PDDA 3 May 2010 Exam Question 1 a) Describe the mechanism of presynaptic inhibition.

[5 marks]

Inhibition of a stimulatory neuron before it synapses, by inhibiting Ca2+ entry and blocking downstream processes, preventing neurotransmitter release, and therefore preventing the neuron generating an excitatory postsynaptic potential. b) Give an example of how this mechanism is clinically relevant in the mechanism of drug action. [1 mark] SSRIs act by inhibiting the reuptake of serotonin after being released in synapses by blocking this 5-HT1 Receptor

Question 2 Describe the pathological mechanisms that underlie ischaemic and haemorrhagic strokes and how these result in impaired brain function. State two aetiological risk factors for each type of stroke. [6 marks] - Stroke results from occlusion of major brain artery/vein.

This can cause rupturing leading to a haemorrhage (blood leaks into brain tissue) and can lead to a full blown stroke. Affected regions of the brain are starved of oxygen leading to mass brain atrophy. Ischaemic stroke is due to a blockage, a clot stops blood supply to read of brain. Whereas a haemorrhage is a brust. Haemorrhage can be due to a head injury and bleeding disorders. Ischaemic stroke due to hyperlipidemia and Sickle cell anemia.

Question 3 a) State six symptoms of generalised anxiety disorder, two of which must be clearly identified as part of autonomic arousal. (Note: only the first six symptoms stated will be considered.) [3 marks] Motor tension Muscle tension, twitching and shaking, restlessness. Apprehension Feeling on edge,unable to cope, poor concentration, insomnia, irritability Autonomic over-activity: Light-headedness, sweating, tachycardia, dry mouth, epigastric discomfort b) Which class of drugs is recommended first line by NICE for the long term treatment of generalised anxiety disorder? Why does NICE recommend this class as first line? [3 marks] GAD: SSRIs: Paroxetine - Paroxetine has a licence for the treatment for GAD - As an SSRI is harmless in overdose. - Less side effects than 1st gen anti-depressants - Meant to be non-addictive Question 4 a) Describe what each of the following terms means: grandiose delusion, ideas of reference, thought insertion, olfactory hallucination. [4 marks]

Grandiosity Beliefs of exaggerated self importance, special powers or wealth Delusion (Ideas) of reference Belief that objects, events or people hold a special significance Thought Insertion Belief that somebody is placing thoughts into your mind

olfactory hallucination - is the smelling of odors that aren't really present

b) Which symptoms of schizophrenia are often considered to be the most significant in making a diagnosis? [2 marks]
Eye blink reflex Acoustic startle / pre-pulse inhibition Normal patients inhibit startle response to a noise stimulus when they have been pre-exposed to a less intense stimulus Schizophrenic patients do not habituate to startle stimuli

Question 5 a) What are the priorities in the symptom management of acute alcohol withdrawal? [2 marks] Minimise severity of withdrawal symptoms Achieve alcohol free state with maximum safety and minimum discomfort Reduction of withdrawal severity will also eliminate negative reinforcement seen with relief drinking Possibly leads to improved level of abstinence

b) Describe why benzodiazepines are particularly useful in the symptomatic management by giving reference to the neurotransmitter effects of alcohol. [4 marks]

Benefits of Benzodiazepines` Predominant pharmacological mechanism mediated via GABA neurotransmitter Effective at reducing anxiety symptoms Have an anticonvulsant effect
Question 6 a) Define what is meant by the term insomnia, what might be the causes? What are the common symptoms encountered? [10 marks] Insomnia is the the inability to sleep. Most common causes of insomnia are: Within mind states: anxiety, depression, worry, anger, grief, anticipation. Changes: moving house/ city/ country. Environment: noise, discomfort, time zone change. Pain-the most common cause Medical conditions: heart, breathing, stomach, digestive, blood pressure, arthritis, anorexia. Use of recreational drugs: nicotine, caffeine, heroin, cocaine, etc. Prescribing drug history: contraceptives, diuretics, slimming pills, beta-blockers, stimulants. Lesions of the VLPO (Ventrolateral Preoptic nucleus) induce insomnia due to the prevention of the inhibitory action mediated by the VLPO.

Symptoms: Tired during the day Frequent headaches, irritable or lack concentration Tired and not refreshed on waking Sleep better away from home Take longer than 30-40 minutes to fall asleep Wake repeatedly during the night Wake early and are unable to get back to sleep b) Outline the therapeutic management options of insomnia, include both drug and non-drug strategies. What are the limitations of drug therapy? [10 marks] Behavioural changes can aid and in some cases cure episodes of insomnia, these include: Changes in the environment e.g. bed, lights, etc. Changes in lifestyle e.g. exercise, establish a routine. Avoiding stimulants, e.g. caffeine. Hypnotic drug therapy: Benzodiazepines e.g. diazepam (long acting) and lorazepam (short acting, longer half life) Sedative antihistamines Z-drugs Zaleplon Zolpidem Zopiclone Limitations of drug therapy Long term use of Benzos lead to: Dependence (addiction) Tolerance, leading to a continual increase in dose or chronic consumption. Withdrawal syndrome Z-drugs are only licensed for 4 weeks maximum thus only a short term treatment. Drugs just try and mask the real cause of not sleeping. Thus, a bad long term solution to such a problem.

Question 7 Name three drugs that are effective in treating primary generalised tonic-clonic (grand mal) seizures. Describe their mechanism of action, pharmacokinetics, cautions and major side effects, and interaction effects with other anti-epileptic drugs. [20 marks] Valproate would be appropriate since it can be used in all types of seizures. Valproate works by reducing electrical excitability of cell membranes blockade of voltage-dependent sodium channels and thus decreasing excitability. Also, has other mechanisms:

(i) Weak inhibitor of enzymes that inactivate GABA, such as GABA transaminase = increase [GABA] thus more inhibition. (ii) May stimulate synthesis of GABA, = increase [GABA] thus more inhibition. (iii) May decrease GABA turnover, = increase [GABA] thus more inhibition. (iv) May block NMDA-mediated responses - Side effects include baldness, teratogenicity, weight gain and liver damage- liver function should be managed - Valproate has metabolic effects and increases plasma lamotrogine levels - There may be an increased risk of poly-cystic-ovary syndrome associated with valproate Carbamazepine can be used in Generalised Tonic-Clonic. - Derivative of tricyclic anti-depressants - Carbamazepine reduces electrical excitability of cell membranes blockade of voltagedependent sodium channels and thus decreasing excitability. - Fewer side-effects than phenytoin - Effective in many forms of epilepsy with the exception of absence epilepsy - Strong enzyme-inducing agent- many interactions with other drugs - REDUCES plasma concentration of clonazepam, lamotrigine, tiagabine, topirmate and valproate. - Side effects include sedation, ataxia, mental disturbances, mild generalised erythematous rash and water retention Lamotrigine can be used in Generalised Tonic-Clonic. - Mechanism of action: o Blocker of Na+ channels, thus lowering excitation in the brain. o Inhibits the release of glutamate (primary excitatory neurotransmitter) - Effective in treating absence epilepsy - Side effects include sedation, dizziness, ataxia and skin rashes (Stevens-Johnson syndrome, especially if used with valproate) - Cautions include close monitoring in the effect of skin rashes, consideration for withdrawal
Question 8 a) How is a diagnosis of bipolar disorder achieved according to the International Classification of Diseases-10, (ICD-10) criteria? [5 marks] Hypomanic or manic episodes in individuals who have had one or more previous affective episodes (depressive, hypomanic, manic, or mixed) should be coded as bipolar affective disorder A disorder characterized by two or more episodes in which the patient's mood and activity levels are significantly disturbed, this disturbance consisting on some occasions of an elevation of mood and increased energy and activity (hypomania or mania) and on others of a lowering of mood and decreased

energy and activity (depression). Repeated episodes of hypomania or mania only are classified as bipolar. There are two forms: Bipolar I: full blown episodes of mania Bipolar II: Episodes of hypomania b) Name 3 drugs listed in NICE guidelines for the long term treatment of bipolar disorder, and describe their individual pharmacological mechanism of action. [15 marks]

The treatment of bipolar disorder is based primarily on psychotropic medication to reduce the severity of symptoms, stabilise mood and prevent relapse. A patient who has four or more acute episodes in a year is defined as having rapid-cycling bipolar disorder. Thus, would be considered for the position of long term treatment. Focus is on optimising long-term treatment rather than on treating individual episodes and symptoms Mood stabilizers may be used like lithium and valproate or carbamazepine. Valproate is good for manic episodes. Valproate works by reducing electrical excitability of cell membranes blockade of voltage-dependent sodium channels and thus decreasing excitability. Also, has other mechanisms: (i) Weak inhibitor of enzymes that inactivate GABA, such as GABA transaminase = increase [GABA] thus more inhibition. (ii) May stimulate synthesis of GABA, = increase [GABA] thus more inhibition. (iii) May decrease GABA turnover, = increase [GABA] thus more inhibition. (iv) May block NMDA-mediated responses Lithium reduces frequency of cycling and smooths the extreme highs & lows of mood (most usually given in BPD 1) Specific mechanism of action evades us: - Li+ alters Na+ transport. - Inhibitory effect on second messenger systems (G-proteins) & - Reduces responsiveness to transmitters. Stabilizes neurons since it gets pumped in but not out, thus reducing excitability. - 10 days required to achieve therapeutic plasma levels - Uses for both prophylaxis & treatment of BPD - Lithium carbonate - Lithium citrate Carbamazepine is rated as effective as lithium in preventing relapses in BPD & treatment of acute mania (rapid cycling). Pharmacological Action:

- Inhibitory effects on second messenger systems (as Li+) - Also inhibits Ca 2+ influx through the NMDA & GABA-B receptors - Na+ channel mediated membrane stabilisation - Potentiation of 2adrenoceptors: Reduced release of NA Drugs used if treating acute mania with antipsychotics, olanzapine, quetiapine or risperidone should normally be used. Question 9 Mr BL is a 68 year old white male recently diagnosed with Parkinsons Disease and referred by his GP to a neurologist. The neurologist wishes to initiate a non-ergot derived dopamine receptor agonist, having decided against using levodopa this early in the treatment of his Parkinsons Disease. a) Which motor symptoms may be present in the early stages of Parkinsons Disease? [5 marks]
Classic triad: tremor, rigidity, bradykinesia, plus Rigidity + tremor = cogwheel Postural instability Mask like faces, fenestinant gait Seborrhoea Excess salivation

b) Name two ergot derived dopamine receptor agonist and two non-ergot derived dopamine receptor agonists. Why has the neurologist decided to use a non-ergot derived dopamine receptor agonists? What would need to be monitored prior to treatment had the neurologist chosen an ergot-derived dopamine receptor agonist? [5 marks]

Ergot bromocriptine, cabergoline, lisuride, pergolide

Non-ergot pramipexole, ropinirole, apomorphine Fibrotic reactions with ergot derived drugs: bromocriptine, cabergoline, lisuride, pergolide 2-6% risk of pulmonary, retroperitoneal and cardiac fibrosis

b) Give five other side effects, in addition to the side effect given in part b, which may be experienced by patients taking dopamine receptor agonists. [5 marks]
May be associated with Nausea/vomiting Postural hypotension Hallucinations Confusion Hallucinations Dyskinesias Reckless Behaviour /Gambling

c) If levodopa had been initiated at this stage of Parkinsons Disease which two effects may have developed as a result of the early levodopa therapy? Explain how these effects are caused by levodopa. [5 marks
After 5 years motor fluctuations (On-off effect) is present in 50% of patients taking levodopa

Hypokinesia(involuntary writhing movements). Majority of patients within 2 yrs of starting levodopa. May decrease levodopa dose but rigidity may return and rigidity may suddenly worsen
May last a few minutes to a few hours Off effect patient may suddenly freeze

Question 10 a) Describe the neuropathological mechanisms underlying the induction of Alzheimers disease? [10 marks]
Deposition of insoluble amyloid.. (APP) abundantly expressed in the membranes of many nerve and glia cells. Function for cell structure & cell-cell recognition. In normal life APP is produced and then secretase enzymes(alpha, beta and gamma) sever the chain and release the Apeptide (sAPP).into the extracellular space. In AD A accumulates to form hard insoluble plaques that cannot be broken down. In AD too much Ais produced or it is not being removed properly but accumulate in -amyloid plaques. As the plaques increase in size they appear to stimulate an automimmune inflammatory response. They may also interfere with synaptic function and the regulation of transmitter reuptake.. Excess extracellular transmitter due to impaired reuptake may generate excitotoxicity; eventually cells adjacent to the plaques die. Formation of neuritic plaques

Formation of tangles with hyperphosphorylated tau protein Inflammatory response Cholinergic deficit

b) Which neurotransmitter system is most affected in Alzheimers disease, (include in your answer details of relevant brain circuitry)? [5 marks]
Cholinergic neurones are particularly badly affected in AD. They die sooner than neurones using other transmitters. Pontinecholinergic neurones appear to be involved in maintaining cortical arousal during waking and REM sleep. There are two other main cholinergic nuclei: in the septal nucleiand above the hypothalamus in the basal nucleu

c) How has the knowledge that this transmitter is depleted led to current drug therapy? [5 marks]
Symptomatic treatment with Acetylcholinesteraseinhibitors Tacrine(Cognex), donepezil (Aricept), rivastigmine, galantamine. They irreversibly bind with & inactivate the enzyme cholinesterase which breaks down acetylcholine. They potentiate the duration of action of ACh in the cholinergic synapse

Question 11 a) Name the three main opioid receptors and describe, for each, its distribution in the body and its physiological role(s). [5 marks] Mu m Responsible for most analgesic effects of opioids Also responsible for key side effects Respiratory depression, euphoria, sedation & dependence Delta d Greater importance in periphery, little analgesic effect Kappa k Contribute to analgesia at spinal level Produce relatively few side effects, some sedation and dysphoria k receptors do not contribute to dependence Some analgesics are relatively k selective

b) Buprenorphine can be described as a partial opioid agonist. Explain what is meant by this term and how buprenorphines pharmacological action links to its therapeutic and adverse effects. [15 marks]
Partial agonist = a compound which possesses affinity for a receptor, but unlike a full agonist, will elicit only a small degree of the pharmacological response peculiar to the nature of the receptor involved, even if a high proportion of receptors are occupied by the compound.

Buprenorphine Dose dependent, inverse relationship between buprenorphine and opiate receptor availability

2mg dose~40% occupancy. 16mg dose~90% occupancy

Partial agonist at the mu opioid receptor and antagonist at the kappa opioid receptor In low doses acts as a mu receptor agonist, but at higher doses this agonist effect plateaus

Advantages of buprenorphine include milder withdrawal symptoms following abrupt cessation and lower risk of overdose or abuse Advantages include fewer sedative side effects and greater blockade of opiate receptors c.f. low dose methadone treatment (some pts may see this as disadvantage) Disadvantages are possible risk of liver dysfunction and difficulties with observed / supervised administration Can be administered with naloxone further reduce abuse potential or risk of overdose