ic15 pharmacotx for parkinson's and alzheimer's

Question 1

what is “parkinson’s disease” and “alzheimer’s disease” (basic definition)

Answer 1

neurodegenerative disease where nerve cells in the brain or peripheral nervous system lose function over time and ultimately die

progressive and incurable

likelihood of developing a neurodegenerative disease dramatically incr with age

Question 2

considering the pathophysiology of PD and AD, would drug effects be antagonistic or agonistic and broadly list the ways that drug can produce such effect

Answer 2

agonist

1. drug incr synthesis of NT
2. drug destroys degrading enzymes
3. drug incr release of NT
4. drug binds to autoreceptors to block their inhibitory effect
5. drug binds to postsynaptic receptors to mimic effect of NT
6. drug block deactivation of NT by blocking degradation or reuptake

Question 3

what kind of sx do PD pts present with and what is is attributed to and are there any further consequences resulting from this primary cause

Answer 3

PD pts present with extrapyrimidal motor sx (tremors, rigidity, bradykinesia) due to striatal dopaminergic deficiency

various other NT systems can get involved over time and produce non-motor sx (autonomic, psychaitric, sensory, ocular, gait imbalance)

Question 4

what is the epidemiology and course of PD (prevalence, types of PD, rate of progression, types of sx in later stages of PD)

Answer 4

prevalence: 1% of those aged >60yo have PD

other types of PD:
i) young onset PD - onset 21-40yo (5-10% of PD pts)
ii) juvenile onset PD - onset <20yo (typically genetically inherited)

rate of progression: markedly higher in early years of the disease (significant disability 10-15years after onset)

sx in later stages: motor fluctuation, dyskinesia and non motor sx like falls, postural instability, postural hypotension, confusion, dementia, speech and sleep disorders

Question 5

what is “dyskinesia”

Answer 5

invountary erratic writhing movements of the face, legs, arms or trunk

Question 6

what are the motor sx of PD and which are the cardinal sx

Answer 6

motor sx of PD:
i) tremor at rest (pill rolling)
ii) rigidity (cogwheeling)
iii) bradykinesia (slowness of movement)
iv) postural instability and gait disturbances

cardinal sx are i) to iii)

Question 7

what is the pathophysiology of PD (what can you see or cannot see if looking at the structure and comparing it to a normal structure vs that in PD)

Answer 7

impaired clearing of abnormal or damaged intracellular proteins by the ubiquitin-proteosomal system and this failure to clear toxins results in accumulation of aggresomes (refers to an aggregation of misfolded proteins) which ultimately causes apoptosis

an eg. of aggresome would be lewy bodies that contains alpha-synuclein and ubiquitin

degeneration of dopaminergic neurons occurs with lewy body inclusions in the substantia nigra which leads to dysfunction of the nigrostriatal pathway

dopaminergic neurons postulated to be most vulnerable possible bc its the most metabolically active (if not all other NT would be just as affected)

normal substantia nigra would be darkly coloured signifying high presence of neuromelanin (pigment) vs PD substantia nigra would appear not as dark coloured or missing dark band

Question 8

what are the components of the basal ganglia (which forms the basal nuclei and which forms the striatum and can rough sketch the location of each component)

Answer 8

1. caudate nucleus
2. putamen
3. globus pallidus
4. subthalamic nucleus
5. substantia nigra

1,2,3 forms the basal nuclei
1,2 forms the striatum

Question 9

what is the main role of the basal ganglia (and what happens if there is a loss of substantia nigra)

Answer 9

for motor control and has strong connections to other areas like thalamus, motor cortex etc

involved in action selection through release of inhibition
i) normally inhibits a number of motor systems
ii) substantia nigra mediated release of inhibition permits a motor system to become active
iii) involved both excitatory D1 and inhibitory D2 receptor

loss of substantia nigra = no release of inhibition = hypokinetic state

Question 10

what makes up the grey and white matter

Answer 10

grey matter are neurons found on the surface of neocortex while white matter are axons, dendrites, processes of neurons

Question 11

what kind of signals does the putamen in the basal ganglia receive

Answer 11

putamen receives excitatory signals via D1 receptors and inhibitory signals via D2 receptors from substantia nigra

Question 12

how does loss of dopaminergic inputs resulting from loss of substantia nigra result in motor sx in PD (relate to the two paths)

Answer 12

[direct path] loss of dopaminergic inputs = hypoactivation of excitatory D1 receptors = weakens striatal inhibition of globus pallidus internal = inhibition of thalamus greater thus weaker activating force on motor cortex = lead to hypokinesia

[indirect path] loss of dopaminergic inputs = hypoactivation of inhibitory D2 receptors = strengthens striatal inhibition of globus pallidus external = weaker inhibition on subthalamic nucleus = stronger excitatory effect on globus pallidus internal = stronger inhibitory effect on thalamus = weaker activation on motor cortex = lead to hypokinesia

DIRECT PATH:
SN excites P, P inhibits GPi, GPi inhibits thalamus, thalamus activates motor cortex

INDIRECT PATH:
SN inhibits P, P inhibits GPe, GPe inhibits subthalamic nucleus, subthalamic nucleus excites GPi, GPi inhibits thalamus, thalamus excites motor cortex

Question 13

how is dopamine synthesised and broken down

Answer 13

synthesis (occurs at presynapse):
i) L-tyrosine -> L-dopa through tyrosine hydroxylase
ii) L-dopa -> dopamine through DOPA decarboxylase

(release of dopamine into synaptic cleft then bind to D1 and D2)

breakdown:
dopamine -> -> homovanillic acid through COMT and MAO

or reuptake via dopamine transporters back into presynaptic cleft and recycled

Question 14

does dopamine and L-dopa pass through BBB

Answer 14

dopamine does NOT pass through BBB but L-dopa passes through

Question 15

what are the possible strategy that can be adopted considering the patho of PD and what drug for each strategy

Answer 15

1. incr synthesis of dopamine: levodopa (synthetic L-dopa aka precursor of dopamine)
2. inhibit dopamine breakdown via COMT: entacapone, tolcapone (COMTi)
3. inhibit dopamine breakdown via MAO: selegiline, rasagiline (MAO-Bi)
4. activate dopamine receptors: pramipexole, pergolide, ropinirole (dopamine receptor agonist)
5. others: amantadine, trihexyphenidyl

Question 16

what are the key features of levodopa

Answer 16

levodopa is the gold standard

contains L-dopa, the precursor of dopamine

typically a 2-in-1 preparation comprising of a peripheral DOPA decarboxylase inhibitor to
i) prevent systemic s/e resulting from excess DA
ii) also bc L-dopa can cross BBB so you inhibit peripheral DOPA decarboxylase means L-dopa stays as how it is in periphery and only converts into dopamine after it cross the BBB (reduces the amount of L-dopa wasted before it reaches brain)

eg. of peripheral DOPA decarboxylase inhibitor:
i) carbidopa
ii) benserazide

Question 17

what are the s/e of levodopa (short term and long term)

Answer 17

short term s/e:
i) N/V
ii) postural hypotension

long term s/e:
i) motor fluctuations
ii) dyskinesia (10% /yr)

Question 18

what is the moa of levodopa

Answer 18

levodopa contains L-dopa which is a dopamine precursor

Question 19

what is the moa of entacapone/ tolcapone

Answer 19

they are inhibitors of COMT to inhibit the conversion of dopamine/ L-dopa into inactive form by COMT

Question 20

what is the key feature of using COMTi (list eg. of COMTi)

Answer 20

COMTi like entacapone and tolcapone

only useful if used as adjunct therapy with levodopa or levodopa combi (w either carbidopa or benserazide which are peripheral DOPA decarboxylase inhibitors) to incr the amount of levodopa available to enter the brain thus can decr the dose and also incr duration of each dose which is beneficial for treating “wearing off” responses

only useful as adjunct bc while it can decr breakdown of dopamine, L-dopa is the one that crosses the BBB so decr breakdown of L-dopa is of significance

Question 21

what are the s/e of COMTi (list the eg. of COMTi)

Answer 21

COMTi are entacapone and tolcapone

s/e incl
i) incr abnormal movements (dyskinesia) *but assoc w taking COMTi alot milder than that assoc w taking levodopa
ii) liver dysfunction (for tolcapone)
iii) N/D
iv) urinary discoloration
v) visual hallucinations (bc excess DA can affect sensory func)
vi) daytime drowsiness, sleep disturbances (bc dopamine is a v impt sleep wake cycle regulator)

Question 22

what is the moa of selegiline and rasagiline

Answer 22

inhibit enzyme MAO-B thus interfering with dopamine breakdown, exhibits mild antiparkinsonism activity

Question 23

what is the indication for selegiline and rasagiline

Answer 23

symptomatic monotherapy for early stages of PD

Question 24

what are the s/e of MAOBi (list the eg. of MAOBi)

Answer 24

MAOBi include selegiline and rasagiline

s/e incl
i) heartburn, loss of appetite
ii) anxiety, palpitation, insomnia
iii) nightmares, visual hallucination

Question 25

what is the moa of pramipexole, pergolide and ropinirole

Answer 25

they are dopamine receptor agonist and act directly on dopamine receptors in the brain to reduce sx of PD, but antiparkinsonism effects not superior to levodopa (thus levodopa still gold standard) can help to prevent or delay motor sx

Question 26

what are the indications for pramipexole, pergolide and ropinirole

Answer 26

monotherapy or adjunct therapy esp for younger PD pts

Question 27

which agent is better suited for younger PD pts and why

Answer 27

dopamine receptor agonists (pramipexole, pergolide, ropinirole) is better suited for younger PD pts bc levodopa long term use assoc w dyskinesia

Question 28

what are the s/e of dopamine receptor agonists (list the eg. of dopamine receptor agonists)

Answer 28

dopamine receptor agonists are pramipexole, pergolide, ropinirole s/e incl i) N/V ii) postural hypotension iii) HA, dizziness iv) arrhythmia specifically for pergolide: since it is an ergot derivative, it has s/e like cardiac valve regurgitation, peritoneal fibrosis *not used in SG anymore specifically for pramipexole and ropinirole: sedation, somnolence and daytime sleepiness

Question 29

what is the moa of amantadine

Answer 29

amantadine is an antiviral agent found to have mild antiparkinsonian effect moa: i) enhance release of stored dopamine ii) inhibit presynaptic uptake of catecholamine iii) dopamine receptor agonist iv) NMDA receptor antagonist (anti-glutamate) (overactivation of glutamate receptors can lead to excitotoxicity bc neurons that become too excited causes an influx of cations which can activate endonucleases and proteases that causes neurons to die) is antidyskinetic

Question 30

what are the indications of amantadine

Answer 30

monotherapy or adjunct to levodopa (aka can decr dose of levodopa) to reduce dyskinesia in pts with PD who have motor fluctuations

Question 31

what are the s/e of amantadine

Answer 31

cognitive impairment (inability to conc), hallucinations, insomnia, nightmares, livedo reticularis (reddish blue swelling due to venule swelling and thromboses) *thus limited use

Question 32

what is the moa of trihexyphenidyl

Answer 32

an anticholinergic, binds to muscarinic receptor

Question 33

what are the advantages of trihexyphenidyl

Answer 33

may be effective in controlling tremor, peripherally acting agents may be useful in treating sialorrhea (excessive saliva flow)

Question 34

what are the s/e of trihexyphenidyl

Answer 34

trihexyphenidyl is an antimuscarinic thus think inhibition of parasympathetic nervous system (aka rest and digest) dry mouth, urinary retention, sedation, constipation, delirium, confusion, hallucination *esp in elderly

Question 35

what are the indications for trihexyphenidyl

Answer 35

monotherapy or adjunct to levodopa to treat tremors and stiffness in PD

Question 36

what is "dementia" and what are its characteristics

Answer 36

not a specific disease affects at least two domains of cognition eg. attention, language, memory, problem solving static or progressive can occur at any age need to occur for at least 6m (if not is considered delirium)

Question 37

what is AD pathologically characterised by and what other features might it have

Answer 37

1. senile plaques and neurofibrillary tangles (pathological characterisation) SENILE PLAQUES i) are aggregates of beta-amyloid (Abeta) peptide and are derived from cleavage of larger amyloid precursor protein (APP) via action of beta and gamma secretases (5%) ii) alternative processing pathway of APP via alpha and gamma secretases does not produce Abeta (95%) iii) plaques known to cause issues in AD bc inflamm in nature thus would activate neurons to produce alot of cytokines and result in chronic inflamm NEUROFIBRILLARY TANGLES i) are hyper-phosphorylated tau protein aggregates forming paired helical filaments (PHF) ii) tau is a tubulin assoc protein needed for microtubule stabilisation and intracellular transport (in AD, tau becomes abnormally phosphorylated eg. phosphorylated in too many sites thus no longer exerts its normal func and would start to dissociate and form its own aggregates PHF thus screwing up intracellular transport and neurons die) 2. also have brain atrophy and neuronal death (neurodegeneration) BRAIN ATROPHY in areas critical to cognition (extreme shrinkage of cerebral cortex (where pyramidal neurons are) and hippocampus (which is impt for learning and memory) and enlarged ventricles) NEURONAL DEATH i) involves neurons of multiple NT systems (eg. cholinergic, serotonergic, glutamatergic) ii) results in neurochemical deficits and alterations thus leading to cognitive decline and neuropsychiatric behaviors

Question 38

what is the hypothesis for PD

Answer 38

cholinergic hypothesis: i) central cholinergic neurons project to widespread areas of the cortex and play impt roles in learning and attentional processes (projections of the nucleus basalis) ii) degeneration in the central cholinergic system consistently reported in AD iii) thus cholinergic deficits may underlie clinical features of AD

Question 39

what are the cholinergic pathways

Answer 39

dorsal tegmental pathway and projections of the nucleus basalis

Question 40

what is the difference between the cholinergic and monoaminergic synapse (illustrate the cholinergic synapse)

Answer 40

degradation enzymes acetylcholinesterase (AChE) is located in the synaptic cleft vs monoamine oxidase degradation of dopamine occurs in the presynapse A from acetyl-CoA combine with Ch to form acetylcholine (ACh) in presynapse then stored in synaptic vesicle and released into synaptic cleft then either i) gets broken down within the synaptic cleft by AChE to and Ch is reuptaken into presynaptic terminal or ii) binds to ACh receptor on postsynaptic terminal (nicotinic and muscarinic types)

Question 41

what are the types of ACh receptors

Answer 41

muscarinic and nicotinic

Question 42

what are the components for clinical diagnosis of AD (also what are the adjunctive ones)

Answer 42

1. pt hx (pt and relative) 2. cognitive deficits (mini mental state exam (MSE), neuropsychological tests) 3. functional deficits in ADL 4. absence of alternative conditions 5. CSF biomarkers of Abeta and pTAU (but not routine) adjunct: neuroimagine (CT, MRI to exclude other brain pathologies) -> will see more and more empty spaces

Question 43

what are the goals in AD management

Answer 43

1. disease modifying (not presently possible) 2. slowing progression (decr cognitive decline and preserving func) 3. delay the need to institutionalise (managing behavioural problems of AD, support and education for family and caregiver) overall goal: improve QoL for both pt and caregiver

Question 44

what is the pharmacotx for AD (for mild, moderate and severe AD)

Answer 44

for mild to moderate: acetylcholinesterase inhibitors (AChEIs): donepezil, galantamine, rivastigmine) donepezil also indicated for severe AD for moderate to severe: non competitive NMDA receptor antagonist (memantine)

Question 45

what is the moa of AChEI

Answer 45

inhibit AChE so that there will be more ACh in the synaptic cleft but effects are only for symptomatic tx (modestly improves cognition, ADL and behavior)

Question 46

compare the differences between galantamine and rivastigmine (formulation, PK, moa)

Answer 46

formulation: rivastigmine has PO and transdermal patch; galantamine has PO PK: [half life] rivastigmine has shorter half life than galantamine [metab] galantamine is metabolised by liver (cyp450); rivastigmine metabolised primarily by kidney moa: galantamine may also act on nicotinic receptors in brain thus contribute to therapeutic effects

Question 47

what are the s/e of AChEIs (list the eg. of AChEIs)

Answer 47

donepezil, rivastigmine, galantamine are AChEIs common s/e arises due to cholinergic hyperactivation: N/V/D (aka too much rest and digest) less common s/e: muscle cramp, bradycardia, loss of appetite, incr gastric juice secretion

Question 48

what is the moa of memantine

Answer 48

non competitive NMDA receptor antagonist (possibly) blocks NMDA receptor mediated excitotoxicty (aka when neurons are overly excited)

Question 49

what are the s/e of memantine

Answer 49

hallucination, confusion, dizziness, HA

Question 50

what kind of sx do AD pts present with and how to manage these

Answer 50

behavioural and psychological sx of dementia (BPSD) or neuropsychiatric behaviours which incl i) depression ii) anxiety iii) agitation iv) aggression v) delusions vi) hallucination vii) overactivity can give relevant pharmacotx for the respective types of behaviours but bc typically elderly, also not cannot give too high doses and effectiveness unclear etc so maybe give try try