Pharmacology

Question 1

Which TCA is selective for Norepinephrine Transporters?

Answer 1

Desipramine

Question 2

State the MOA of MAOi

Answer 2

MAO inhibitors (MAOIs) increase biological availability of monoamines (Dopamine, Serotonin and Norepinephrine) by preventing their degradation.

Question 3

State the 2 major forms of MAO and what neurotransmitters they break down

Answer 3

MAO-A: Serotonin (mainly broken down by MAO-A), Dopamine, Norepinephrine

MAO-B: Dopamine

Question 4

ADRs of MAOi

Answer 4

1) Postural hypotension
2) Restlessness and insomnia (due to CNS stimulation)
3) Serotonin Syndrome (hyperexcitability, myoclonus, inc muscle tone, loss of consciousness)

Question 5

State the MOA of Cheese Reaction

Answer 5

Tyramine competes with norepinephrine for vesicular storage leading to increased NE release into the synapses causing sympathomimetic effect

Question 6

ADRs of TCAs (3 classes of ADR)

Answer 6

1) Sedation (from H1 antagonism)
2) Postural hypotension (from α adrenoceptor sympathetic block) and reflex tachycardia (not listed)
3) Constipation, dry mouth, urinary retention, blurred vision (from muscarinic receptor antagonism)

Question 7

What 2 receptors do most atypical antipsychotics block?

Answer 7

D2 and 5HT-2A

Question 8

MOA of most antipsychotics involve

Answer 8

Blocking of Dopamine receptors in the mesolimbic tract

Question 9

The extrapyrimidal pathway involves which parts of the brain?

Answer 9

Basal ganglia, Substantia nigra and Striatum

Question 10

Between D1,2,3,4, which one is the most culpable in causing EPSE?

Answer 10

D1

Question 11

State the 4 potential reasons why atypical antipsychotics produce less EPSE

Answer 11

o Potent 5-HT2A receptor antagonism vs. weak D2 antagonism -> lower EPS and higher efficacy against negative symptoms
 Clozapine, olanzapine

o High D3 to D2 antagonism ratio favours actions on the nucleus accumbens over the striatum (mostly D1, D2 present).
 Amisulpride

o High D4 to D2 antagonism ratio favours actions in the prefrontal cortex over the striatum.
 Clozapine

o High D2 to D1 antagonism ratio reduces impact of antagonism in the striatum (D1 is the worst in causing EPS)
 Amisulpride, risperidone
 A higher D2 to D1 antagonism ratio should confer less complete blockade of dopaminergic function in the striatum as D2 antagonism will increase dopamine release.

Question 12

State the MOA of TCAs

Answer 12

Inhibit the reuptake of Monoamines (Dopamine, NE, Serotonin), causing build up in the synaptic cleft

Question 13

State the monoamine theory of depression

Answer 13

Deficits in monoamine neurotransmitters
(noradrenaline, dopamine and 5 HT) cause depression.

Question 14

What are the general side effects of SSRI (7)

Answer 14

1) GI
2) Sexual dysfunction
3) Insomnia
4) Sedation
5) Bleeding risk
6) SIADH (and or hyponatremia) (esp for elderly)
7) Serotonin syndrome (hyperthermia, tremor, CV collapse)

Question 15

State the Schizo symptoms that Antipsychotics do not have much effect on

Answer 15

Negative symptoms (affective flattening aka no emotion, avolition aka no interest)

Question 16

State the receptor affinity of Amisulpride

Answer 16

selective D2/D3 antagonist (but recently also reported to have 5-HT7 antagonism)

Question 17

State the potential MOAs of treatment of neurodegenerative diseases (6)

Answer 17

1) Increase synthesis of neurotransmitter (NT) (e.g by inc amt of precursor)

2) Destroy enzymes that degrade NT

3) Inc release of NT from terminal button

4) Bind to autoreceptor and block their effect on inhibiting NT release

5) Block reuptake of NT

6) Bind to postsynaptic receptor and inc effect of NT

Question 18

Pathophysiology of Parkinsons

Answer 18

• Impaired clearing of abnormal/damaged intracellular proteins by ubiquitin-proteasomal system.
• Failure to clear toxic proteins lead to aggregation of aggresomes -> induce oxidative stress and molecular abnormalities -> Degeneration of dopaminergic neurons (more metabolically active -> more vulnerable) with Lewy body (a type of aggresome) inclusions in substantia nigra -> dysfunction of nigrostriatal pathway -> No release of inhibition that allows motor system to become active -> hypokinetic state

Question 19

State how the loss of dopaminergic input leads to motor symptoms for direct and indirect pathway

Answer 19

Direct pathway:
- Loss of dopaminergic input lead to hypoactivation of excitatory D1 receptor that weaken strialtal inhibition of GPi (Globus pallidus internal) -> Hypokinesia

Indirect pathway:
- Loss of dopaminergic input lead to hypoactivation of inhibitory D2 receptor that strengthens striatal inhibition of GPe (Globus pallidus external) -> Hypokinesia

Question 20

State MOA of COMT inhibitors

Answer 20

o Blocks COMT conversion of dopamine/ L-DOPA into an inactive form leading to:
- More levodopa being available to enter the brain (reduces required dose)
- Increases duration of each dose of Levodopa -> beneficial in treating “wearing off” responses

Question 21

List the names of COMT inhibitors

Answer 21

Entacapone, Tolcapone

Question 22

State ADR specific to both Pramipexole and Ropinirole (3)

Answer 22

Sedation, somnolence, daytime sleepiness

Question 23

State ADR specific to Pergolide (2)

Answer 23

Peritoneal fibrosis, cardiac valve regurgitation

Question 24

State the MOA of Amantadine (4)

Answer 24

o Enhance release of stored dopamine
o Inhibit presynaptic uptake of catecholamine
o Dopamine receptor agonist (Upregulates D2 receptors, ↑ sensitivity of D2 receptors)
o NMDA receptor antagonist (anti-glutamate)

Question 25

ADRs of Amantadine (7)

Answer 25

o Nausea
o light headed
o Cognitive impairment (inability to concentrate, confusion),
o hallucination,
o insomnia,
o nightmares
o Livedo reticularis (serious; Venule swelling due to thromboses leading to limb discolouration)

Question 26

State when Amantadine may be indicated in PD

Answer 26

o Given as adjunct to levodopa (may help to alleviate tardive dyskinesia of Levodopa by a little bit and reduce dose of Levodopa required)

Question 27

State the indication of anticholinergics in PD

Answer 27

o Anticholinergic agents have limited use. Typically used as adjunct to levodopa to treat tremors and stiffness in Parkinson’s disease

Question 28

State where the primary cholinergic pathway is

Answer 28

Nucleus Basalis

Question 29

State what is the secondary cholinergic pathway

Answer 29

Dorsal tegmental pathway

Question 30

State how the cholinergic synapse differs from the dopaminergic synapse

Answer 30

Cholinergic synapse differs from Monoaminergic synapse where breakdown of ACh occurs in the synaptic cleft whereas the breakdown of Dopamine via enzymes occurs inside the presynaptic neuron

Question 31

State the ADRs of Acetylcholinesterase inhibitors (AChEIs) (5)

Answer 31

1) N/V/D, Loss of appetite (most common)
2) Muscle cramp
3) Bradycardia
4) Increased gastric juice secretion

Question 32

State the ADR of Memantine (5)

Answer 32

Constipation, headaches (most common)

Hallucination, confusion, dizziness

Question 33

State MOA of Memantine

Answer 33

Non-competitive NMDA receptor antagonist

Question 34

MOA of acetylcholinesterase inhibitors

Answer 34

Inhibits Acetylcholinesterase from breaking down ACh in the synaptic cleft

Question 35

List the peripheral DOPA-decarboxylase inhibitors

Answer 35

Carbidopa, Benserazide

Question 36

Does Dopamine pass through the BBB?

Answer 36

No

Question 37

State what dopamine is broken down into and what enzymes break it down

Answer 37

Homovanilic acid

Broken down by COMT and MAOB in non-sequential manner

Question 38

State some non-pharmacological ways to manage PD (4)

Answer 38

1) Physiotherapy
- Stretching, transfers, posture,
- Walking (e.g Draw lines at home to guide them to walk)
- Includes mitigating strategies for freezing (E.g using light to trigger patient and allow them to walk again after freezing)

2) Occupational Therapy
- Mobility aids, home and
- Workplace safety

3) Speech & swallowing
4) Surgery

Question 39

What is the mechanism of action of SSRIs?

Answer 39

Selective inhibition of serotonin reuptake transporters (SERT)

Question 40

What is the mechanism of action of SNRIs?

Answer 40

Dual inhibition of serotonin (SERT) and norepinephrine (NET) reuptake transporters

Question 41

Dopamine blockade of which part of the brain causes hyperprolactinemia?

Answer 41

Anterior pituitary gland