Lecture 15: Nerves IV – neurodegenerative diseases Flashcards
*Describe what is meant by a neurodegenerative disease.
A neurodegenerative disease is a devastating disease of the CNS which is characterised by the progressive loss of
selected neurons in discrete brain areas resulting in characteristic disorders of movement, cognition or both.
E.G. Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis (ALS).
With reference to the above the only degenerative diseases with specific pharmacological treatments are
Parkinson’s and Alzheimer’s
*Describe the dopaminergic pathways in the CNS.
- The nigrostriatal pathway – accounts for 75% of the
dopamine in the brain. It comprises neuronal cell bodies in
the substantia nigra that terminate in the corpus striatum. - The mesolimbic/mesocortical pathway. It comprises neuronal cell bodies in the midbrain with fibres that project to parts of the limbic system especially to the amygdaloid nucleus and nucleus accumbens.
- The tubero-hypophoseal pathway – Group of short neurones that runs from the ventral hypothalamus to the
median eminence and pituitary gland.
*Give an overview of the pathophysiology of Parkinson disease detailing the role of the substantia nigra in disease progression.
Parkinson’s disease (PD) is characterized by an insidious
onset with slowing of emotional and voluntary movement,
muscular rigidity, postural abnormality and tremor.
The disease is due to the striatal deficiency of dopamine following neuronal degeneration within the substantia nigra.
*Describe in detail the dopamine precursor group of anti-Parkinson drugs. This should include name, indications, adverse effects, contraindications and drug interactions of a member of this drug class.
Levodopa
Indications: Treatment of Parkinson’s disease.
Adverse effects (combination therapies): Nausea, loss of appetite, palpitations, incoordination, twitching, depression, tiredness, depression, excess excitability, vomiting, angina, reduced libido, shortness of breath, arrythmia, hallucination, confusion, significant psychiatric disturbances (rare).
Contraindications: Pregnancy, lactation, children. Use with caution in patients with psychiatric conditions, heart disease, ulcers, epilepsy, osteoporosis, osteomalacia, glaucoma. Do not take if suffering from glandular disease, severe lung, liver or kidney disease, psychoses, melanoma, Huntingtons chorea.
Drug interactions: Antihypertensives, TCAs, phenothiazines, risperidone, isoniazid, phenyoin, MAOI, selegiline, generalanaesthetics.
*Describe in detail the mode of action of the dopamine precursor group of anti-Parkinson drugs.
Levadopa = precursor group
Mechanism of action: Metabolic precursor of dopamine which is enzymatically converted to dopamine in the neurones of the substantia nigra. Used in combination with other anti-parkinson drugs to enhance effects.
*Describe in detail the class of anti-parkinson drugs that act as inhibitors of dopamine or levodopa metabolism. This should include name, indications, adverse effects, contraindications and drug interactions of a member of this drug class.
Name: Carbidopa – used in combination therapies (Kinson (levodopa + carbidopa), Sinemet (levodopa + carbidopa), Stalevo (levodopa + carbidopa + entacapone) )
Indications: Treatment of Parkinson’s disease.
Adverse effects (combination therapies): Nausea, loss of appetite, palpitations, incoordination, twitching, depression, tiredness, depression, excess excitability, vomiting, angina, reduced libido, shortness of breath, arrythmia, hallucination, confusion, significant psychiatric disturbances (rare).
Contraindications: Pregnancy, lactation, children. Use with caution in patients with psychiatric conditions, heart disease, ulcers, epilepsy, osteoporosis, osteomalacia, glaucoma. Do not take if suffering from glandular disease, severe lung, liver or kidney disease, psychoses, melanoma, Huntingtons chorea.
Drug interactions: Antihypertensives, TCAs, phenothiazines, risperidone,
isoniazid, phenyoin, MAOI, selegiline, general anaesthetics.
*Describe in detail the mode of action of the class of anti-parkinson drugs that act as inhibitors of dopamine or levodopa metabolism.
Carbidopa is a dopa decarboxylase inhibitor that diminishes the metabolism of levodopa in the GI tract and peripheral tissues thus increasing the availability of levodopa to the CNS. This allows a lowering on the levodopa dose by 4-5 fold, decreasing the severity of the dopamine side effects.
*Describe in detail the contribution of the accumulation of senile plaques to the aetiology of AD.
One of the hallmarks of Alzheimer’s disease is the
accumulation of amyloid plaques between nerve cells
(neurons) in the brain. Amyloid is a general term for protein fragments that the body produces normally. Beta-amyloid is a fragment of a protein that is snipped from another protein called amyloid precursor protein (APP). In a healthy brain,
these protein fragments would be broken down and
eliminated. In Alzheimer’s disease, the fragments accumulate to form hard, insoluble plaques.
*How is amyloid precursor protein involved in Alzheimer’s disease.
Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation and neural plasticity. APP is best known and
most commonly studied as the precursor molecule whose
proteolysis generates amyloid beta, a 39- to 42-amino acid
peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer’s
*Describe in detail the contribution of neurofibrillary tangles to the aetiology of AD.
Neurofibrillary tangles consist of insoluble twisted
fibres that are found inside of the brain’s cells. They
primarily consist of a protein called tau, which forms part
of a structure called a microtubule. The microtubule
helps transport nutrients and other important substances
from one part of the nerve cell to another. In
Alzheimer’s disease, however, the tau protein is
abnormal and the microtubule structures collapse.
*Describe with examples the mode of action of the acetylcholinesterase inhibitors used in the treatment of AD
= primary Tx mild/moderate AD
E.G. Donepezil, rivastigmine, tacrine (all uncompetitive inhibitors) and galantamine (a competitive inhibitor)
MOA = preferentially inhibit CNS acetylcholinesterase
resulting in improved cholinergic transmission in
those neurons still functioning. Pts with AD have decreased activity of the cholinergic system in the cerebral cortex, these drugs enhance cholinergic function in CNS; by increasing [acetylcholine] through reversible inhibition of acetylcholinesterase.
All of these drugs (with the exception of rivastigmine) interact with drugs that alter cytochrome P450 enzyme activity.
Common adverse effects include nausea, vomiting,
diarrhoea, anorexia and (myalgia) muscle
cramps. Tacrine is also associated with
hepatotoxicity.
What are the three distinguishing anatomical/histological features of Alzheimer’s disease
- Accumulation of senile plaques (β-amyloid
accumulations) - Formation of numerous neurofibillary tangles
- Loss of cortical neurones especially cholinergic
neurons
What are the 2 types of anti-alzheimer drugs?
ACYTLCHOLINESTERASE INHIBITORS
NMDA RECEPTOR ANTAGONIST
Give examples of ACYTLCHOLINESTERASE INHIBITORS
Donepezil
Rivastigmine
Tacrine
Galantamine
what are some types of Anti-Parkinson Drugs?
we focus =
DOPAMINE PRECURSORS
INHIBITORS OF DOPAMINE OR LEVODOPA METABOLISM
Dopamine receptor agonist
Antimuscarinic agents
Amantadine
