylactic treatment for migraine
• Must be discontinued gradually over several weeks to avoid
severe seizures or status epilepticus occurrence ® Used for myoclonic, atonic, and generalized tonic-clonic
seizures
• Positive allosteric modulators of GABAA receptor at low ® Used for generalized absence seizures
concentrations; directly activate GABAA receptors at high ® Used for focal seizures (less effective than carbamazepine
concentrations or phenytoin)
• Adverse Effects ® Used for status epilepticus (IV)
® Sedation, cognitive issues, ataxia, hyperactivity • Pharmacokinetics
• Oldest of the currently available antiseizure drugs ® Well absorbed after oral dose (bioavailability: >80%)
(sedating) ® Peak blood levels observed within 2 hours; food may delay
® Introduced in 1912 as sleeping aid but was useful as absorption
treatment of epilepsy ® Highly bound to plasma proteins but reaches saturation as
• No longer a first choice in the developed world because of its concentration increases at upper end of therapeutic range
sedative properties and many drug interactions • Drug Interactions
• Still useful for neonatal seizures ® Inhibits the metabolism of several drugs, such as
PRIMIDONE phenobarbital and ethosuximide
§ Levels of phenobarbital may rise steeply causing stupor or
• 2-desoxyphenobarbital – derivative of phenobarbital coma
® Displaces phenytoin from plasma proteins → ↑ free fraction
• Clinical Uses of phenytoin
® Effective for treatment of essential tremor and some ® Levels of carbamazepine epoxide may be increased
movement disorders ® Can dramatically decrease the clearance of lamotrigine,
® Effective against focal seizures and generalized tonic- resulting to 2 to 3-fold prolongation of its half life
clonic seizures
® Overall effectiveness is less because of high incidence of
acute toxicity on initial administration and chronic
sedative effects at effective doses
• Pharmacokinetics
® Has larger clearance than most antiseizure drugs (2L/kg/d)
® Half-life: 6-8 hours
® Severe adverse effects on initial dosing: drowsiness,
dizziness, ataxia, nausea, and vomiting
• Widely used until 1960s but abandoned due to its high
incidence of adverse effects
FELBAMATE
• Dicarbamate used in the treatment of focal seizures and in
Lennox-Gastaut Syndrome (LGS)
• Can cause both aplastic anemia and severe hepatitis
® Used only for patients with refractory seizures who respond
poorly to other medications Figure 10. Drug interactions of valproate and their effect on serum levels
• Oral felbamate is well absorbed (>90%)
• 30-50% excreted unchanged in the urine • Toxicity
• Remainder is metabolized by CYP3A4 and CYP2E1 in the liver ® Nausea, vomiting, other GI complaints such as abdominal
• Mean terminal half-life of 20 hours in monotherapy decreases o pain and heartburn
13-14 hours in presence of phenytoin or carbamazepine ® Fine tremor is seen at higher levels
® Reversible adverse effects: weight gain, increased
• Decreases the clearance of phenytoin and valproic acid and
appetite, hair loss
increases their blood levels
® Orofacial and digital abnormalities; cognitive impairment
• Reduces serum levels of carbamazepine but increases ® Idiosyncratic adverse effects: hepatotoxicity and
levels of carbamazepine epoxide (carbamazepine metabolite) thrombocytopenia
® Associated with adverse effects: dizziness, diplopia, ® Fatal hyperammonemic encephalopathy in patients with
headache genetic defects in urea metabolism
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 ® 1-2% risk of neural tube defects (i.e. spina bifida) when
used during the first trimester
TOPIRAMATE
• Broad-spectrum
• Also commonly used for migraine headache prophylaxis Figure 11. Drug interactions of zonisamide and its effect on serum levels
• Clinical Uses d. DRUGS USED FOR GENERALIZED ABSENCE SEIZURES
® Effective in the treatment of focal seizures, primary
generalized tonic-clonic seizures ETHOSUXIMIDE
® Lennox-Gastaut syndrome • First-line drug for the treatment of generalized absence
® Juvenile myoclonic epilepsy seizures
® Infantile spasms • Can be used as monotherapy
® Dravet’s syndrome (severe myoclonic epilepsy in infacy) • If generalized tonic-clonic seizures are also present
® Childhood absence seizures ® Valproic acid is preferred
• Pharmacokinetics ® Ethosuximide + another drug effective against generalized
® Rapidly absorbed (2 hours); bioavailability: 80% tonic-clonic seizures
§ Minimal food effect • Can be used in combination with valproate or other agents such
§ Minimal plasma protein binding (15%) as benzodiazepine when monotherapy does not lead to seizure
§ Moderate metabolism (20-50%); no active metabolites control
formed • Pharmacokinetics
§ Primarily excreted in the urine (50-80%) ® Absorption is complete following oral administration
• Drug interactions do occur and can be complex § Peak levels: 3-7 hours
• Major effect: topiramate levels rather than on levels of other ® Not protein bound
antiseizure drugs ® 20% is excreted unchanged in the urine
• Adverse Effects ® CYP3A hydroxylation: in liver, remaining drug is
® Cognitive side effects - frequent reason for discontinuation metabolized to inactive metabolites
® Impaired expressive language function (dysomnia and ® Has a very low total body clearance (0.25L/kg/d); Half-life:
diminished verbal fluency) 40hrs
® Impaired verbal memory • Drug Interactions
® General slowing of cognitive processing ® Administration of the drug with valproic acid results in a
® Effects are unlike other antiseizure drugs and often occur decrease in ethosuximide clearance
without sedation or mood change
® Paresthesias - during initiation of therapy or at high doses
® Acute myopia and angle-closure glaucoma
® Somnolence, dizziness, fatigue, nervousness, confusion
® Urolithiasis (0.5-1.5% of patients on long term therapy; Figure 12. Effect of valproic acid on serum ethosuximide levels
more common in men)
® Decreased sweating (oligohydrosis) and body temperature
elevation • Adverse Effects
® Long term: significant weight loss ® Gastric distress (including pain, nausea and vomiting);
® Oral cleft formation in newborns transient lethargy or fatigue, headache, dizziness, hiccup,
euphoria
ZONISAMIDE
• Broad-spectrum antiseizure drug VALPROIC ACID
• Has high bioavailability; Protein binding: >50-60%; Half-life: 1-3
days e. DRUGS USED FOR MYOCLONIC SEIZURES SUCH AS IN
THE SYNDROME OF JUVENILE MYOCLONIC EPILEPSY
® Can be administered once daily
• Extensively metabolized by: • Valproic acid - drug of choice
® Acetylation to form N-acetyl-zonisamide • Other drugs effective: levetiracetam, zonisamide, topiramate,
§ Excreted unchanged in urine and lamotrigine
® CYP3A4 to form 2-sulfamoylacetylphenol f. DRUGS USED FOR ATONIC SEIZURES SUCH AS IN THE
§ Excreted as glucuronide LENNOX-GASTAUT SYNDROME
• Clinical Uses • Most widely used: valproic acid in combination with lamotrigine
® Used for focal and generalized tonic-clonic seizures in and a benzodiazepine
adults and children ® Also used: topiramate, felbamate, lamotrigine, clobazam,
® Some myoclonic epilepsies and rufinamide
® Infantile spasms • Sodium-channel blocking antiseizure drugs such as
® Improvements in generalized onset tonic-clonic seizures phenobarbital and vigabatrin should be used with caution
and atypical absence seizures ® May worsen atonic seizures
• Adverse Effects
® Drowsiness, cognitive impairment, renal stones, and g. DRUGS USED FOR INFANTILE SPASMS (WEST’S
potentially serious skin rashes SYNDROME)
• No clinically significant effects on the pharmacokinetics of • Treated with ACTH hormone by intramuscular injection or oral
other antiseizure drugs corticosteroids such as prednisone or hydrocortisone
• Both zonisamide and topiramate are associated with weight ® Mechanism is still unknown
loss and formation of kidney stones (rare) • Vigabatrin is often used in cases associated with tuberous
• Drugs that induce CYP3A4 (carbamazepine, phenytoin, sclerosis
phenobarbital) increase the clearance of zonisamide, • Other drugs used: valproate, topiramate, zonisamide, or a
shortening its half-life benzodiazepine such as clonazepam or nitrazepam

PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease 7 of 17
VIGABATRIN
• Clinical Uses
® Effective in focal seizures but not generalized seizures
® Effective in infantile spasms especially when associated
with tuberous sclerosis
• Adverse Effects
® Most important: irreversible visual loss (retinal
dysfunction)
® Reserved for patients with seizures refractory to other
treatments
® Onset of vision loss: within weeks of starting treatment or
after months or years
® Other adverse effects: somnolence, headache, dizziness,
and weight gain, agitation, confusion, psychosis
® Relative contraindication: preexisting mental illness
h. OTHER DRUGS USED IN MANAGEMENT OF SEIZURES
AND EPILEPSY
BENZODIAZEPINES
• Seven benzodiazepines play roles in the treatment of
seizures and epilepsy.
• All produce their functional effects by positive allosteric
modulation of GABA-A receptors.
• As in the case for all benzodiazepines, sedation is
prominent, especially on initiation of therapy.
• Certain benzodiazepines are the first-line acute treatment for
seizures, either in status epilepticus or acute repetitive seizures
(seizure clusters)
• 2 prominent aspects of benzodiazepines limit their usefulness in
the chronic therapy of epilepsy → infrequently used
® Pronounced sedative effects in children
§ There may be a paradoxical hyperactivity, as is the case
with other sedative agents (barbiturates)
® Tolerance
§ Seizures may respond initially but recur within a few
months
1. Diazepam
• Given intravenously is a first-line treatment for status
epilepticus
• Also used in a rectal gel formulation for the treatment of
acute repetitive seizures (seizure clusters)
• Occasionally given orally on a long-term basis, although it
is not considered very effective in this application, because of
the development of tolerance
2. Lorazepam
• More commonly used in treatment of status epilepticus due
to its more prolonged duration of action after bolus IV
injection
3. Intramuscular Midazolam
• Water soluble; preferred in the out-of-hospital treatment of
status epilepticus
® delay required to achieve IV access may be avoided
4. Clonazepam
• Long acting benzodiazepine that on a milligram basis is one
of the most potent antiseizure agents known
• Has documented efficacy in the treatment of absence, atonic,
and myoclonic seizures
• Sedation is prominent, especially on initiation therapy
5. Nitrazepam
• Not marketed in the USA but is used in many other countries
for infantile spasms and myoclonic seizures
6. Clonazepam dipotassium
• Approved in the USA for the treatment of focal seizures
7. Clobazam
• For atonic seizures
CARBONIC ANHYDRASE INHIBITORS
• Carbonic Anhydrases are enzymes that catalyze
interconversion between CO2 and bicarbonate
PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease
• Inhibitors of Carbonic Anhydrase, particularly the cytosolic
forms CA II and CA VII, exhibit antiseizure activity
• Mode of Action
® Bicarbonate efflux through GABA-A receptors can exert a
depolarizing (excitatory) influence especially relevant
during intense GABA-A receptor activation
® Carbonic anhydrase inhibition prevents the replenishment
of intracellular bicarbonate and depresses the depolarizing
action of bicarbonate
1. Sulfonamide (Acetazolamide)
• Broad spectrum antiseizure activity in animal models
• Believed to have clinical antiseizure activity against most
types of seizures including focal, generalized tonic-clonic
seizures, and generalized absence seizures
• Rarely used for chronic therapy because tolerance develops
rapidly, with return of seizures usually within a few weeks
• Often used in the intermittent treatment of menstrual seizure
exacerbations in women
• DOC for Acute Mountain Sickness
2. Sulthiame
• Established in the treatment of focal seizures in the 1950s
• Has been reported to be effective in benign focal epilepsy
with centrotemporal spikes (BECTS) and infantile spasms
3. Topiramate and Zonisamide
• Sulfur containing molecules with weak carbonic anhydrase
activity
C. STATUS EPILEPTICUS
• Defined as abnormally prolonged or repetitive seizures
• Presents in several forms:
® Convulsive Status Epileptics
§ Consisting of repeated generalized tonic-clonic seizures
with persistent postictal depression of neurologic function
between seizures
§ A life-threatening emergency that requires immediate
treatment
§ Defined as more than 30 minutes of either
- Continuous seizure activity
- Two or more sequential seizures without full recovery
of consciousness between seizures
§ May evolve to nonconvulsive status epilepticus
® Nonconvulsive Status Epilepticus
§ A persistent change in behavior or mental process with
continuous epileptiform EEG but without major motor
signs
® Focal Status Epilepticus
§ With or without altered awareness
§ Treatment is similar to convulsive status epilepticus
§ In some cases, oral antiseizure drug therapy is sufficient
§ Should be distinguished from Absence Status
Epilepticus
- A prolonged, generalized absence seizure that
usually lasts for hours or even days
- Can be treated with benzodiazepine followed by IV
valproate or oral or nasogastric ethosuximide
- Occurs when an inappropriate antiseizure drug
(tiagabine or carbamazepine) is used in a patient with
idiopathic generalized epilepsy
• Treatment should be begun when the seizure duration reaches
5 minutes (generalized tonic-clonic) or 10 minutes (focal
seizures with or without impairment of consciousness)
® Due to the fact that persistent seizure activity is believed to
cause permanent neuronal injury and the majority of
seizures terminate in 2-3 minutes
BENZODIAZEPINES
• Initial treatment of choice
• Either intravenous lorazepam or diazepam
® Evidence suggests that intramuscular midazolam may be
the equally effective
® Lorazepam
§ Less lipophilic than diazepam
8 of 17
 § Does not undergo as rapid redistribution form brain to
peripheral tissues like diazepam
§ Has less extensive peripheral tissue uptake thus
remaining in the central compartment longer than
diazepam
• In pre-hospital setting, rectal diazepam, intranasal midazolam,
or buccal midazolam are acceptable alternative first treatments
• If seizures continue, a second therapy is administered
SECOND THERAPY
• IV fosphenytoin or phenytoin (most common in the USA)
® No evidence that these are superior to intravenous
valproate or levetiracetam
• Phenobarbital
® Also acceptable
® However, has a long half-life causing persistent side
effects such as severe sedation, respiratory depression,
and hypotension
• Lacosamide
® IV form available
® Little published experience to assess efficacy
• If second therapy fails, an additional second-line agent is tried
REFRACTORY STATUS EPILEPTICUS
• Occurs when seizures continue or recur at least 30 minutes
after treatment with first and second therapy agents
• Treated with anesthetic doses of pentobarbital, propofol,
midazolam, or thiopental
• Case reports indicate that ketamine may be effective
• Super-refractory
® If status epilepticus continues or recurs 24 hours or more
after the onset of anesthesia
® Recognized when anesthetics are withdrawn and seizures
recur
® No established therapies other than to reinstitute general
anesthesia
D. ACUTE REPETITIVE SEIZURES
• Also known as seizure clusters
• Groups of seizures that occur more frequently than the patient’s
habitual frequency
• Clusters can occur rapidly over several minutes, or they may
occur over a longer time period of 1 or 2 days
• There is complete recovery between seizures so patients do not
meet the definition of status epilepticus
• The condition is concerning because without treatment,
prolonged seizures or status epilepticus can occur
DRUGS/TREATMENT
• Treated in the ER with IV benzodiazepines or other antiseizure
drugs
• For out-of-hospital treatment:
® Diazepam rectal gel (in USA)
® Rectal paraldehyde (outside USA)
® Buccal (oromucosal) midazolam
§ Treatment solution is administered to the buccal using an
oral syringe (commonly used in Europe and elsewhere)
® Intranasal midazolam, diazepam, and lorazepam are also
efficacious
§ However, not approved for this route in the USA
§ Some clinicians use intranasal midazolam or oral
benzodiazepine on an off-label basis
Rectal medications are difficult, time consuming, and
embarrassing; thus only limited to use in children
E. TERATOGENICITY AND BREASTFEEDING
TERATOGENICITY
• Most pregnant women with epilepsy are still required to
continue antiseizure drug therapy for seizure control
• However, no antiseizure drug is known to be completely safe for
the developing fetus
• Valproate
® A known human teratogen
PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease
® First-trimester exposure is associated with approximately
3-fold increase of major congenital malformations most
commonly spina bifida
® Aside from congenital malformations, first-trimester
exposure is also associated with cognitive impairment
§ A dose-dependent reduction in cognitive abilities across a
range of domains including IQ
® Exposure may also be associated with an increased risk of
autism spectrum disorder
• Phenobarbital
® Also associated with an elevated risk of major congenital
malformation, most often cardiac defects
• Topiramate
® First-trimester exposure is associated with an
approximately 10-fold increase in oral clefts risk
Valproate, phenobarbital, and topiramate should be avoided in
women with childbearing potential
• However, if cannot be eliminated, the lowest possible dose
should be used because the risk, at least for Valproate, is
shown to be dose-dependent
• Other antiseizure drugs present a lower risk of major congenital
malformations or risk is poorly understood
® Although, risk for most drugs including carbamazepine,
phenytoin, and levetiracetam are not zero
• Lamotrigine or Levetiracetam
® Safer with regard to cognition
® Lowest risks of major congenital malformation
BREASTFEEDING
• Primidone, Levetiracetam, Gabapentin, Lamotrigine, and
Topiramate
® Penetrate into breast milk in relatively high concentrations
• Valproate, phenobarbital, phenytoin, and carbamazepine
® Highly protein-bound
® DO NOT penetrate into breast milk substantially
• Studies have not reported any adverse effects on the newborn
of exposure
® However, some reports of sedation with the barbiturates
and benzodiazepines
Breastfeeding should not be discourage given the lack of
evidence of harm and the known positive benefits
F. SUICIDALITY
• Presence of either suicidal behavior or suicidal ideation was
0.37% in patients taking the drugs and 0.24% in patients taking
placebo
® Led to an alert of an increased risk of suicide in patients
taking antiseizure drugs
• Data suggest a possible association of lamotrigine,
levetiracetam, and topiramate, however, further research is
needed
• Patients and their families have to be informed of the risk
G. WITHDRAWAL
• Antiseizure drugs may not need to be taken indefinitely
• Children who are seizure free for 2-4 years while on anti-seizure
medications will remain so when medications are withdrawn in
70% of cases
® Risk of recurrence depends on the seizure syndrome
• Resolution is common for generalized absence epilepsy but not
for juvenile myoclonic epilepsy
• Risk factors for recurrence
® Abnormal EEG
® Presence of neurologic deficits
® Seizure controls have been difficult to achieve
• Little information on antiseizure drug withdrawal in seizure-free
adults
• Withdrawal is successful in patients with generalized epilepsies
who exhibit a single seizure type
9 of 17
 ® Longer duration of epilepsy, an abnormal EEG, and certain ® Personality changes
epilepsy syndrome (such as juvenile myoclonic epilepsy) ® Apathy
are associated with increased risk of recurrence ® Fatigue
• Drugs are usually withdrawn slowly over a 1- to 3-month period ® Abnormalities of autonomic function (sphincter or sexual
or longer dysfunction, dysphagia and choking, sweating
® Abrupt cessation may be associated with return of seizures abnormalities, sialorrhea, or disturbances of blood
and even a risk of status epilepticus pressure regulation)
• Some drugs are more easily withdrawn than others ® Sleep disorders
• Physical dependence occurs with barbiturates and ® Sensory complaints or pain
benzodiazepines • Incurable, progressive, and leads to increasing disability with
® A well-recognized risk of rebound seizures with abrupt time
withdrawal is seen ® However, pharmacologic treatment may relieve motor
•

H. DRUGS IN DEVELOPMENT symptoms and improve the quality of life

PATHOGENESIS
ACUTE REPETITIVE SEIZURES
• A combination of impaired degradation of proteins, intracellular
• Staccato (thermal aerosol inhaled) alprazolam protein accumulation and aggregation, oxidative stress,
• Intranasal midazolam mitochondrial damage, inflammatory cascades, and apoptosis
STATUS EPILEPTICUS • Genetic factors are important especially when disease occurs
• Allopregnanolone <50 years old
• Ganaxolone • Genetic mutations include:
® Also for rare epilepsy syndromes ® Mutations of the a-synuclein gene at 4q21 or duplication and
FOCAL SEIZURES triplication of the normal synuclein gene are associated with
this disease and is now widely recognized as
• Cannabidiol
synucleinopathy
® Also for epileptic encephalopathies
® Mutations of the luceine-rich repeat kinas 2 (LRRK2) gene at
• Cannabidivarin
12cen, and the UCHL1 gene may also cause autosomal
• Cenobamate (YKP3089) dominant parkinsonism
DRAVET’S SYNDROME ® Mutations in the parkin gene (6q25.2-q27) cause early-onset
• Fenfluramine autosomal recessive, familiar parkinsonism, or sporadic
• Stiripentol juvenile-onset parkinsonism
• Environmental or endogenous toxins may also be important in
II. ANTI-PARKINSONISM the etiology of the disease
• Studies reveal that cigarette smoking, coffee, anti-inflammatory
A. PARKINSON’S DISEASE
drug use, and high serum uric acid levels are protective
• Also known as paralysis agitans • There is increased incidence in:
• A neurologic disorder that results in a progressive loss of ® People working in teaching, healthcare, and farming
coordination and movement ® Those with lead or manganese exposure or with vitamin D
® Neurons involved in coordination and movement are deficiency
located in the striatum • Lewy bodies (inclusion bodies containing a-synuclein) in fetal
® Striatum receives information from neocortex and dopaminergic cells transplanted into the brain of patients with
substantia nigra Parkinson’s suggest that it may be a prion disease
§ Cortex: relays sensory information and transfers future • Since normally high dopamine in the basal ganglia is reduced in
actions Parkinsonism, pharmacologic attempts to restore dopaminergic
§ Substantia Nigra: sends dopamine that helps coordinate activity alleviate many of the motor features of the disorder
all inputs
® Parkinsonism develops when the neurons connecting the
substantia nigra to the striatum progressively degenerates
® Dopaminergic neurons from substantia nigra normally exert
inhibitory effects on GABA neurons in striatum
§ Too little dopamine > more GABA > increased inhibition of
thalamus and reduced excitatory input to motor cortex
§ The same dopaminergic neurons also exert inhibitory
effects on the excitatory cholinergic neurons in the
striatum
§ Without enough dopamine, there is increased production
of acetylcholine > chain of abnormal signaling > impaired
mobility
§ There is an imbalance between excitatory and inhibitory
activity leads to the symptoms
• Characterized by a combination of rigidity, bradykinesia
(akinesia), resting tremor, and postural instability (TRAP)
® Usually idiopathic
® Bradykinesia should be present before being diagnosed
with parkinsonism
• Focal dystonic features may be present Figure 13. Neurons Involved in Parkinsonism
• Cognitive decline occurs in many patients as the disease
advances DOPAMINERGIC NEURON
• Nonmotor symptoms include: • Dopamine is synthesized in two steps starting with tyrosine:
® Affective disorders (anxiety or depression) ® Tyrosine is converted to Levodopa with the help of tyrosine
® Confusion hydroxylase
® Cognitive impairment
PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease 10 of 17
 ® Aromatic L-amino acid decarboxylase decarboxylates the
Levodopa to dopamine
• Dopamine is loaded into synaptic vesicles and is released by
physiologic stimuli to the extracellular space where it can bind to
the dopamine receptors that are expressed in the postsynaptic
neuron
• Excess dopamine gets re-uptaken to the neuron or glial cells
where it gets metabolized by MAO or COMT
® In glial cells, it is MAO type B that is predominantly found
B. DRUGS/TREATMENT
LEVODOPA
• Dopamine does not cross the BBB and if given into the
peripheral circulation has no therapeutic effect in parkinsonism
• On the other hand, Levodopa enters the brain via an L-amino
acid transporter (LAT) where it is decarboxylated to dopamine
• Dopamine Receptors (5 subtypes)
® D1
§ Together with the D5 receptor, it is classified as the D1
receptor family based on genetic and biochemical factors
§ Located in the pars compacta of the substantia nigra and
pre-synaptically on striatal axons coming from cortical
neurons and from dopaminergic cells in the substantia
nigra
® D2
§ Together with the D2, D3, D4 receptors, they are grouped
as belonging to the D2 receptor family
§ Located post-synaptically on striatal neurons and pre-
synaptically on axons in the substantia nigra belonging to
the neurons in the basal ganglia
§ Benefits of anti-parkinsonism drugs appear to depend
mostly on stimulation of this subtype
- However, D1 stimulation may be require for maximal
benefit
§ Dopamine agonists or partial agonist ergot derivatives
(lergotile and bromocriptine) stimulate this receptor
§ In addition, dopamine blockers that are D2 selective can
induce parkinsonism
• Pharmacokinetics
® Absorption and Administration
§ Rapidly absorbed from the small intestine; depends on
rate of gastric emptying and pH of gastric contents
§ Food ingestion delays the appearance of levodopa in
plasma
§ Certain amino acids from food can compete with
absorption
® Peak plasma concentration: 1-2 hours (after an oral dose)
® Plasma half-life: Varies between 1 and 3 hours
® Bioavailability:
§ 1-3% of levodopa enters the brain unaltered; remainder is
metabolized extra-cerebrally predominantly by
decarboxylation to dopamine
§ Thus, levodopa must be given in large amounts when
used alone
§ When given in combination with dopa decarboxylase
inhibitor (Cardiopa), peripheral metabolism is reduced
- Plasma levels are higher
- Plasma half-life is longer
- More dopa available for entry
- Reduced daily requirement of levodopa by
approximately 75%
® Metabolism
§ Metabolized by dopa decarboxylase (DDC) and catechol-
O-methyltransferase (COMT)
- DDC gives dopamine
- COMT give 3-O-methyldopa
® Excretion
§ 2/3 of the dose appears in the urine as metabolites within
8 hours after an oral dose
§ Main metabolic products: Homovanillic acid (3-methoxy-4-
hydroxyphenyl acetic acid) and Dihydroxyphenylacetic
acid
PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease
• Clinical Uses
® Best results of treatment are obtained in first few years of
treatment
§ This is because daily dose of Levodopa must be reduced
over time to avoid adverse effects
® Some become less responsive
§ Probably due to loss of dopaminergic nigrostriatal nerve
terminal
§ Or probably due to pathologic process directly involving
striatal dopamine receptors
® Benefits of Levodopa treatment begin to diminish after 3 or 4
years of therapy regardless of initial therapeutic response
® Therapy does not stop progression but early initiation lowers
mortality rate
§ Long-term therapy may lead to problems such as the On-
Off Phenomenon
- Switch between mobility and immobility which may
result to worsening motor function
- Occurs as end-of-dose of wearing-off worsening of
motor function
- Off-periods of marked akinesia alternate over on-
periods of improved mobility but often marked
dyskinesia
- Patients with severe off-periods who are unresponsive
to other measures, SQ apomorphine may provide
benefit but may increase dyskinesias
- Most likely occurs in patients who responded well to
treatment initially
- Exact mechanism is unknown
® Generally given in combination with Carbidopa (a peripheral
dopa decarboxylase inhibitor)
§ Combination treatment is started with a small dose (eg.
Carbidopa 25 mg Levodopa 100 mg 3x a day and
gradually increased)
§ Taken 30-60 minutes before meals
® Levodopa can ameliorate many of the clinical motor feature
of parkinsonism particularly bradykinesia and disabilities
resulting from it
® When possible and if necessary, add a dopamine agonist to
reduce the risk of development of response fluctuations
® Controlled-release formulation of Carbidopa-Levodopa
§ Helpful in patients with established response fluctuations
§ Means of reducing dosing frequency
§ Delivers drugs precisely and continuously over a longer
period of time, resulting in better compliance
® Extended-release formulation
§ Release slowly over time
§ Helpful for response fluctuations
• Adverse Effects
® Gastrointestinal Effects
§ Without a peripheral decarboxylase inhibitor, anorexia,
nausea, and vomiting occur in 80% of patients
§ Effects can be minimized by:
- Taking the drug in divided doses
- With or immediately after meals (however, absorption
is altered)
- Increasing the total daily dose very slowly
- Antacids 30-60 minutes before the dose may be
beneficial
§ Vomiting is due to stimulation of the chemoreceptor trigger
zone located in the brainstem but outside the BBB
§ Tolerance to the emetic effect develops
§ Additional dose of carbidopa taken with the regular
Carbidopa-Levodopa dose is often helpful
§ Domperidone may also relieve persistent nausea
§ Antiemetics such as phenothiazines should be avoided
because they reduce the anti-parkinsonism effects of the
drug and may exacerbate the disease
® Cardiovascular Effects
§ Cardiac arrhythmias including tachycardia, ventricular
extrasystoles, and rarely atrial fibrillation
- Due to increased catecholamine formation peripherally
11 of 17
 - Incidence is low even in the presence of established
cardiac disease
- Incidence is further reduced if taken in combination
with a peripheral decarboxylase inhibitor
§ Postural hypotension is common but often asymptomatic
and diminishes with continuing treatment
§ Hypertension may occur especially in the presence of
non-selective MAOIs or sympathomimetics or when
massive doses are being taken
® Behavioral Effects
§ Depression, anxiety, agitation, insomnia, somnolence,
sleep attacks, confusion, delusions, hallucinations,
nightmares, euphoria, and other changes in mood or
personality
§ Common in patients taking levodopa in combination with a
decarboxylase inhibitor because higher levels of levodopa
are reached in the brain
§ May be precipitated by intercurrent illness or surgery
§ Necessary to reduce or withdraw the medication
§ Antipsychotic agents that have low affinity for D2
receptors (clozapine, olanzapine, quetiapine, and
risperidone) are helpful in counteracting these
complications
§ Pimavanserin
- Selective serotonin 5-HT2A inverse agonist
- Helps in treating hallucinations and delusion of PD
psychosis
- Should not be used for dementia-related psychosis and
should be avoided in patients with QT prolongation
§ Dopamine Dysregulation Syndrome
- Characterized by compulsive overuse of dopaminergic
medication as well as by other impulsive behaviors
- More common with dopamine agonists then levodopa
- Management: close regulation of dopaminergic intake
§ Punding
- The performance of stereotyped, complex, but
purposeless motor activity
- This include sorting or lining up various objects or
repetitive grooming behavior
- Responds to reduction in dose of dopaminergic agents
or to atypical antipsychotic agents
® Dyskinesia and Response Fluctuations
§ Occur in up to 80% of patients receiving Levodopa for
more than 10 years
§ Choreoathetosis of the face and distal extremities (most
common presentation)
§ Development is dose-related
§ Pathogenesis is unclear
- May be related to an unequal distribution of striatal
dopamine
- May also be because of dopaminergic denervation plus
chronic pulsatile stimulation of dopamine receptors with
levodopa
§ Reduction of levodopa dose alleviates this but motor
symptoms may worsen
§ Mild forms require no treatment
§ Amantadine and clozapine helps to reduce troublesome
dyskinesias
§ Fluctuations relate to the timing of levodopa intake
(wearing-off reactions or end-of dose akinesia)
§ Some patients experience the on-off phenomenon
® Miscellaneous Adverse Effects
§ Mydriasis may occur and may precipitate an attack of
acute glaucoma
§ Others reported but rare adverse effects: (NTK)
- Blood dyscrasias
- A positive Coombs’ test with evidence of hemolysis
- Hot flushes
- Aggravation or precipitation of gout
- Abnormalities of smell or taste
- Brownish discoloration of saliva, urine, or vaginal
secretions
PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease
- Priapism
- Mild (usually transient) elevations of BUN, serum
transaminases, alkaline phosphatase, and bilirubin
• Drug Holidays
® Discontinuance of the drug for 3-21 days may temporarily
improve responsiveness to levodopa and alleviate some
adverse effects
® Usually of little help in the management of the on-off
phenomenon
® Carries the risk of aspiration pneumonia, venous thrombosis,
pulmonary embolism, and depression resulting from
immobility accompanying severe parkinsonism
® Not recommended
• Drug Interactions
® Pyridoxine (Vitamin B6) enhances the extracerebral
metabolism of levodopa and may therefore prevent its
therapeutic effect unless a peripheral decarboxylase inhibitor
is also taken
® Should not be given to patients taking monoamine oxidase A
inhibitors or within 2 weeks of their discontinuance (may lead
to hypertensive crises)
• Contraindications
® Psychotic patient
§ Exacerbates mental disturbance
® Angle-closure glaucoma
§ Okay for chronic open-angle glaucoma if IOP is well-
controlled and can be monitored
® Active peptic ulcer disease
§ Managed carefully since GI bleeding has occasionally
occurred with levodopa
® History of melanoma or with suspicious undiagnosed skin
lesions
§ Levodopa is a precursor of melanin and may activate
malignant melanoma
§ Use with particular care
§ Should be monitored regularly by a dermatologist
DOPAMINE RECEPTOR AGONISTS
• Drugs acting directly on postsynaptic dopamine receptors
may have a beneficial effect in addition to that of levodopa
• First line therapy for Parkinson’s disease
• Unlike Levodopa:
® They do not require enzymatic conversion to an active
metabolite
® Act directly on the postsynaptic dopamine receptors
® Have no potentially toxic metabolites
® Do not compete with other substances for active transport
into the blood and across the blood-brain barrier
• The older dopamine agonists (bromocriptine and pergolide)
are not used to treat Parkinsonism since they have serious side
effects
• Their side effects are more concern than those of the newer
agents (pramipexole and ropinirole)
• Apomorphine is a potent dopamine agonist used as a rescue
drug for patients with disabling response fluctuations to
levodopa
• Provide less symptomatic benefit and are more likely to cause
mental side effects, somnolence, and edema compare with
levodopa
• First line of defense to Parkinson’s since it lowers incidence of
the response fluctuations and dyskinesia that occur with long-
term Levodopa therapy
• Sometimes low dose of Carbidopa + Levodopa is introduced
and add dopamine agonist
• Dose of dopamine agonist is build-up gradually depending on
the response and tolerance of the patient
• May be given to patients with Parkinsonism who are taking
levodopa and who have end-of-dose akinesia or on-off
phenomenon or are becoming resistant to treatment with
Levodopa.
® It is generally necessary to lower the dose of Levodopa
to prevent intolerable adverse effects
12 of 17
• The response to a dopamine agonist is generally disappointing
in patients who have never responded to Levodopa
1. Bromocriptine
• Ergot derivative
• D2 agonist
• Widely used to treat Parkinson’s disease in the past but is
now rarely used
2. Pergolide
• Another ergot derivative
• Directly stimulates both D1 and D2 receptors
• No longer available in the United States because its use has
been associated with the development of valvular heart
disease
• Still used in some countries
3. Pramipexole
• Not an ergot derivative
• Has preferential affinity for D3 family of receptors
• It is effective as monotherapy for mild parkinsonism and is
also helpful in patients with advanced disease, permitting the
dose of levodopa to be reduced and smoothing out response
fluctuations
• A possible neuroprotective effect
• Pharmacokinetics
® Rapidly absorbed after oral administration
® Peak plasma concentrations in approximately 2 hours
® Excreted largely unchanged in the urine
® Renal insufficiency may necessitate dosage adjustment
• An extended-release preparation is generally more
convenient for patients and avoid swings in blood levels of
the drug over the day since drug release would be slower
4. Ropinirole
• Pure D2 receptor agonist
• Effective as:
® Monotherapy in patients with mild disease
® A means of smoothing the response to levodopa in
patients with more advanced disease and response
fluctuations
• Metabolized by CYP1A2; other drugs metabolized by this
isoform may significantly reduce its tolerance
5. Rotigotine
• Delivered daily through a skin patch is approved for
treatment of early Parkinson’s disease
• Benefits and side effects are similar to those of other
dopamine agonist
• Adverse Effects of Dopamine Agonist
® Gastrointestinal effects
§ Anorexia and nausea and vomiting
§ minimized by taking the medication with meals
§ Constipation, dyspnea, bleeding from peptic ulceration
and symptoms of reflux esophagitis
® Cardiovascular effects
§ Postural hypotension
§ Painless digital vasospasm is a dose-related complication
of long term-treatment with the ergot derivatives
(bromocriptine or pergolide)
§ When cardiac arrhythmias occur, they are an indication for
discontinuing treatment.
§ Peripheral edema is sometimes problematic
§ Cardiac valvulopathy may occur with pergolide
® Dyskinesias
§ Abnormal movements similar to those introduced by
levodopa may develop
§ Reversed by reducing the total dose of dopaminergic
drugs being taken
® Mental disturbances
§ Confusion, hallucinations, delusions, and other psychiatric
reactions may develop as a feature of Parkinson’s disease
or as complications of dopaminergic treatment and are
PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease
more common and severe with dopamine receptor
agonists than with levodopa
§ Occur earlier in older patients and become more common
as the disease advances
§ For psychotic problems such as delusions, etc., respond
to atypical anti-psychotic agents such as clozapine,
olanzapine, quetiapine, and risperidone or to pimvanserin.
§ Disorders of impulse may lead to compulsive gambling,
shopping, betting, sexual activity, and other behaviors.
- Prevalence as high as 15-25% in Parkinsonian
patients treated with dopamine agonists
- They relate to activation of D2 and D3 dopamine
receptors in the mesocorticolimbic system
- Resolve on withdrawal of the offending medication
® Miscellaneous
§ Headache, nasal congestion, increased arousal,
pulmonary infiltrates, pleural, and retroperitoneal fibrosis,
and erythromelalgia frp, ergot-derived dopamine agonists
§ Erythromelalgia – red, tender, painful, swollen feet, and
occasionally hands at times associated with arthralgia
§ Signs and symptoms clear within a few days of withdrawal
of the causal drug
§ Uncontrollable tendency to fall asleep at inappropriate
times has occurred (patients using Pramipexole and
Ropinirole)+
• Contraindications
® History of psychotic illness
® Recent myocardial infarction
® Active peptic ulceration
® Peripheral vascular disease (ergot derived agents)
MONOAMINE OXIDASE INHIBITORS
• Two types of monoamine oxidase have been distinguished in
the nervous system
® Monoamine oxidase A
§ Metabolizes norepinephrine, serotonin, and dopamine
® Monoamine oxidase B
§ Metabolizes dopamine selectively
Additional notes from 2022 Trans
• 1st line of drug in mild Parkinson’s disease to delay introduction
of Levodopa
• Antioxidant – reduces oxidation and injury and retard loss of
substancia nigra neurons (slows progression of the condition)
• Side effects
® GI: Anorexia, constipation, diarrhea, vomiting
® CNS: Insomnia, confusion, hallucinations, delusions,
depression, anxiety, confusion, dyskinesia
® CV: Arrythmia, orthostatic hypotension, angina
1. Selegiline
• Selective irreversible inhibitor of MAO B at normal doses
• At higher doses, it inhibits monoamine oxidase A as well
• Retards the breakdown of dopamine
• It enhances and prolongs the antiparkinsonism effect of
levodopa (thereby allowing the dose of levodopa to be
reduced) and may reduce mild on-off or wearing-off
phenomena
• Metabolism is mainly in the liver through CYP450
mediated oxygenation to desmethyl-selegiline and
amphetamine metabolites
• It is therefore used as adjunctive therapy for patients with a
declining or fluctuating response to levodopa.
• Has only a minor therapeutic effect on parkinsonism when
given alone
• Adverse Effect
® May cause insomnia when taken later during the day
2. Rasagiline
• MAO B inhibitor
• More potent than selegiline in preventing MPTP
(methyltetrahydropiridine)-induced parkinsonism
• Used for early treatment in patients with mild symptoms
13 of 17
3. Safinamide
• MAO B inhibitor
• Recently approved by the FDA
• Used to reduce response fluctuations in patients taking
Carbidopa-Levodopa, diminishing off-periods in patients with
wearing-off effect or on-off phenomena
• Not effective as monotherapy
• Contraindications
® Avoid tyramine-rich food
® Patients receiving meperidine, tramadol, methadone,
propoxyphene, cyclobenzaprine, or St. John’s wort
® Antitussive dextromethorphan (cough/cold preparations)
® Patients receiving tricyclic antidepressants or serotonin
reuptake inhibitors (serotonin syndrome)
® Hypertension
® Patients on Levodopa
- Levodopa in combination with nonselective MAO
inhibitors can cause hypertensive crises due to
peripheral accumulation of norepinephrine
- Dyskinesias, mental changes, nausea, and sleep
disorders, may be increased by these drugs
CATECHOL-O-METHYLTRANSFERASE INHIBITORS
• Selective COMT inhibitors (tolcapone and entacapone) also
prolong the action of levodopa by diminishing its peripheral
metabolism
• These agents may be helpful in patients receiving levodopa
who have developed response fluctuations leading to:
® Smoother response
® More prolonged on-time
® The option of reducing total daily levodopa dose
• Entacapone is generally preferred because it has not been
associated with hepatotoxicity
• Tolcapone and Entacapone:
® Similar pharmacologic effects
® Rapidly absorbed
® Bound to plasma proteins
® Metabolized before excretion
• The half-life of both drugs is approximately 2 hours, but
tolcapone is slightly more potent and has a longer duration of
action
• However, Tolcapone has both central and peripheral effects,
whereas the effect of Entacapone is peripheral
• Adverse effects
® Adverse effects relate in part to increased levodopa
exposure and include dyskinesias, nausea, and
confusion
- Sometimes it is necessary to decrease the dose of
levodopa by about 30% in the first 48 hours to
reverse such complications
® Other adverse effects include diarrhea, abdominal pain,
orthostatic hypotension, sleep disturbances, and an
orange discoloration of the urine
® Tolcapone may cause an increase in liver enzyme levels
and has been associated rarely with death from acute
hepatic failure. No such toxicity has been reported with
entacapone
1. Stalevo
• Commercial preparation consists of a combination of
Levodopa with both Carbidopa and Entacapone
• Simplifies the drug regimen
• May provide greater symptomatic benefit than Carbidopa-
Levodopa alone
• However, use of Stalevo rather than Carbidopa-Levodopa
has been associated with earlier occurrence and increased
frequency of dyskinesia
• There is a question of whether there is increased risk for
cardiovascular events
PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease
APOMORPHINE
• Subcutaneous injection of apomorphine hydrochloride
(Apokyn), a potent nonergoline dopamine agonist that interacts
with postsynaptic D2 receptors in the caudate nucleus and
putamen
• Effective for temporary relief (“rescue”) of off-periods of akinesia
in patients on optimized dopaminergic therapy
• It is rapidly taken up in the blood and then the brain, leading to
clinical benefit that begins within about 10 minutes of injection
and persists for up to 2 hours
• Adverse Effects
® Nausea is often troublesome, especially at the initiation of
apomorphine treatment
§ Pre-treat patients with anti-emetics for 3 days is
recommended before apomorphine is introduced and is
then continued for at least 1 month, if not indefinitely.
® Other adverse effects include dyskinesias, drowsiness,
insomnia, chest pain, sweating, hypotension, syncope,
constipation, diarrhea, mental or behavioral disturbances,
panniculitis, and bruising at the injection site
• Contraindications
® It should not be used in patients taking serotonin 5-HT3
antagonist because severe hypotension may result
AMANTADINE
• Amantadine, an antiviral agent, was by chance found to have
relatively weak antiparkinsonism properties
• An antagonist of the NMDA-type glutamate receptor, suggesting
an antidyskinetic effect
• Its mode of action in parkinsonism is unclear, but it may
potentiate dopaminergic function by influencing the synthesis,
release, or reuptake of dopamine
• It has been reported to antagonize the effects of adenosine at
adenosine A2A receptors, which may inhibit D2 receptor
function
• Clinical Uses
® Less efficacious than levodopa, and its benefits may be
short-lived, often disappearing after only a few weeks of
treatment
® Nevertheless, during the time it may favorably influence the
bradykinesia, rigidity and tremor of parkinsonism
® May also help in reducing iatrogenic dyskinesias in patients
with advanced disease
• Adverse Effects
® Undesirable central nervous system effects, all of which can
be reversed by stopping the drug
® These include restlessness, depression, irritability, insomnia,
agitation, excitement, hallucinations, and confusion
® Overdosage may produce an acute toxic psychosis or can
lead to convulsions
® Livedo reticularis sometimes occurs in patients taking
amantadine and usually clears within 1 month after the drug
is withdrawn
§ Livedo reticularis is a net-like pattern of red-blue skin
discoloration and is associated with the spasms of blood
vessels or an abnormality in the circulation near the skin
surface
® Peripheral edema which is not accompanied by signs of
cardiac, hepatic, or renal disease and responds to diuretics
® Others include headache, heart failure, postural hypotension,
urinary retention, and gastrointestinal disturbances (eg.
Anorexia, nausea, constipation, and dry mouth)
• Amantadine should be used with caution in patients with a
history of seizures or heart failure
Acetylcholine-Blocking Drugs
• These agents may improve the tremor and rigidity of
parkinsonism but have little effect on bradykinesia
• Adverse Effects
® Blurred vision, dryness of mouth and eyes, bradycardia,
urinary retention, confusion, hallucination
14 of 17
 ® Antimuscarinic drugs have a number of undesirable CNS and ® Presence of additional findings (dysautomania, cerebellar
PNS effects and are poorly tolerated by the elderly or deficits, eyes movement abnormalities, or early cognitive
cognitively impaired and behavioral changes).
® Dyskinesias occur in rare cases • Disorders include:
® Acute suppurative parotitis sometimes occurs as a ® Multisystem Atrophy
complication of dryness of the mouth ® Progressive Supranuclear Palsy
C. DRUG-INDUCED PARKINSONISM ® Corticobasal Degeneration
® Diffuse Lewy Body Disease
• Drugs that produce parkinsonian syndrome, usually within 3 • Prognosis is worse than Parkinson’s disease and the response
months after introduction to antiparkinsonian treatment may be limited
• The disorder tends to be symmetric with inconspicuous • Treatment is symptomatic
tremor but is not always the case.
• The syndrome is related to high dosage and clears over F. OTHER MOVEMENT DISORDERS (NICE TO KNOW)
several weeks or months after withdrawal 1. Tremor
• Reserpine and the related drug tetrabenazine deplete biogenic • Rhythmic oscillatory movement around a joint
monoamines from their storage sites • Types of Tremor
• Haloperidol, metoclopramide, and the phenothiazines block ® Postural Tremor
dopamine receptors § Occurs during maintenance of sustained posture
• If treatment is necessary, antimuscarinic agents are preferred § DOC: Metoprolol. Propanolol
• Levodopa is of no help if neuroleptic drugs are continued ® Intention Tremor
and may aggravate the mental disorder for which antipsychotic § Occurs during movement which is commonly caused by
drugs were prescribed originally cerebellar lesion or alcohol toxicity

D. INITIATION OF THERAPY 2. Huntington’s Disease

• Autosomal dominant inherited disorder caused by an
abnormality of the huntingtin (HTT) gene
• Progressive chorea and dementia that usually begin in
adulthood
3. Chorea
• Irregular and involuntary muscle jerks that occur in different
parts of the body because of overactivity in dopaminergic
pathways
• Proximal muscles of the limbs are at most severely affected
• Drugs:
® Reserpine and Tetrabenazine- impair dopamine receptors
(alleviate chorea)
® Phenothiazines and Butyrophenones- block dopamine
Figure 14. Initiation of Therapy
receptors (alleviate chorea)
• Figure 14 ® Dopamine-like drugs (Levodopa) – exacerbate chorea
® LEFT: 4. Athetosis
§ You can have a dopamine agonist with a • Continuous, involuntary writhing movements that prevents
levodopa/carbidopa combination. maintenance of a stable posture
§ If the dose of the combination is getting higher or given ® Phenothiazines and Butyrophenones- block dopamine
more frequently, you can add COMT inhibitor or MAO-B receptors
inhibitor 5. Dystonia
® RIGHT: • Involuntary, sustained, or intermittent muscle contractions that
§ You can start with levodopa/carbidopa combination cause twisting repetitive movements or abnormal postures
§ If required to have higher doses and more frequently, add • Patients with dystonia commonly have psychiatric
COMT inhibitor or MAO-B inhibitor complications such as depression, that affect the quality of life
§ After adding COMT inhibitor or MAO-B inhibitor and there • DOC: Diphenhydramine
is still no response à initiate adjunct therapy 6. Tics
§ Adjunct therapy
• Sudden coordinated abnormal movements that tend to occur
- Tremors: add anticholinergic repetitively particularly in the face and head (especially in
- Drug-induced dyskinesias: add amantadine children)
- Freezing (“off”) episodes: add apomorphine • Common tics are repetitive sniffing or shoulder shrugging
§ If all of those did not work, consider surgical options
• Gilles de la Tourette Syndrome – chronic multiple tics
- Rarely happens
• DOC: Fluphenazine, Pimozide, Tetrabenazine
• In planning the treatment, take in considerations the ff:
7. Drug Induced Dyskinesias
® Age
• Caused by dopamine agonists drugs like Levadopa and can
® Cognitive status
be reversed by dose reduction
® Clinical type
• Related to dyskinesia that has similar treatment for drug-
® Finances
induced parkinsonism
® Adverse effects that are related to monotherapy and
combination therapy
® Tardive dyskinesia - long term use of dopamine receptor
blockers; characterized by a variety of abnormal
E. ATYPICAL PARKINSONISM SYNDROMES movements and is a common complication of long-term
neuroleptic or metoclopramide drug treatment
• Differs from classic Parkinson’s disease because of:
® Inconspicuous tremor ® Tardive dystonia- a permanent dystonia; usually
segmental or focal, and occurs in younger children
® Symmetry of neurologic findings
® Tardive akathisia- inner tension and compulsive drive to

PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease 15 of 17
 move body; treated similarly to drug-induced Parkinsonism OVERVIEW: CHOLINESTERASE INHIBITORS AND NMDA
® Rabbit syndrome- rhythmic vertical movements of the
mouth
8. Restless Legs Syndrome
• Unpleasant creeping discomfort that seems to arise deep
within the legs and sometimes on arms
• DOC: Pramipexole
9. Wilson’s Disease
• Recessively inherited disorder of copper metabolism which
can result to increased concentration of copper in the brain
and viscera
• Neurologic signs include tremor, choreiform movements,
rigidity, hypokinesia and dysarthria and dysphagia.
• DOC: Penicillamine and Trientine hydrochloride: a chelating
agent of copper
• Other drugs:
® Tetrathiomolybdate- better than trientine for preserving
neurologic function
® Zinc acetate- increased fecal excretion of copper
® Zinc Sulfate- decreased copper absorption Figure 15. Mechanisms of cholinesterase inhibitors and NMDA receptor
antagonists
III. DRUGS FOR ALZHEIMER’S DISEASE
CHOLINESTERASE INHIBITORS
A. ALZHEIMER’S DISEASE • Butyrylcholinesterase and acetylcholinesterase breaks down
• Neurodegenerative disease characterized by progressive acetylcholine on the synaptic cleft to acetate and choline
memory impairment, dementia, and cognitive dysfunction, and • Alzheimer’s disease was linked to the deficiency of
may lead to a completely vegetative state, resulting in early acetylcholine on the brain
death. • Inhibition of this enzymes can lead to increased level and
• Early onset is associated with several gene defects duration of acetylcholine on the synaptic cleft
® Trisomy 21 (chromosome 21) NMDA RECEPTOR ANTAGONISTS
® Mutation of presenilin-1 gene on chromosome 14 • Belongs to the family of ionotropic GLUTAMATE receptors
® Allele epsilon-4 for lipid-associated ApoE on which mediates most of the excitatory signals on brain
chromosome 19 • Activation of this receptors results to influx of calcium
THREE HYPOTHESIS ON ALZHEIMER’S DISEASE • Beta amyloid proteins can lead to abnormal rise of glutamate to
1. Cholinergic Hypothesis extra synaptic space caused by
• Due to loss of central cholinergic neurons that results to a ® Inhibiting glutamate reuptake
marked decrease in choline acetyltransferase and other ® Release of glutamate from glial cells
markers of cholinergic activity. • Overstimulation by glutamate can lead to cell death
2. Beta-Amyloid Hypothesis • Blockage of this receptor can prevent overstimulation
• Accumulation of beta-amyloid proteins (waste product in the
fluid between neurons) => clumping => plaque formation => B. DRUGS/ TREATMENT
neuroinflammation => disruption of normal neuronal CHOLINESTERASE INHIBITORS
communication 1. Tacrine
3. Tau Hypothesis
• Tetrahydroaminoacridine (THA), is a long acting
• Abnormal accumulation of tau proteins that leads to tangles cholinesterase inhibitor and muscarinic modulator
• In a healthy brain, tau protein helps lengthen and support • It was the first drug to show beneficial effects on Alzheimer’s
microtubules structure which has a crucial role in information disease.
and nutrient transport
• Hepatotoxic
• In Alzheimer’s disease: microtubule assembly is 2. Dolnepezil, Rivastigmine, Galantamine
compromised à malfunction in biochemical communication
• Newer cholinesterase inhibitors
• Orally active, have adequate penetration into the CNS
• Decrease the rate at which neurotransmitters are broken
down.
• Less toxic than tacrine
• Significant adverse effects: nausea, vomiting, diarrhea, and
other peripheral cholinomimetic effects.
• Rivastigmine = only drug which inhibits both
butyrylcholinesterase and acetylcholinesterase
• Adverse Effects
® GI: Anorexia, nausea, vomiting, diarrhea, abdominal pain
(most frequent during titration period)
® CNS: Fatigue, dizziness, headache, somnolence,
insomnia
• Drug Interactions
® Inducers of CYP2D6 and CYP3A4 may increase the rate
of elimination of Donepezil and Galantamine
§ Drugs involved: Phenytoin, Carbamazepine,
Dexamethasone, Rifampicin, Phenobarbital

PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease 16 of 17
 ® Inhibitors of CYP2D6 and CYP3A4 may increase Cmax of IV. REVIEW QUESTIONS
Donepezil and Galantamine 1. This is a major enzyme inducing antiepileptic drug. It has
§ Drugs involved: Quinidine (CYP2D6) and Ketoconazole clinical applications for focal seizures, generalized tonic-
(CYP3A4) clonic seizures as well as myoclonic seizures, but may
NMDA RECEPTOR ANTAGONIST worsen absence seizures.
1. Memantine a. Phenytoin
• MOA: non-competitive NMDA receptor antagonist in a dose b. Phenobarbital
dependent manner c. Valproic Acid
• Indicated in moderate to severe Alzheimer’s disease 2. This antiseizure medication may be used in status
• Less toxic than cholinesterase inhibitors epilepticus and myoclonic seizures as it blocks Na channels
and is known to cause adverse effects in the
• Protects brain cells against excess glutamate, a chemical
messenger involved in learning and memory gastrointestinal system, including hepatotoxicity.
Combination with carbamazepine increases serum
• Adverse Effects carbamazepine epoxide levels.
® Insomnia, dizziness, headache, hallucination a. Phenytoin
• Drug Interactions b. Phenobarbital
® May potentiate effect of anticholinergic drugs and c. Valproic Acid
dopaminergics 3. This anticonvulsant medication may be used for focal
® May reduce effects of neuroleptics and barbiturates seizures and infantile spasms. The main adverse effect is
® No dose adjustment necessary in hepatic impairment blindness or retina dysfunction
® Dose adjustment in moderate renal impairment a. Levetiracetam
§ Not recommended in severe renal impairment b. Vigabatrin
C. FIVE US FDA APPROVED DRUGS FOR THE TREATMENT c. Diazepam
OF ALZHEIMER’S DISEASE 4. This drug is used in Parkinson’s disease and it has both
central and peripheral effects. It may cause hepatic failure
Table 4. Five US FDA Approved Drugs for the Treatment of Alzheimer’s Disease a. Memantine
Drug Brand Approved for Adverse effects b. Entacapone
Name c. Tolcapone
Donezapil Aricept All stages Nausea, vomiting, 5. This drug is approved for use in mild to moderate stages of
loss of appetite, Alzheimer’s disease. Its main adverse effect include liver
increased damage
Galantamine Razadyne Mild to moderate frequency of a. Memantine
bowel b. Tacrine
movements
c. Rivastigmine
Rivastigmine Exelon Mild to moderate
ANSWERS: 1B, 2C, 3B, 4C, 5B
Tacrine Cognex Mild to moderate Liver damage, V. REFERENCES
nausea and Recording and PPT of Dr. Flores’s lecture on ANTICONVULSANTS, ANTI-
vomiting PARKINSONISM AND OTHER MOVEMENT DISORDER, DRUGS FOR
ALZHEIMER’S DISEASE
A-Med 2022 ANTICONVULSANTS, ANTI-PARKINSONISM AND OTHER
MOVEMENT DISORDER, DRUGS FOR ALZHEIMER’S DISEASE
Memantine Namenda Moderate to Headache, Trans
severe constipation, Katzung, B. & Trevor, J. (2019). Pharmacology Examination and Board
confusion Review 12th ed. New York: McGraw Hill.
And dizziness
VI. APPENDIX
® Only alleviates mildly the symptoms but not a definitive
treatment for Alzheimer’s
Table 5. TWG Assignment
D. FUTURE TREATMENT TWG Assignment TEG Assignment
Member Member
BETA-AMYLOID PLAQUES Alquitran, K. Pg. 1-5 Agnes, J. Pg. 1-5
• Beta-secratase and Gamma-secretase cleaves the amyloid Cac, C. Pg. 5-8 Agustin, M. Pg. 5-8
precursor protein (APP) on membrane of neurons which results
to fragments that can be formed into plaques Agreda, A. Pg. 8-12 Bongco, B. Pg. 8-12
1. Solanezumab and Bapineuzumab Antonil, J. Pg 12-15 Carpio, E. Pg 12-15
• Are two amyloid antibodies drugs but FAILED to improve
Co, J. Pg 15-17 Chua, E. Pg 15-17
cognition or slow progression in recent clinical trials
2. Verubecestat Agapito, S. EIC Boligor, L. EIC
• MOA: Beta-site amyloid precursor protein cleaving enzyme
1(BACE1) inhibitor
• Reduces beta-amyloid production
• This drug showed safety in an early clinical trial and longer
term phase 3 trials for efficacy are underway
TAU PROTEINS
1. Epothilone-D
• MOA: microtubule disassembly inhibitor
• Accumulation of tau appears to be associated with
dissociation from microtubules in neurons, which has
stimulated interest in drugs that inhibit microtubule
disassembly.

PHA.1.07 Anticonvulsants, Anti-Parkinsonism and Other Movement Disorders, Drugs for Alzheimer’s Disease 17 of 17