Pharm 226: Pharmacology 1

Department of Pharmacy
Saint Louis University
Neurodegenerative Diseases PARKINSON’S DISEASE
Chapter 6

Unit 4: DRUGS FOR Parkinson’s Disease (PD), Huntington’s Disease (HD), - Aka: paralysis agitans, shaking palsy
PHARMACOLOGY OF THE NEURODEGENERATIVE DISEASES Alzheimer’s Disease (AD), Multiple Sclerosis (MS), and
Amyotrophic Lateral Sclerosis (ALS) are
- Neurodegenerative disorder
CENTRAL NERVOUS SYSTEM
I. Drug Treatment of Parkinson’s Disease neurodegenerative diseases characterized by Clinical syndrome that comprises main features of PD:
II. Drug Treatment of Alzheimer’s Disease progressive loss of neuronal function in a particular
1. BRADYKINESIA (slowness or poverty of movement)
part of the CNS.
*Spasmolytic Agents 2. RIGIDITY (inability to initiate movements)
3. RESTING TREMOR (involuntary trembling when a
The signs and symptoms of neurodegenerative
limb is at rest)
Compiled by: diseases do not reflect a normal age-related loss of
4. Abnormalities in posture and gait.
Cristopherson P. Mata, RPh, MS Pharm brain neurons. Instead, these progressive diseases
Sources:
states are the result of an underlying pathologic
▪ Brenner, G. M., & Stevens, C. W. (2013). Pharmacology. Philadelphia, PA: Saunders/Elsevier. process.
▪ Katzung, B.G., & Trevor, A.J. (2015). Basic and Clinical Pharmacology [E-Book]. ISBN: 978-0-07-
182505-4.
▪ Leonard, B.E. (2003). Fundamentals of Psychopharmacology, 3rd edition. [E-Boo]. ISBN. 0-471-52178-7

PARKINSON’S DISEASE PARKINSON’S DISEASE

ETIOLOGY and PATHOGENESIS ETIOLOGY and PATHOGENESIS
NON-DEGENERATIVE DEGENERATIVE
- Disease result from the DEGENERATION OF - Cholinergic neurons in the basal ganglia do not appear
• Induced by neuroleptics • Idiopathic
DOPAMINERGIC NEURONS that arise in the to be damaged in PD, however it is postulated that the • Tumors • Multiple system atrophy
substantia nigra and project to the other symptoms of the disease arise because of the lack of • Viral Infections • Neurofibrillary tangles
structures of the basal ganglia. inhibitory control of the excitatory cholinergic functions. • Manganese * Aging
*Basal ganglia is a group of subcortical nuclei → inhibitory control of excitatory functions are linked
responsible for motor function, procedural and to inhibitory DA neurons. Juvenile-onset PD Late-onset PD
habit learning, eye movement, cognition, and PARKIN Oxidative Stress Theory
emotion - Protein located in the - Metabolic oxidation of DA in
substantia nigra where it the basal ganglia by MAO-B
plays a role in protein yields H2O2 as a by product
degradation. - H2O2 reacts with Cuprous and
- Mutation in parkin leads to Ferrous ions to form highly
accummulation of proteins in reactive hydroxyl radicals
the substantia nigra leading - Free radicals attack
to early apoptosis of this cell dopaminergic neurons that
lead to their degeneration

DRUG TREATMENT for PD
I. Drugs that increase DA levels
II. DA receptor agonists
III. Ach receptor antagonists
I. Drugs that increases DA levels
LEVODOPA/l-dopa
- biosynthetic precursor of DA.
* DA itself is not effective in the treatment of PD when
administered systemically because it does not enter the
BBB to a significant extent.
DRUG TREATMENT for PD
Drugs Combined with Levodopa
Drug CARBIDOPA
False substrates of LAAD thereby
reducing the conversion of levodopa to
MOA and
DA in peripheral tissues and so
Effect
increasing the amount of levodopa that
enters the brain.
Does not cross the BBB hence it does not
inhibit the formation of DA in the brain.
Combination of levodopa-carbidopa is
available in immediate-release and
sustained-release formulations that
contain different ratio of the two drugs
→ designed to reduce the Weaning-off
effect of levodopa.
Adverse Effects:
DRUG TREATMENT for PD • Nausea and vomiting (80%)
• Orthostatic hypotension (25%)
Levodopa Effects: • Cardiac dysrhythmias (10%)
Pharmacokinetics:
1. As a form of replacement therapy, it increases • Dyskinesia (30%)
• Absorbed with the same process as amino acids. concentration of DA in the brain and is the main treatment - Aka: Peak-dose dyskinesia
• In peripheral tissues Levodopa is metabolized by LAAD used to alleviate motor dysfunction in patients with PD. - occurs during long-term (2-5 years) of
(l-amino acid-decarboxylase) to DA and COMT to 3OMD 2. As PD progresses overtime, more DA neurons are lost therapy as a result of excessive DA
(3-O-methyldopa) thereby its bioavailability after which affects the effectiveness of Levodopa such as: concentrations in the striatum.
systemic administration is greatly reduced. a. Wearing off effect
Manifestations:
• Exhibits extensive first-pass metabolism (only about → motor symptoms arise toward the end of dosage • Patients appear as if they are chewing food
1% of the administered dose of levodopa reaches the interval of levodopa. while lips their lips are protruded.
brain tissue). b. On-off periods • Flinging movements of the arms and legs.
→ a state where patients may suddenly switch from Management:
good therapeutic control to severe motor symptoms. → Reduce dose however therapeutic effect of
Mechanism of Action: → occurs in 50% of patients after 5 or more years of Levodopa is compromised.
Levodopa in the brain tissue is taken up by therapy and may eventually occur in 90% of
• Psychotic effects
dopaminergic neurons in the striatum and is patients after more than a decade of therapy.
- excessive DA concentrations in the mesolimbic
converted to DA by AADC. and mesocortical pathways.
Rationale: 1. To increase the bioavailability of Levodopa after DRUG TREATMENT for PD
systemic administration.
2. To reduce the GI and autonomic adverse effects. I. Drugs that increases DA levels
ENTACAPONE TOLCAPONE SELEGILINE & RASAGILINE AMANTADINE
Inhibitor of peripheral COMT, the Inhibitor of central COMT, the → An antiviral agent better tolerated than levodopa and
MOA:
enzyme that metabolizes levodopa enzyme that metabolizes levodopa
1. Irreversible inhibitors of central MAO-B thereby dopamine agonists bus less effective in the treatment
to 3OMD in the peripheries, and so to 3MT in the CNS, and so
increases DA levels. of PD.
increasing the amount of levodopa increasing the amount of levodopa.
that enters the brain. 2. Decreases formation of H2O2 (neuroprotective).
MOA:
Few reports of hepatitis as adverse Uses: 1. Increases release of DA from nigrostriatal neurons.
No reports of liver toxic effects
effect. • Monotherapy for the treatment of early to mild PD. 2. Inhibits reuptake of DA.
• Adjunct with levodopa-carbidopa for advanced PD
states.
Available only in a single
Available in combination products
ingredient product.
with levodopa and carbidopa.
 B. Non-Ergot Alkaloids Additional lecture discussion can be viewed using this link:
DRUG TREATMENT for PD DRUG TREATMENT for PD
Pharmacology-Drugs for Parkinson’s Disease (Made Easy):
PRAMIPEXOLE and ROPINIROLE https://www.youtube.com/watch?v=Z84iypHdftQ
II. DA Receptor Agonists Other Indication: Restless Leg Syndrome III. Ach Receptor Antagonists
MOA: → centrally-acting anticholinergic drugs.
ROTIGOTINE (new agent under this class)
→ are more effective in reducing tremors and relieves
1. Directly activates Dopamine-2 receptors in the
striatum even in the absence of endogenous muscle rigidity but not akinesia.
Dopamine.
C. APOMORPHINE Agents:
A. Ergot Alkaloids → short-acting D1 and D2-like receptor agonist. BIPERIDEN
BROMOCRIPTINE According to Carbone et. al., 2019, it is the only drug proven BENZTROPINE
Use: Adjunct with levodopa to have an efficacy equal to levodopa. TRIHEXYPHENIDYL
Adverse Effect: Same with Levodopa → Clinical trials have also shown that intermittent
Apomorphine injections provide rapid and effective
PERGOLIDE relief from unpredictable “off-periods”.
*withdrawn in the market because it can damage heart valves
→ Continuous Apomorphine infusion reduced around 50%
of daily “off-periods”.
Source:
Carbone, F., Djamshidian, A., Seppi, K. & Poewe, W. (2019). Apomorphine for
Parkinson’s Disease: Efficacy and Safety of Current and New Formulations, CNS
Drugs, 33(9). 905-918. https://doi.org/10.1007./s40263-019-00661-z.

ALZHEIMER’S DISEASE NEUROPATHOLOGICAL HALLMARKS of ALZHEIMER’S DISEASE

- Most common type of dementia.
Reduction of Ach Increased Glutamate Neurotransmission
- Characterized as a severe, chronic, progressive,
Loss of cholinergic tone and Ach levels in the Neuronal excitotoxicity from excessive N-Methyl-
irreversible neurodegenerative and incurable
brain is hypothesized to be responsible for the D-Aspartate (NMDA) receptor activation leads to
disorder with memory loss, cognition impairment,
gradual cognitive decline. neuronal damage and loss.
abnormalities in behavior, and personality changes
as the main clinical manifestations. Drugs: Drug:
- Characterized by NEURONAL DEATH. Centrally-acting Acetycholinesterase inhibitors
TACRINE (withdrawn because of liver toxicity) MEMANTINE
DONEPEZIL MOA and Effect: Non-competitive antagonist at
RIVASTIGMINE NMDA receptors; cannot prevent neuronal loss,
worsening of dementia, and modify AD progression.
GALANTAMINE
Effect: Slows the loss of cognitive function temporarily
but does not delay AD progression.
 NEUROPATHOLOGICAL HALLMARKS of ALZHEIMER’S DISEASE NEUROPATHOLOGICAL HALLMARKS of ALZHEIMER’S DISEASE
Deposition of Amyloid plaques or Neuritic plaques Aggregation of Neurofibrillary Tangles (NFTs)
• Accumulation of Amyloid β (Aβ) is postulated to be the Also known as hyperphosphorylated tau proteins cause
primary cause of AD. neuronal death.

• The misfolded sticky proteins are insoluble aggregates No currently approved drugs are known to
and are neurotoxic. target this cause.
• Research shows that Aβ build-up enhances the activity of Tau-aggregation inhibitors
glutamate.

No currently approved drugs are known to target Additional lecture discussion can be viewed using this link:
this cause.
Pharmacology-Drugs for Alzheimer’s Disease (Made Easy):
https://www.youtube.com/watch?v=euzRPrvrwj0

Agents:
NEURODEGENERATIVE DISEASE (Others) SPASMOLYTIC AGENTS
ORPHENADINE
- Are more commonly termed as muscle relaxants
Neurodegenerative
Etiology and Clinical Manifestations Pharmacologic Interventions
CARISOPRODOL
Disease Note: → both agents have unknown mechanisms of action
→ commercially available in combination with
Muscle Relaxants is an umbrella term for two specific class of Paracetamol.
drugs namely: spasmolytics and neuromuscular blocking
Huntington’s Disease Norgesic® (Orphenadine + Paracetamol)
agents (Curare drugs and Succinylcholine). The main
Lagaflex® (Carisoprodol + Paracetamol)
difference between the two classes is that spasmolytic agents
act centrally while neuromuscular blockers act peripherally. → usually prescribed to patients suffering from
muscle overexertion and injury.
- Generally indicated to patients with spastic disorders like:
Multiple Sclerosis Benzodiazepine & Barbiturates
• Multiple Sclerosis
• Cerebral palsy
• Spasticity associated with muscle overexertion and injury.
BACLOFEN
MOA: GABAB-receptor agonist.
Amyotropic Lateral Effect: Reduction of motor neuron excitability.
Sclerosis (ALS)
 SPASMOLYTIC AGENTS

DANTROLENE BOTULINUM TOXIN-A

MOA: Ryanodine receptor antagonist thereby prevents the MOA: Inhibition of the release of Ach.
release of calcium ions from the sarcoplasmic
reticulum in muscle fiber.
Effect: Skeletal muscle relaxation
Adverse Effects of Spasmolytic Agents:
Indications:
• Euphoria
• Malignant hyperthermia
• Light-headedness/dizziness
• Neuroleptic malignant syndrome
• Fatigue
• Multiple Sclerosis
• Muscle weakness
• Cerebral Palsy
• CNS depression (drowsiness)
• Spinal cord injuries
Additional lecture discussion can be viewed using this link:

Muscle Relaxers - Mechanisms, Indications and Side Effects:

https://www.youtube.com/watch?v=6noV8AHcM6E