Answer ALL questions. For each question, there is ONE correct answer. Use the answer grid provided for ALL your answers.

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1 UNIVERSITY OF EAST ANGLIA School of Pharmacy Main Series UG Examination CENTRAL NERVOUS SYSTEM PHA-7001B Time allowed: 2 hours Part ONE Answer ALL questions. For each question, there is ONE correct answer. Use the answer grid provided for ALL your answers. Part TWO Answer TWO of the THREE questions. Use a SEPARATE answer book for EACH question in Part TWO. All questions have equal weighting. Answer ALL parts of each of the individual questions you select. The mark allocation for the paper is: Part ONE carries 50% of the total mark Part TWO carries 50% of the total mark This paper consists of 14 pages in total. The following is provided: Multiple choice answer grid. Dictionaries are not permitted in this examination. Notes are not permitted in this examination. Do not turn over until you are told to do so by the Invigilator. Do not take this question paper out of the examinations room. (PHA-7001B) Module Contact: Dr Julie Sanderson, PHA Copyright of the University of East Anglia Version 1

2 2 PART ONE SECTION A TYPE 1 MCQ Answer ALL questions. For each question there is ONE correct answer. Use the answer grid provided for ALL your answers. 1. What would you expect to be the consequence to a patient who has had a stroke which caused a lesion in Broca s area? Loss of movement in limbs on the right-hand side of the body Loss of movement of limbs on the left-hand side of the body Loss of understanding of spoken language Loss of coherence in speaking Loss of control of muscles involved in speaking 2. Which of the following is NOT associated with long-term potentiation (LTP)? Release of glutamate Activation of AMPA receptors Activation of NMDA receptors Increase in Ca 2+ in the post-synaptic cell Sustained hyperpolarization 3. Which of the following cellular systems combine to form a functional bloodbrain barrier? Cerebral microvascular endothelium, neuron, choroid plexus Fenestrated endothelium, astrocyte foot processes, pericyte Cerebral microvascular endothelium, astrocyte foot processes, pericyte Fenestrated endothelium, astrocyte foot processes, pericyte Neuron, pericyte and astrocyte foot processes. 4. Which of the following physicochemical drug parameters would be MOST LIKELY associated with low blood-brain barrier penetration? A low number of hydrogen bonding groups A polar surface area of 125 Å 2 An affinity for an amino acid uptake transporter A logpoctanol/water of 4.5 No affinity for the ABCB1 ATP-binding cassette transporter

3 3 5. Which of the following is an anti-parasitic drug that is efficiently effluxed by P-glycoprotein in the blood-brain barrier? Digoxin Ivermectin Loperamide Morphine Paracetamol 6. Which one of the following statements about protein misfolding is INCORRECT? The misfolded state does not perform the protein s usual physiological function The misfolded state is often thermodynamically less stable than the native conformation The misfolded state is stabilised by internal hydrogen bonding Some misfolded proteins can be corrected and return to the native state Misfolded proteins can aggregate to higher order structures 7. Mrs CM attends the memory clinic with her husband, who is increasingly concerned about her memory loss and personality changes. The psychiatrist suspects Alzheimer s disease but she is 43 years old with no other conditions or syndromes. Which of the following genetic status could be associated with the onset of Alzheimer s disease in Mrs CM? ApoE 2+3 ApoE 3+3 ApoE 4+4 S182 (Paisa) mutation Trisomy In Parkinson s disease, loss of dopaminergic neurons is associated predominantly with which one of the following pathways? The mesocortical pathway The mesolimbic pathway The nigrostriatal pathway The septahippocampal pathway The tuberohypophyseal pathway TURN OVER

4 4 9. Which one of the following is INCORRECT regarding absence seizures? Duration is typically 2-5 minutes First presentation is often in childhood They are characterised by unresponsiveness of the patient Recovery after a seizure is usually rapid They can occur many times per day 10. Nociceptive afferent neurons are classified on several features. Which one of the following is CORRECT? A-delta fibres have medium conduction velocity (15 m/s) A-beta fibres are associated with sharp immediate pain sensation C fibres are unmyelinated and have a slow conduction velocity (<2.5 m/s) C fibres have a fast conduction velocity (4-30 m/s) Only A-beta fibres detect mechanical stimuli 11. Morphine has the highest affinity at which one of the following opioid receptors? The delta ( ) receptor The kappa ( ) receptor The mu ( ) receptor The orphan receptor The sigma ( ) receptor 12. According to the Portoghese theory, pethidine binds to the opioid receptor through which of the following? The phenylalanine site and the glycine site The tyrosine site, the phenylalanine site and the glycine site The phenylalanine site only The glycine site only The phenylalanine and the tyrosine site

5 5 13. A 35-year-old man comes to the pharmacy with a prescription for methadone hydrochloride 20 mg once daily for maintenance therapy in the management of his opioid addiction. He is not taking any other medication. He asks for your advice about driving whilst taking methadone. What is the appropriate advice to give this man? Continue to drive as normal, methadone does not affect the ability to drive Do not drive whilst taking this medicine The dose of methadone is unlikely to affect driving, therefore continue to drive Only drive if his ability to drive is not impaired by methadone The police would only consider him unfit to drive whilst taking illicitly obtained methadone, therefore continue to drive 14. A patient has been prescribed MST 60 mg tablets bd. The patient takes no other medication. The doctor would like to know the appropriate dose of oral morphine 10 mg/5 ml to prescribe for breakthrough pain every 2-4 hours when required. Which of the following is the most appropriate dose of oral morphine 10 mg/5 ml to prescribe for breakthrough pain in this patient? 2.5 ml 5 ml 10 ml 15 ml 20 ml 15. Glaucoma is defined as an optic neuropathy. Which classes of retinal neurons undergo degeneration in glaucoma? Amacrine cells Bipolar cells Horizontal cells Photoreceptors Retinal ganglion cells 16. Drug permeation across cornea is highly restricted when administered topically. Which of the following retards paracellular drug permeation from the tear film into intercellular spaces of the epithelium as well as inner layers of the cornea? The lipoidal nature of the corneal epithelium The presence of collagen fibrils in the stroma The highly hydrated structure of stroma The ribbon-like tight junctional complexes of superficial corneal epithelium The hexagonal-shaped corneal endothelium cells TURN OVER

6 6 17. Which of the following are inhalation anaesthetics? Etomidate and Thiopental Halothane and Sevoflurane Ketamine and Propofol Nitrous oxide and Ketamine Propofol and Thiopental

7 7 SECTION B EXTENDED MATCHING MCQ Answer ALL questions. For each question there is ONE correct answer. Use the answer grid provided for ALL your answers. CNS Functional Anatomy (F) (G) Brain stem Cerebellum Cerebrum Hippocampus Hypothalamus Medulla Oblongata Thalamus For each of the following statements, select the corresponding region of the brain from the list above. Each option may be used once, more than once, or not at all. 18. Long-term potentiation is associated with memory in this area of the brain 19. The major homeostatic control centre of the brain 20. The region containing centres for non-vital reflexes Neurotransmitters (F) (G) Acetylcholine Dopamine γ-aminobutyric acid (GABA) Glutamate Glycine Nitric oxide Noradrenaline For each of the following statements, select the corresponding neurotransmitter from the list above. Each option may be used once, more than once, or not at all. 21. The main excitatory neurotransmitter in the central nervous system 22. A neurotransmitter acting at ligand-gated Cl - channels that are potentiated by benzodiazepines. TURN OVER

8 8 Epilepsy (F) (G) Carbamazepine Ethosuxamide Gabapentin Midazolam Sodium valproate Tiababine Vigabatrin For each of the following statements, select the most appropriate anti-epileptic drug from the list above. Each option may be used once, more than once, or not at all. 23. Ms DP is concerned that the medication she takes for epilepsy has been recently reported in mainstream media due to causing congenital malformations (MCMs) including neural tube defects. What is she most likely to be taking? 24. Ms WN stabilised on a new antiepileptic. She normally takes Microgynon (combined oral contraceptive) but has been informed that her new antiepileptic will reduce the effectiveness of her contraception and a new strategy including a barrier method will need to be devised. What is she most likely to have been stabilised on for her epilepsy? 25. An ambulance is called for Mr UI who is in status epilepticus. What would be the most appropriate drug for the paramedic to use to try to terminate the seizure? 26. Mr PB has been recently started on a new medication for his epilepsy after sodium valproate failed control his seizures. He is now complaining of an itchy body wide rash. What drug is he most likely to be taking?

9 9 Epilepsy For each of the following statements, select the most appropriate anti-epileptic drug from the list above. Each option may be used once, more than once, or not at all. 27. A drug that needs metabolic conversion to the active species. 28. A drug that is an amino acid. TURN OVER

10 10 Analgesics (F) (G) (H) Aspirin 75 mg dispersible tablet Aspirin 300 mg tablets Co-codamol 8/500 effervescent tablets Dihydrocodeine/paracetamol 7.46/500 mg tablets Ibuprofen 400 mg tablets Ibuprofen 100 mg/5 ml suspension Naproxen 250 mg tablets Paracetamol 250 mg/5 ml suspension Select from the above list the most suitable analgesic for the patient described. The patients have presented in your pharmacy to purchase analgesia. 29. A 4-year-old boy who has no long-term medical conditions has sprained his ankle earlier in the day and is experiencing mild pain. An ice pack was used immediately after the injury and the ankle is slightly swollen. The boy is allergic to penicillin. 30. A 35-year-old woman has a painful ankle after spraining it playing tennis. She takes the following medication: Citalopram 20 mg tablets for depression Zopiclone 3.75 mg tablets for insomnia She is known to be a poor metaboliser of codeine.

11 11 PART TWO Answer TWO of the THREE questions. Use a SEPARATE answer book for EACH question. 31. Answer ALL parts (a) to (e). (a) The drug memantine is an NMDA antagonist. Explain the difference between a NMDA inverse agonist and an antagonist, and the advantage of using an antagonist. [15%] (b) The major metabolite of memantine is the alcohol below. Explain how this metabolism occurs, give a mechanism with chemical diagrams, and explain the effect of metabolism on drug action. [15%] (c) Suggest the major pathway of Phase II metabolism of memantine. [10%] Question 31 continues... TURN OVER

12 12...question 31 continued. (d) Memantine is similar in structure to the simpler amantadine, an antiviral drug. A Cochrane review did not find sufficient evidence for the benefits of using amantadine in Alzheimer s disease. Explain how the structural changes in memantine leads to a superior drug compared to amantadine. [10%] (e) Memantine (brand name Ebixa ) is licensed for the treatment of Alzheimer s disease-related dementia, where it has been shown to marginally improve cognitive symptoms. Discussing its pharmacological profile, the pathophysiological changes and behavioural and cognitive disturbances that are characteristic of the disease, in what ways might memantine act to treat Alzheimer s disease and its symptoms? [50%]

13 Answer ALL parts (a) to (e). (a) With the aid of chemical structures, describe the reaction catalysed by the enzyme catechol O-methyltransferase (COMT), and explain why COMT inhibition is important in the treatment of Parkinson s disease. [15%] (b) Entacapone and tolcapone are clinically used COMT inhibitors. Predict which of these drugs can cross the blood-brain barrier, with a reason for your choice. [10%] (c) In tolcapone, the two phenolic groups have pka values of 4.5 and Which phenol is more acidic, and why is there a large difference in acidity compared to the other phenolic group? [10%] (d) Tolcapone has a poorer safety profile than entacapone and has been withdrawn in some countries due to hepatotoxicity. Predict the major phase I and phase II metabolites formed from tolcapone, and suggest which of these might be responsible for toxicity. [15%] (e) In addition to breakdown by COMT, there are other significant challenges associated with treating a patient with Parkinson s disease using L-DOPA and these have led to the development of combined preparations and various formulations. Describe the challenges and how they can be overcome when designing treatment regimes for patients with Parkinson s disease that rely on L-DOPA, using examples of licensed medicines where appropriate. [50%] TURN OVER

14 Answer BOTH parts. (a) Critique the three fundamental theories underlying migraine pathophysiology and discuss the evidence for the role that 5-hydroxytryptamine (5-HT) has in its pathogenesis. [50%] (b) Mr AB has been suffering from migraine for a few years without treatment. His migraines start with a slow prodrome in which he suffers from classical aura before nausea and occasional vomiting. A unilateral pulsating headache then occurs which builds in intensity and can last up to 8 hours. He is left washed out for about a day afterwards. Devise a migraine management plan for Mr AB. [50%] END OF PAPER

15 UNIVERSITY OF EAST ANGLIA School of Pharmacy Main Series UG Examination Registration Number PHA-7001B CENTRAL NERVOUS SYSTEM Part ONE Answer Grid Question No. Answer Question No Answer Staff only No. correct: No. wrong: No. not attempted: Final: Signature and check signature: (PHA-7001B)

16 School of Pharmacy Examination Feedback Summary Module Name Central Nervous system Module Code PHA-7001B Year Overall marks Mean mark: Max. mark Min. mark: Grade distribution: 1 st Fail 15.4% 34.6% 41.0% 9.0% MCQ (Questions 1 to 30): Mean mark: 75.98% Max. mark : 93.33% Min. mark: 56.67% Comments: Overall students performed well in MCQs including scenario and extended matching questions Question: 1 No. of attempts 44 Comments: (a) Surprisingly, the difference between an inverse agonist and an antagonist was not clearly explained in many scripts. The potential advantages of not shutting down basal signalling were also not mentioned by everyone. (b) Many scripts did not identify the metabolism as an oxidation occurring through P450 enzymes. The majority predicted correctly that oxidation will reduce blood-brain barrier penetration. (c) Majority of scripts mentioned glucuronidation, which takes place on the amine and does not require prior hydroxylation. (d) Majority mentioned the increased blood-brain barrier penetration, and some also suggested potentially improved binding to the target. (e) The question is specific to memantine. A significant number of students still discussed acetylcholinesterase inhibitors eg. donepezil, rivastigmine. No credit possible for this. Many students struggled to link memantine s actions as an NMDA antagonist to the excitotoxic effects of increased intracellular Ca2+ and how the changes in AD brain affect NMDA-mediated Ca2+ influxes. Those that did, did it well. Some students spent a lot of time on the genetic basis of Aβ42 production despite the question not asking anything about this. No credit given here either. Question: 2 No. of attempts 72 Comments (a) A number of scripts focused on dopamine and the CNS, whereas the key point is the reduction of L-DOPA metabolism peripherally. (b) Answered well, most students recognized that tolcapone is more hydrophobic. (c) Some students correctly mentioned conjugation with the nitro group, which is only possible in the ortho-phenol making it more acidic. Some scripts compared entacapone with tolcapone, whereas the question specifically referred to the phenols in tolcapone. School of Pharmacy Summative exam feedback (V1) January 2013 Page 1 of 2

17 (d) The major Phase I metabolites are catechol methylation by COMT and methyl group oxidation by P450, while Phase II is predominantly glucuronidation. Only a minority noticed that only one of these pathways is specific to tolcapone and hence most likely responsible for the toxicity. Question: 3 No. of attempts 40 Comments: This question explore migraine pathophysiology (a) and then asked student to devise a management plan (b). Good students were able to describe the three main theories of migraine pathophysiology and make appropriate recognition of the role 5HT plays. Several students confused the theories and what is proposed in each one. In the management plan this patient had not received treatment before so there was no need to focus on prophylaxis but instead focus on acute management. Good students started with simple analgesia explaining dosages and when to use it. They then went on to explain the role of triptans and explain their appropriate use combining with an antiemetic. Lastly good students explained the need for a migraine diary and the importance of self-management and prevention/awareness where possible. Top students explore the rationale for different formulations and dosages of each product in this patient. Several students recommended Migralieve that is not recommended as it includes an ineffective dose of codeine. It was important to link any recommendation to this explicit patient and justify why. Question: 4 Comments: Question: 5 Comments: No. of attempts No. of attempts School of Pharmacy Summative exam feedback (V1) January 2013 Page 2 of 2