Pharmacology 3 (PHD 1103)

LECTURE 7

Neurodegenerative disorders
D e p a rtm ent o f P h a rm ac ology a n d To xic ology
C o l lege o f P h a rm ac y
U m m Al - Q u ra U n i v ers ity
Learning Outcomes
➢ At the end of this lecture, you will be able to:

▪ Define neurodegenerative diseases

▪Define Alzheimer diseases

▪ List the classification of anti-Alzheimer’s drugs

▪Describe the mechanism of action, clinical indication and adverse effect of anti-Alzheimer’s drugs

▪.Define Parkinsonism

▪ List the classification of anti-parkinsonism drugs

▪ Describe the mechanism of action, clinical indication and adverse effect of parkinsonism drugs

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The neurodegenerative diseases
▪Neurodegenerative disorders are characterized by progressive and irreversible loss of neurons
from specific regions of the brain.
▪Prototypical neurodegenerative disorders include Parkinson diseases (PD), where the loss of
neurons from structures of the basal ganglia results in abnormalities in the control of movement
▪Alzheimer diseases (AD) the loss of hippocampal and cortical neurons leads to impairment of
memory and cognitive ability.

Common Features of Neurodegenerative Disorders

Proteinopathies : accumulation of particular proteins in cellular aggregates, for example
α-synuclein in PD; amyloid β (Aβ) and the microtubule-associated protein tau in AD.

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The neurodegenerative diseases
Selective Vulnerability
A common feature of neurodegenerative disorders is the selectivity of the disease processes for
particular types of neurons in different brain regions.
For example, in PD, there is extensive destruction of the dopaminergic neurons of the substantia
nigra.

Genetics and Environment

Each of the major neurodegenerative disorders can be inherited due to genetic mutations,
Apolipoprotein A (APOE) genotype constitutes an important risk factor for AD.
 Pathophysiology of Alzheimer's disease
▪ Cholinergic hypothesis → under activity ▪ Tau hypothesis
o Loss of central cholinergic neurons → deficiency in o Accumulation of Tau protein (intracellular
Acetylcholine → Ach involves in memory & microtubules)
learning →  neurofibrillary tangles
→  support microtubules structures for
nutrition & neuronal communication
▪ Amyloid hypothesis → over activity
o Accumulation of ꞵ-amyloid protein
→  amyloid plaques
→ Neuroinflammation & disrupt neuronal
communication

Figure 2. The pathophysiology of Alzheimer's disease Figure 2. The pathophysiology of Alzheimer's disease , cont.
 Pathophysiology of Alzheimer's disease
▪ Brain shrinkage & localised loss of neurons which can be extensive, mainly in the hippocampus
▪ Loss of cholinergic neurons in the hippocampus & frontal cortex
▪ Diffuse atrophy of cerebral cortex & enlargement of ventricular system

Figure 2. The pathophysiology of Alzheimer's disease

 Anti-Alzheimer's drugs
▪ Drug therapy strategy
o Symptomatic improvement
❖ Enhanced & improved in the cognitive & behavioural dysfunction
o Disease modification
❖ Progression of dementia and symptoms
o Primary prevention of disease
❖ Intervention in key pathogenic mechanisms at a pre-symptomatic stage

▪ Acetylcholinesterase inhibitors (AChEIs)

o Donepezil
o Rivastigmine
o Galantamine
o Tacrine
o Huperzine A

▪ Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist

o Memantine
 1-AChEIs
Mechanism of Reversible inhibit AChE enzyme → prevent the degradation of the
action neurotransmitter →  levels of Ach in the CNS synaptic cleft →
enhanced cholinergic transmission & improve memory and cognition
Drug sub- •Donepezil → milde & sever AD
class and •Rivastigmine → carbamate AChE inhibitor
therapeutic •Mild & moderate AD
indications •Patient not tolerating or not responding to donepezil
•Galantamine → intranasal route of adminestration → avoid GI SEs
•Mild & moderate AD
•Huperzine A → natural AChEIs derived from the Chinese herb Huperzia
serrata
•Disease-modifying treatment → antioxidant and
neuroprotective properties
•Tacrine
Averse effect •GI symptoms → nausea, vomiting, cramp, diarrhea & weight loss
•Cardiac bradycardia
•Hepatotoxicity → Tacrine → not widely used
Contraindicati In patient with symptomatic bradycardia, or with a history of falls or
on syncope
Figure 1. The mechanism of action of AChEIs
 2-NMDA receptor antagonist

Drug sub-class Memantine: Moderate to sever AD

Mechanism of • Block overexcited NMDA receptor →blocks Ca++ entry →  glutamate

action levels → protecting CNS neuron from its excitatory effect Improve
→ inhibit neurotoxicity processes cognition

• Uncompetitive NMDA antagonist → low affinity and rapid

blocking/unblocking kinetics → to preserve physiologic function of
NMDA receptors to be activated by glutamate

• Inhibits & reverses protein phosphatase (PP)-2 → inhibit abnormal

hyperphosphorylation & accumulation of Tau
Figure 2. The mechanism of action of Memantine
Adverse effect • CNS → headache, insomnia, dizziness & confusion → mild & reversible SEs
• GI → diarrhea

Important point • Memantine is used in combination with a cholinesterase inhibitor in

patients with severe AD
 New medications approved for AD
▪Lecanemab is a humanized immunoglobulin gamma 1 (IgG1) against
aggregated soluble and insoluble forms of amyloid-β peptide.
▪It received its first approval for this indication on 6 January 2023 in the
USA under the Accelerated Approval Pathway
▪It is used in patients with mild cognitive impairment or mild dementia
stage of disease, and a confirmed presence of amyloid beta pathology
 New medications approved for AD
▪Aducanumab is a human monoclonal antibody
▪Used in patients with mild cognitive impairment due to Alzheimer disease
or mild Alzheimer disease dementia.
▪Common adverse events: amyloid-related imaging abnormalities
(ARIA).
•Amyloid-related imaging abnormalities: cerebral edema, cerebral hemorrage
•Others: Diarrhea, headache, confusion
Parkinson Disease (PD)
▪Definition: Parkinsonism is a progressive neurological disorder of muscle movement as
a clinical syndrome
▪It consists of 4 cardinal features:
o Bradykinesia (slowness of movement) and, in extreme cases, a loss of physical
movement (akinesia)
o Muscular rigidity
o Resting tremor (which usually disappears during voluntary movement)
o Impairment of postural balance leading to disturbances of gait and falling
Parkinson Disease
▪The pathological hallmark of PD is the loss of the pigmented,
dopaminergic neurons of the substantia nigra.
▪While DA neuron loss is the most well-recognized feature of the disease,
the disorder affects a wide range of other brain structures, including the
brainstem, hippocampus, and cerebral cortex
Pathophysiology
of PD
Anti-Parkinsonism Drugs
▪ Drugs acting on dopaminergic system
o Dopamine precursors – Levodopa (l-dopa)
o Peripheral decarboxylase inhibitors – carbidopa and benserazide
▪ Dopaminergic agonists
o Bromocriptyne, Ropinirole and Pramipexole
▪ Catechol-O-Methyltransferase (COMT) Inhibitors
o Entacapone, Tolcapone
▪ Dopamine facilitator
o Amantadine
▪ Drugs acting on cholinergic system Central anticholinergics
o Teihexyphenidyl (Benzhexol), Procyclidine, Biperiden
Anti-Parkinsonism Drugs
▪Levodopa MOA
oMetabolic precursor of dopamine: Prodrug
o Single most important drug
o Manages all major manifestations but not progression of disease
oIn the brain, levodopa is converted to dopamine by decarboxylation primarily within the
presynaptic terminals of dopaminergic neurons in the stratium (by action of L-aromatic
amino acid decarboxylase).
 Anti-Parkinsonism Drugs
▪ If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the
peripheral sites so that little unchanged drug reaches the cerebral circulation.
▪ In addition, dopamine release into the circulation by peripheral conversion of levodopa
produces undesirable effects
▪In practice, levodopa is administered in combination with a peripherally acting inhibitor of
aromatic L-amino acid decarboxylase, such as carbidopa, that do not penetrate into the
CNS.
▪ Inhibition of peripheral decarboxylase markedly increases the fraction of administered
levodopa that crosses the blood-brain barrier and reduces the incidence of peripheral
side effects.
 Anti-Parkinsonism Drugs
▪Pharmacological effect:
oCNS: – Marked improvement in symptoms, Akinesia first, then rigidity & tremors – Other
symptoms improve gradually – General alerting response; ↑ excitability, sexual activity,
psychosis
▪Pharmacokinetic:
o T1/2: 1-3 hrs
o 95% peripheral decarboxylation (GIT, liver, other tissues)
o Less than 1 % reaches CNS
 Anti-Parkinsonism Drugs
▪Adverse effect:
oGIT: Nausea, vomiting, alteration of taste
o Cardiovascular: postural hypotension, palpitations, Sinus tachycardia, cardiac
arrhythmias, exacerbation of angina
▪ DDI:
o Phenothiazines, metoclopramide : block DA receptors
o Non-selective MAO inhibitors: hypertensive crisis
 Anti-Parkinsonism Drugs
▪ If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the
peripheral sites so that little unchanged drug reaches the cerebral circulation.
▪ In addition, dopamine release into the circulation by peripheral conversion of levodopa
produces undesirable effects
▪In practice, levodopa is administered in combination with a peripherally acting inhibitor of
aromatic L-amino acid decarboxylase, such as carbidopa, that do not penetrate into the
CNS.
▪ Inhibition of peripheral decarboxylase markedly increases the fraction of administered
levodopa that crosses the blood-brain barrier and reduces the incidence of peripheral
side effects.
 Anti-Parkinsonism Drugs
▪Carbidopa
oExtra cerebral dopa decarboxylase inhibitors inhibit conversion of l dopa to dopamine in
periphery
oDo not inhibit conversion of L dopa to dopamine in the brain as they do not cross BBB
oDose of levodopa ↓ to ¼ , plasma t ½ ↑
o Less side effects: nausea, vomiting, tachycardia
oOn & off effect is minimized since cerebral dopamine levels more sustained
o Enhanced efficacy e.g of potentiation
 Anti-Parkinsonism Drugs
▪Co-administration of Carbidopa with Levodopa
owill decrease metabolism of levodopa in GI Tract and peripheral tissues
o increase levodopa concentration in
 Anti-Parkinsonism Drugs
▪Dopamine receptors agonists
oD1 and D2 receptors express differentially – different areas of brain
o D1 is excitatory (cAMP and PIP3)
oD2 is inhibitory (Adenylyl cyclase and K+ and Ca++ Channels)
o Both present in striatum – involved in therapeutic response of levodopa
oStimulation of Both – smoothening movement and reduced muscle tone
o Bromocriptine, pergolide, Ropinirole and Pramipexole:
o Bromocryptine – potent D2 agonist and D1 partial agonist and antagonist
o Pergolide – Both D1 and D2 agonist Newer (Pramipexole and Ropinirole) – D2 and D3
effect with low D1 effect
 Anti-Parkinsonism Drugs
▪Dopaminergic receptors agonists
oBromocriptine Ropinirole & pramipexole – Supplementary drugs to L dopa in advanced
cases , better tolerated fewer GIT side effects
oBromocriptine – Synthetic ergot derivative
oQuick improvement of PD symptoms and longer lasting (1 hr and 6-10 Hrs)
oThey are not used as a monotherapy: High doses and expensive Intolerable side effects
– vomiting, hallucinations, hypotension (1st dose) and nasal stuffiness
o Adverse events : Fatigue, somnolence, nausea, peripheral edema, dyskinesia,
confusion , postural hypotension
 Anti-Parkinsonism Drugs
▪Apomorphine.
o A dopaminergic agonist that can be administered by subcutaneous injection or as a
sublingual formulation
oApomorphine is FDA approved as a “rescue therapy” for the acute intermittent treatment
of off episodes in patients with a fluctuating response to dopaminergic therapy.
 Anti-Parkinsonism Drugs
▪Catechol O methyl transferase inhibitors
o Mechanism of action: Inhibit catechol O methyl transferase (COMT) which is
responsible for the conversion of dopa into methyl dopa.
oElevated levels of methyldopa decreases the response to levodopa, because
methyldopa competes with levodopa for an active carrier mechanism that governs its
transport across the blood-brain barrier.
o Prolong the action of levodopa by diminishing its peripheral metabolism.
o These agents may be helpful in patients receiving levodopa to reduce dose and
decrease fluctuations in response
o Side effects are similar to levodopa
 Anti-Parkinsonism Drugs
▪Amantadine is an antiviral agent.
oIts mode of action in parkinsonism is unclear
o Clinical Use: Amantadine is less potent than levodopa and its effects disappear after
only a few weeks of treatment
oAdverse Effects: Peripheral edema, headache, postural hypotension, urinary retention
gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry mouth).
oContraindications: Amantadine should be used with caution in patients with a history of
seizures or heart failure.
 Anti-Parkinsonism Drugs
▪Acetylcholine blocking drugs: Benztropine
oClinical Use: Antimuscarinic drugs may improve the tremor and rigidity of
parkinsonism but have little effect on bradykinesia.
oAdverse Effects:
oCentral nervous system effects, including drowsiness, restlessness, confusion,
agitation, hallucinations, and mood changes. Dyskinesias occur in rare cases
o Atropine – like actions: dryness of the mouth, blurring of vision, urinary retention,
nausea and vomiting, constipation, tachycardia, palpitations, and cardiac arrhythmias.
withdrawal should be gradual in order to prevent acute exacerbation of parkinsonism.
Contraindications: Prostatic hyperplasia, obstructive gastrointestinal disease (eg,
paralytic ileus) and angle-closure glaucoma.
References
1. Basic & clinical pharmacology, Bertram G. Ketzung, 12th edition

2. Lippincott Review of Pharmacology 6th edition(2014)

3. Bertram G. Katzung, Marieke Kruidering-Hall, Anthony J. Trevor – Katzung & Trevor’s.

Pharmacology. Thirteenth Edition.

4. Goodman & Gilman’s Manual of Pharmacology and Therapeutics, 5th edition

5. The pharmacological management of Alzheimer's disease, Progress in Neurology and Psychiatry

10.1002/pnp.151 | DeepDyve

6. Clinical trials.gov