LIA CHAUHAN 240319 SAF G34 LEARNING OBJECTIVES PD neuropathology Identify the dopaminergic pathway in the brain which degenerates amp how the loss of DA triggers the motor clinical symptoms and explain which other neuronal pathways are affected in PD amp what is the underlying pathologi ID: 914276
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Slide1
MM Pharmacology Weekend
PARKINSONIAN DRUGS, ALZHEIMER’S & ANTIDEPRESSANTS
LIA CHAUHAN 24.03.19SAF G34
Slide2LEARNING OBJECTIVES
PD neuropathology: Identify the dopaminergic pathway in the brain which degenerates & how the loss of DA triggers the motor clinical symptoms; and explain which other neuronal pathways are affected in PD & what is the underlying pathological process.
PD clinical features: summarise the principle motor & non-motor clinical features of the disease. Anti-parkinsonian drugs:
summarise
& compare the MOA of drugs used to treat PD. Explain why they are used in conjunction & their limitations.
AD: identify the underlying pathology, the clinical symptoms & risk factors.
AD medication: summarise & compare the MOA of drugs used to treat AD.
Monoamine oxidases: evaluate the validity of the monoamine theory of depression. Anti-depressants: explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
Parkinson’s Disease:
Alzheimer’s Disease:
Depression:
Slide3PARKINSON’S DISEASE
Slide4PD – NEUROPATHOLOGY
L.O1: Identify the dopaminergic pathway in the brain which degenerate & how the loss of DA triggers the motor clinical symptoms; and explain which other neuronal pathways are affected in PD & what is the underlying pathological process.
4 main dopaminergic pathways:
1. Nigrostriatal
2. Mesolimbic
3.
Mesocortical4. Tuberoinfundibular
Substantia
nigra pars compacta (SNc) striatum (caudate) Involved in regulating movement
Ventral tegmental area (VTA) to the nucleus
accumbens
Reward pathway
Inhibition
-
ve
schizophrenia symptoms
Ventral tegmental area (VTA)
cerebrum
Involved in executive functioning & complex
behavioural
patterns Stimulation +ve schizophrenia symptoms
Arcuate nucleus
median eminence
Regulates prolactin release from the anterior pituitary
Slide5PD – NEUROPATHOLOGY
Dopaminergic
Signalling
:
DA removed by re-uptake transporters – DAT or NET
DA metabolized by 3 main enzymes:
MOA-A
MOA-B COMT L.O1: Identify the dopaminergic pathway in the brain which degenerate & how the loss of DA triggers the motor clinical symptoms; and explain which other neuronal pathways are affected in PD & what is the underlying pathological process.
Slide6PD – NEUROPATHOLOGY
Pathophysiology:
L.O1: Identify the dopaminergic pathway in the brain which degenerate & how the loss of DA triggers the motor clinical symptoms; and explain which other neuronal pathways are affected in PD & what is the underlying pathological process.
Neurofilaments & proteins (
ubiquitin & alpha-synuclein
) become abnormally phosphorylated
They aggregate within inclusions known as Lewy bodies/neurites Lewy bodies – cell body Lewy neurites – neuronal axon Lewy bodies/neurites lead to neurodegeneration of neurons within the nigrostriatal pathway motor dysfunction Severe neurodegeneration of the dopaminergic neurons within the nigrostriatal pathway
Slide7PD – CLINICAL FEATURES
L.O2:
Summarise the principle motor & non-motor clinical features of the disease.
Motor:
Non-motor:
Resting tremor
Bradykinesia Rigidity Postural instability
Anosmia Orthostatic hypotensionConstipation Erectile dysfunction Urinary incontinence Hypersalivation
Autonomic nervous system:
Neuropsychiatric:
Insomnia
Cognitive decline
Dementia
Depression
Anxiety
Irritability
Stooped, shuffling gait
Loss of arm swing
Hypomimia
Micrographia
4 cardinal signs:
Other signs:
Slide8PD – ANTI-PARKINSONIAN DRUGS
L.O3:
Summarise & compare the MOA of drugs used to treat PD. Explain why they are used in conjunction & their limitations.
2 Divisions of Anti-Parkinsonian Drugs:
1. Drugs that replace DA
2. Drugs that increase the activation of the DA receptors
1.
Levodopa (L-DOPA)
2.
DA receptor agonists
3.
MAO
B
inhibitors
Slide9PD – ANTI-PARKINSONIAN DRUGS
L-DOPA:
L.O3:
Summarise
& compare the MOA of drugs used to treat PD. Explain why they are used in conjunction & their limitations.
Given orally Gold-standard for PD General info:Why L-DOPA?
DA cannot be given directly – does not efficiently cross the BBB
MOA:
L-DOPA is the precursor of DA
L-DOPA can cross the BBB
L-DOPA is rapidly converted to DA by DOPA-D
Slide10PD – ANTI-PARKINSONIAN DRUGS
L.O3:
Summarise & compare the MOA of drugs used to treat PD. Explain why they are used in conjunction & their limitations.
L-DOPA:
Limitations:
Broken down by peripheral DOPA-D
Poor efficacy – low levels of DOPA-D reach the brain
Side effects – high levels of peripheral DA stimulate the chemoreceptor trigger zone (CTZ) nausea & vomiting Long-term side effectsDyskinesias’On-off effects’ Efficacy reduces with time
Slide11PD – ANTI-PARKINSONIAN DRUGS
L-DOPA:
L.O3:
Summarise
& compare the MOA of drugs used to treat PD. Explain why they are used in conjunction & their limitations.
Adjuncts:
DOPA-D inhibitorsExamples – Carbidopa, Benserazide MOA – inhibit peripheral DOPA-D only (cannot cross the BBB) Reduce the required dosage of L-DOPA COMT inhibitorsExamples – Entacapone, Tolcapone MOA – increase levels of L-DOPA reaching the brain by inhibiting peripheral metabolism Reduce ‘on-off’ effects
Slide12PD – ANTI-PARKINSONIAN DRUGS
DA Receptor Agonists:
L.O3:
Summarise
& compare the MOA of drugs used to treat PD. Explain why they are used in conjunction & their limitations.
MOA:
Increase the activation of the DA receptors D2 receptor agonist examples:
Ergot derivatives:
Bromocriptine, Pergolide
Non-ergot derivatives –
Ropinirole,
Rotigotine
Limitations
Ergot derivatives are associated with cardiac fibrosis
valvulopathies
Not as effective as L-DOPA
Slide13PD – ANTI-PARKINSONIAN DRUGS
MAO-B Inhibitors:
MOA:
Inhibit MAO-B and therefore reduce metabolism of DA
Increased DA availability within the synapse
General info:
Examples –
Selegiline,
Rasagiline
Generally used as adjuncts alongside L-DOPA
Can be used as monotherapy to increase time until L-DOPA is required
L.O3:
Summarise
& compare the MOA of drugs used to treat PD. Explain why they are used in conjunction & their limitations.
Slide14PD – ANTI-PARKINSONIAN DRUGS
L.O3:
Summarise & compare the MOA of drugs used to treat PD. Explain why they are used in conjunction & their limitations.
Summary:
Drug
Category
Key PointsL-DOPADA replacement therapy Gold standard Converted to DA by DOPA-DGiven with adjuncts (DOPA-D inhibitor/COMT inhibitor)Long-term side effects of dyskinesias & ‘on-off’ effectsBromocriptine/PergolideIncrease activation of DA receptors D2 receptor agonists Associated with cardiac fibrosis Ropinirole/
RotigotineIncrease activation of DA receptors D2 receptor agonists Selegiline/RasagilineIncrease activation of DA receptors Inhibit MOA-B enzyme Generally used as adjuncts but can be given as monotherapy
Slide15PD – SBA
1. Parkinson’s Disease results from a loss of neurons within the substantia
nigra
. Where do these project to?
Cortex
Thalamus
Hypothalamus
Striatum Nucleus accumbens
Slide16PD – SBA
2. Which of the following anti-parkinsonian drugs is associated with cardiac fibrosis?
Ropinirole
Levodopa
Bromocriptine
Selegiline
Rotigotine
Slide17PD – SBA
3. Which of the following motor signs are one of the 4 cardinal signs observed in Parkinson’s Disease?
Expressionless face
Rigidity
Loss of arm swing
Shuffling gait
Small writing
Slide18PD – SAQ
4. With the following anti-parkinsonian drugs, write down whether they act peripherally or centrally & their main mechanism of action – Carbidopa,
Entacapone
, Bromocriptine, Ropinirole.
Slide19PD – SAQ
5. Why is it that Dopamine antagonists can cause
hyperprolactinaemia
?
Slide20ALZHEIMER’S DISEASE
Slide21AD – BACKGROUND
L.O4: Identify the underlying pathology, the clinical symptoms & risk factors.
Epidemiology:
Most common form of dementia
Huge discrepancy between cost of AD on the NHS and research investment
Leading cause of death in the UK
AD can be divided into 2 forms: Sporadic95% of cases Sporadic mutations + environmental factors Key risk factor gene involved in increasing risk of AD = ApoE Familial (FAD) <5% of cases Specific mutations = the cause Pre-senile AD (<65 yrs)
Slide22AD – PRESENTATION
L.O4: Identify the underlying pathology, the clinical symptoms & risk factors.
Risk Factors:
AGE
Head injury
Down’s Syndrome
Obesity Smoking Clinical Symptoms:
Memory loss (recent info) Disorientation
Confusion Language problems Personality changes Poor judgement
Slide23AD – NEUROPATHOLOGY
L.O4: Identify the underlying pathology, the clinical symptoms & risk factors.
1. Amyloid Hypothesis
Protein known as
APP
resides within the brain
2 pathways in which it is broken down: Non-amyloidogenic Amyloidogenic Non-amyloidogenic: Normal Alpha-secretase & gamma-secretaseAmyloidogenic: Abnormal & increased in AD Beta-secretase & gamma-secretase Leads to production of amyloid-beta (A) A aggregates & deposits on neurons neurodegeneration
Slide24AD – NEUROPATHOLOGY
L.O4: Identify the underlying pathology, the clinical symptoms & risk factors.
2. Tau Hypothesis
Tau is a soluble protein that normally stabilizes microtubules (part of the neuronal cytoskeleton)
In AD tau becomes
hyperphosphorylated
and disassociates from the microtubules microtubule instability Hyperphosphorylated tau is insoluble and so aggregates into NFTs within the neurons (toxic) The microtubule instability + neurotoxicity neurodegeneration
Slide25AD – NEUROPATHOLOGY
L.O4: Identify the underlying pathology, the clinical symptoms & risk factors.
3. Inflammation Hypothesis
Microglia are a type of glial cell within the CNS
They are specialized immune cells – act like macrophages to mop up pathogens
In AD, the microglia:
Release more inflammatory mediators & cytotoxic proteins Phagocytose more Release fewer neuroprotective molecules This all leads to increased inflammation within the brain of AD patients
Slide26AD – DRUGS
L.O5:
Summarise & compare the MOA of drugs used to treat AD.
Currently licensed drugs - Anticholinesterases:
1. Donepezil
2. Rivastigmine
3. Galantamine
Reversible
Long plasma half-life (once daily) Most commonly used
Pseudo-reversible
Inhibits acetylcholinesterase &
butyrylcholinesterase
(SEs)
Short oral half-life (twice daily)
Transdermal patch formulation available
Reversible
Short half-life
Less potent inhibitor of acetylcholinesterase
Also acts as an alpha-7
nAChR
agonist
Slide27AD – DRUGS
L.O5:
Summarise & compare the MOA of drugs used to treat AD.
Currently licensed drugs - Memantine:
4. Memantine
Use-dependent, non-competitive NMDA receptor blocker
Has low affinity for the NMDA receptor (therefore works best when there are high levels of glutamate activity)
Long plasma half-life (70 hrs) Used for moderate-severe AD only
Slide28AD – DRUGS
L.O5:
Summarise & compare the MOA of drugs used to treat AD.
Drugs that have been trialed:
1. Gamma-secretase inhibitors
2. A-beta antibodies
3. Tau inhibitors
Work to reduce production of A-beta within the brain
Examples: Tarenflurbil binds to APP and reduces gamma-secretase mediated cleavage Semagacestat binds directly to gamma-secretase to inhibit its action
Work to clear A-beta from the brain
Examples:
Bapineuzumab &
Solanezumab
– humanized antibodies, unsuccessful
Aducanumab
– promising in early trials, potential future therapy
Vaccines also looking promising
Work to reduce the phosphorylation of tau
Example:
Methylene blue
– used in the lab as a stain, licensed for
methaemoglobinaemia, currently in Phase III trials
Slide29AD – SBA
1. Which of the following drugs is a gamma-secretase inhibitor?
Tarenflurbil
Aducanumab
Memantine
Donepezil
Rivastigmine
Slide30AD – SBA
2. Tau is a protein that is hypothesized to be involved in the pathogenesis of Alzheimer’s Disease. Where is tau normally located?
Within the brain parenchyma
Within neuronal cell bodies
Bound to plasma proteins
Bound to microtubules
Within microglial cells
Slide31DEPRESSION
Slide32DEPRESSION – BACKGROUND
L.O6: Monoamine oxidases: evaluate the validity of the monoamine theory of depression.
Definition:
Depression is a type of
affective disorder
It is diagnosed via a patient having a specific set of symptoms
Symptoms:
Anhedonia
Low self-esteem Overeating/undereating Gaining/losing weight Suicidal thoughts Loss of libido Insomnia/hypersomnia
Slide33DEPRESSION – BACKGROUND
L.O6: Monoamine oxidases: evaluate the validity of the monoamine theory of depression.
Unipolar:
Mood goes in the same direction
Onset in adults
Can be reactive or endogenous:
Reactive (75%) – in response to life events, not inherited Endogenous (25%) – not related to life events, tends to run in the family Classification:Bipolar:
Mood swings between depression and mania
Onset in adolescents
Hereditary
Less common
Slide34DEPRESSION – BACKGROUND
L.O6: Monoamine oxidases: evaluate the validity of the monoamine theory of depression.
Monoamines = a group of neurotransmitters that have a particular structure
Examples = Noradrenaline, Adrenaline, Dopamine, Serotonin
Depression is caused by a
deficit of monoamine neurotransmitters within the CNS (mania is when there is an excess)Drugs that increase monoamine signaling have been shown to improve depressive symptoms = strong pharmacological evidence Not everyone with depression has low levels of monoamines = inconsistent biochemical evidence
Monoamine Theory of Depression:
Slide35DEPRESSION – BACKGROUND
L.O6: Monoamine oxidases: evaluate the validity of the monoamine theory of depression.
Monoamine Theory of Depression:
Slide36DEPRESSION – BACKGROUND
L.O6: Monoamine oxidases: evaluate the validity of the monoamine theory of depression.
Something that doesn’t make sense:
Antidepressants have a
delayed onset of action
(2-3 weeks) however they instantly cause a rise in monoamines Reasoning behind this may be: Down-regulation of alpha-2, beta and 5-HT receptors has been observed in those on antidepressants May indicate that the antidepressant effect of these drugs is due to adaptive changes in receptor levels (which may take 2-3 weeks) Other theories of depression: High cortisol (stress) Damage to the hippocampus
Monoamine Theory of Depression:
Slide37DEPRESSION – BACKGROUND
L.O6: Monoamine oxidases: evaluate the validity of the monoamine theory of depression.
Anti-depressant Therapies:
Drug
Mechanism of Action
TCAsBlocks NA & 5-HT reuptakeMAO inhibitorsInhibits breakdown and therefore increases stores of NA & 5-HT Electroconvulsive therapy Increases CNS responses to NA & 5-HT DrugMechanism of Action Methyldopa
Inhibits NA synthesisElectroconvulsive therapy Increases CNS responses to NA & 5-HT ReserpineInhibits NA and 5-HT storageAlpha-MethyltyrosineInhibits NA synthesis Improve mood
Worsenmood
Slide38DEPRESSION – DRUGS
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
Example =
Amitriptyline
1. Tricyclic Antidepressants:
MOA:
Block monoamine transporter proteins
more monoamines within the synapse
SERT (serotonin transporter) NET (noradrenaline transporter) Other receptor actions: Alpha-2 adrenoceptor, mAChR, Histamine receptors, 5-HT receptor Delayed down—regulation of beta-adrenoceptors & 5-HT2 receptors (adaptive changes)
Slide39DEPRESSION – DRUGS
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
1. Tricyclic Antidepressants:
Side effects:
Oral drug
Rapidly absorbed
Highly plasma-protein bound (90-95%) Hepatic metabolism can produce active metabolites renally excreted as glucuronide conjugates Long plasma half life: 10-20 hrs Pharmacokinetics:
Therapeutic doses:
Dry mouth, constipation, bladder dysfunction
Postural hypotension
Sedation
Overdose:
CNS excitement, delirium, seizures, respiratory depression
Cardiac arrhythmias sudden death
Slide40DEPRESSION – DRUGS
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
1. Tricyclic Antidepressants:
Aspirin and phenytoin are also highly plasma protein bound displace TCAs high levels of TCA in plasma side effects
Neuroleptics & oral contraceptive pills utilize the same liver enzymes as TCAs to be metabolized slow TCA metabolism high levels of TCA in plasma side effects
TCAs potentiate CNS depressants (e.g. alcohol)
TCAs can affect anti-hypertensive drugs (BP should be monitored regularly) Drug Interactions:
Slide41DEPRESSION – DRUGS
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
Example =
Phenelzine, Moclobemide
2. Monoamine Oxidase Inhibitors:
MOA:
Prevent the breakdown of monoamines
more monoamines within the synapse
MAO-A breaks down NA & 5-HT MAO-B breaks down DA Most MAOIs are irreversible long duration of action Delayed down-regulation of beta-adrenoceptors & 5-HT2 receptors (adaptive changes)
Slide42DEPRESSION – DRUGS
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
2. Monoamine Oxidase Inhibitors:
Side effects:
Oral drug
Rapidly absorbed
Short plasma half life Long duration of action due to irreversible inhibition Pharmacokinetics:
Dry mouth, constipation, bladder dysfunction (less so than TCAs)
Postural hypotension
Sedation
Weight gain
Hepatotoxicity (contraindicated in liver disease)
Slide43DEPRESSION – DRUGS
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
2. Monoamine Oxidase Inhibitors:
Cheese reaction:
Tyramine is found in food (e.g. cheese, red wine)
It induces the release of NA from nerve terminals
This excess NA is normally broken down by MAO enzymes When taking MAO inhibitors more NA within the synapse hypertensive crisis Headache Raised ICP Haemorrhage MAOIs + TCAs hypertensionMAOIs + pethidine hyperpyrexia, restlessness, coma & hypotension Drug Interactions:
Slide44DEPRESSION – DRUGS
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
Example =
Fluoxetine (Prozac)
3. Selective Serotonin Re-uptake Inhibitors:
MOA:
Selectively inhibit the re-uptake of serotonin
more serotonin within the synapse
Less effective in severe depression Safer in overdose
Oral drug
Average half-life (18-24
hrs
)
Delayed onset of action
Pharmacokinetics:
Side effects:
If co-administered with TCAs/MAOIs toxicity
Nausea,
diarrhoea
, insomnia, loss of libido
Slide45DEPRESSION – DRUGS
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
Venlafaxine:
Dose-dependent reuptake inhibitor
5-HT>NA>DA
2nd line treatment for severe depression
4. Others:
Mirtazapine:Alpha-2 receptor antagonistIncreases the release of NA & 5-HT Useful for SSRI intolerant patients
Slide46DEPRESSION – Drugs
Summary:
L.O7: Explain the MOA of clinically useful anti-depressant drugs & how this contributes to efficacy & side effects. Identify proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.
Drug Class
MOA
ExampleTCAs Block monoamine transporter proteins Amitriptyline MAOIs Inhibit the metabolism of monoamines by MAO enzymes PhenelzineMoclobemideSSRIsSelectively inhibit the re-uptake of serotonin Fluoxetine
Slide47DEPRESSION – SBA
1. Which of the following drugs is an example of a tricyclic antidepressant?
Venlafaxine
Prozac
Amitriptyline
Fluoxetine
Phenelzine
Slide48DEPRESSION – SBA
2. Which of the following statements is true of antidepressant drugs?
MAOIs have a long plasma half-life
The effect of antidepressants are felt after 24
hrs
SSRIs are very effective in severe depression
MAOIs can only be given as subcutaneous injections
TCAs are highly plasma protein bound
Slide49DEPRESSION – SAQ
3. Explain why certain foods like cheese shouldn’t be consumed alongside MAOIs?
Slide50Thank you!
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