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Year 2: LCRS > Pharmacology & Therapeutics 3 > Flashcards

Pharmacology & Therapeutics 3 Flashcards

1
Q

Where is GABA distributed in the brain in high concentrations?

A
  • Cerebral cortex, cerebellum, hippocampus, corpus striatum (basal ganglia) and the hypothalamus
  • Dorsal horn of the spinal cord
  • Little in the PNS
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2
Q

What types of neurons utilise GABA?

A

30% of synapses have GABA receptors on their surfaces

  • Short inhibitory interneurones
  • Some longer tracts e.g. striato-nigral and cerebellar
  • Means that it has a widespread inhibitory action in the CNS
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3
Q

What are the functions of GABA?

A

1) Motor activity- reflected in high concentrations of GABA in the cortex, cerebellum and spinal cord
2) Extrapyramidal activity- reflected by concentrations in basal ganglia
3) Emotional behaviour- reflected by presence in limbic system e.g. hippocampus and amygdala
4) Endocrine function- reflected by high concentration in hypothalamus

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4
Q

What is GABA synthesised from?

A 
Glutamate decarboxylase (GAD)
- It is specific for GABAergic neurons.
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5
Q

How is GABA synthesised?

A
  • Glutamate decarboxylase originates from the Krebs cycle
  • Alpha-oxoglutarate is converted into glutamate by GABA transaminase (GABA-T) which is converted into GABA
  • GABA is broken down to succinic semialdehyde, and then by SSDH to succinate to return to the Krebs cycle- this is known as the GABA shunt
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6
Q

How is GABA stored and released?

A
  • Stored in GABAergic vesicles, which contain high affinity transporters in their membranes
  • They pick up GABA from the cytoplasm and transport it into the vesicle
  • With arrival of the action potential in the nerve terminal, depolarisation opens voltage sensitive calcium channels. Calcium influx stimulates exocytotic release of GABA
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7
Q

What are the GABA receptors?

A

GABA-A: type 1 ionotropic, linked to chloride channels

GABA-B: type 2 metabotropic: G-protein coupled

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8
Q

How is GABA inactivated?

A
  • Primarily by reuptake into neurons and surrounding glial cells
  • This reuptake is Na+ dependent, ATP dependent and therefore is saturable
  • Once reuptake has occurs, metabolism occurs
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9
Q

How is GABA metabolised?

A
  • Broken down by GABA transaminase to succinic semialdehyde. Then again by succinic semialdehyde dehydrogenase to succinic which acid which returns to the Krebs Cycle
  • The enzymes are mitochrondiral
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10
Q

Give examples of inhibitors of GABA metabolism

A

Sodium vaproate (epilim)
Vigabatrin (sabril)
- Inhibitors result in large increase in brain concentrations of GABA. This is associated with an enhancement of GABA-mediated inhibition

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11
Q

What are the properties of GABA-A receptors?

A
  • Pentameric: 2α12β2γ2 - 5 subunits
  • Mostly postsynaptic
  • Mode of action: Conformational change in the subunits- Opening of Cl channels. Results in increase in Cl- influx into the post-synaptic neurone which leads to hyperpolarisation and inhibition of post-synaptic firing.
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12
Q

What is an agonist of GABA-A receptors?

A

GABA and muscimol (selective GABA-A agonist

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13
Q

What are antagonists of GABA-A receptors?

A
  • Bicuculline (competitive inhibitor)
  • Picrotoxin (non-competitive inhibitor)
  • Both are convulsants, tending to generate seizures by reducing GABA transmission. Therefore not used therapeutically
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14
Q

What drugs that interact with GABA-A receptors are therapeutically useful as sedatives?

A

Benzodiazepines

Barbiturates

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15
Q

What are the properties of GABA-B receptors?

A
  • Mostly presynaptic
  • Inhibit NT release on presynaptic autoreceptors as well as heteroreceptors.
  • G-protein linked receptors therefore require activation of a G-protein in the pre-synaptic cell membrane, resulting in reduced calcium conductance. This decreases exocytotic NT release and decreases cAMP levels.
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16
Q

What is an agonist of GABA-B receptors?

A

Baclofen
- Selective for GABA-B receptors.
Therapeutically useful as a skeletal muscle relaxant acting in the spinal cord
- Useful in spasticity associated with MS- is a spasmolytic

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17
Q

What is an antagonist of GABA-B receptors?

A

Saclofen (competitive)

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18
Q

What four proteins is the GABA-A receptor complex composed of?

A
  • GABA- A receptor
  • Barbiturate receptor
  • Benzodiazepine
  • Chloride channel
  • GABA modulin allows the BDZ receptor to link to the GABA receptor protein
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19
Q

What happens when benzodiazepines bind to their receptor on the GABA-A receptor complex?

A
  • Enhancement of GABA action
  • Enhancement of GABA binding to the GABA receptor protein and this effect is reciprocated
  • Increases the frequency of opening of chloride channels
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20
Q

What happens when Barbiturates bind to their receptor of the GABA-A receptor complex?

A

Increases the duration of the opening of the chloride channel

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21
Q

How do barbiturates differ from benzodiazepines?

A

Barbiturates are less selective than benzodiazepines

  • Therefore less excitatory transmission and other membrane effects
  • Might explain induction of surgical anaesthesia and low margin of safety
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22
Q

What are the clinical uses of Benzodiazepines (BDZ) and Barbiturates (BARB)?

A

1) Anaesthetics- BARB only: THIOPENTONE
2) Anticonvulsants: Diazepam, Clonazepam, Phenobarbital
3) Anti-spastics- Diazepam
4) Anxiolytics
5) Sedatives
6) Hypnotics

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23
Q

What are anxiolytics?

A

They remove anxiety without impairing mental or physical activity
- Minor tranquillisers

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24
Q

What do sedatives do?

A

Reduce mental and physical activity without producing loss of consciousness

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25
Q

What do hypnotics do?

A

Induce sleep

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26
Q

What barbiturate is used as a sedative/hypnotic?

A

Amobarbital

  • For severe intractable insomnia
  • Half life= 20-25 hours
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27
Q

What are the unwanted effects of barbiturates?

A

1) Low safety margins- depresses respiration so overdosing lethal
2) Alter natural sleep and decreases REM- hangovers/irritability
3) Enzyme inducers
4) Potentiate effect other CNS depressants (e.g. alcohol)
5) Dependence- withdrawal syndrome: insomnia, anxiety, tremor, convulsions, death

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28
Q

What are the pharmacokinetics of benzodiazepines?

A

1) Administration:
- Well absorbed
- Peak plasma: 1 hour
- Can be given IV for status epileptics for prolonged seizure activity
2) Distribution:
Bind plasma proteins strongly. Highly lipid soluble therefore wide distribution
3) Metabolism: Usually extensive in the liver
4) Excretion: in urine as glucuronide conjugates
5) Duration of action: short acting and long acting (slow metabolism and/or active metabolites)

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29
Q

Give examples of short acting benzodiazepines

A

Temazepam
Oxazepam
(half life of 8hrs)

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30
Q

Give examples of long acting benzodiazepines

A

Diazepam
(32 hours)
- Involves metabolism via temazepam and oxazepam or via nordiazepam

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31
Q

What are the uses of long acting benzodiazepines and give examples

A

Anxiolytics

  • Diazepam (valium), Chlordiazepoxide (librium), Nitrazepam
  • Oxazepam is used in cases of hepatic impairment to prevent toxicity
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32
Q

What are the uses of short acting benzodiazepines and give examples

A

Sedatives/hypnotices

- Temazepam, Oxazepam

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33
Q

What are the advantages of benzodiazepines over barbiturates?

A
  • Wide margin of safety (overdose only causes prolonged rousable sleep- treated with flumazenil)
  • Mild effect on REM sleep
  • Does not induce liver enzymes
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34
Q

What are the unwanted effects of benzodiazepines?

A

1) Sedation, confusion, ataxia
2) Potentiate other CNS depressants (e.g. alcohol)
3) Tolerance (less than BARBs; only tissue tolerance)
4) Dependence
- Withdrawal syndrome similar to BARBs but less intense
- Withdraw slowly
5) Increase in free plasma concentration of different drugs including aspirin and heparin

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35
Q

What is choral hydrate used for?

A

Sedatives/hyponotics

- Metabolised in the liver to trichloroethanol (active drug)

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36
Q

What other drugs are used as anzxiolytics other than BDZs and BARBs?

A 
Propranolol:
- Non selective beta blocker 
- Improves physical symptoms on anxiety such as tachycardia and tremor 
- Used for stage fright 
Busiprone:
- 5HT-1A agonist 
- Slow onset of action (days-weeks) 
- Few side effects 
- Downside is that we don't really understand the interaction with the 5HT transmission
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37
Q

What are the dopaminergic pathways?

A

1) Nigrostriatal: Cell bodies originate in the substantia nigra zona compacta and project to the striatum
- Control of movement
2) Cell bodies originate in the ventral tegmental area and project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercule
- Involved in emotion
3) Tuberinfundibular system: Short neurones running from the arcuate nucleus of the hypothalamus to the medial eminence and pituitary gland
- Regulates hormone secretion

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38
Q

What are the different dopamine receptors?

A

D1 family - D1 & D5

D2 family- D2, D3, D4

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39
Q

What are the cardinal signs of Parkinson’s Disease

A

Rest tremor: Shaking of the limb when relaxed
Rigidity: Stiffness, limbs feel heavy/weal
Bradykinesia: slowness of movement
Postural abnormality

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40
Q

What are the presenting symptoms of Parkinson’s Disease?

A
  • Pill-rolling rest tremor
  • Difficulty with fine movements- micrographia
  • Poverty of blinking
  • Impassive face
  • Monotomy of speech and loss of volume of voice
  • Disorders of posture- flexion of the neck and trunk
  • Lack of arm swing
  • Loss of balance- lack of righting reflex retropulsion
  • Short steps, shuffling gait
  • Symptoms appear on one side of the body at first (unilateral onset)
  • Symptoms spread to both sides of the body
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41
Q

What are the non-motor symptoms of Parkinson’s Disease?

A
  • Depression
  • Pain
  • Taste/smell disturbances
  • Cognitive decline/Dementia
    Autonomic dysfunction:
  • Constipation
  • Postural hypotension
  • Urinary frequency/urgency
  • Impotence
  • Increased sweating
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42
Q

What brain areas are affected in Parkinson’s Disease?

A

Principle area: Substantia nigra
And
- Locus coruleus, Dorsal vagus nucleus, Nucleus Basalis of Mynert

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43
Q

What biochemical changes occur in Parkinson’s Disease?

A
  • Marked reduction in caudate nucleus/ putamen dopamine content
  • Necessary to lose 80-85% of the dopaminergic neurons and deplete 70% of the striatal dopamine before symptoms appear
  • Compensatory mechanisms prevent the appearance of clinical symptoms
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44
Q

What is the dopamine replacement therapy- L-DOPA?

A
  • DOPA is the precursor to dopamine, converted to dopamine in the brain by enzyme DOPA decarboxylase (DD)
  • DD is present in peripheral tissues.
  • If administered alone, 95% of L-DOPA is metabolised to dopamine in the periphery.
  • L-DOPA can cross BBB to be centrally converted to hopamine
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45
Q

What drugs are used in dopamine replacement therapy using L-DOPA?

A

Peripheral DOPA decarboxylase inhibitor & L-DOPA

Preaparations: Sinamet and Madopar

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46
Q

What does L-DOPA treat?

A

Hypokinesia
Rigidity
Tremor

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47
Q

What are the acute side effects of L-DOPA?

A
  • Nausea: prevented by Doperidone (peripheral acting antagonist)
  • Hypotension
  • Psychological effects: Schizophrenia like syndrome with delusions, hallucinations, also confusion, disorientation and nightmares
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48
Q

What are the chronic side effects of L-DOPA?

A

Dyskinesias: Abnormal movements of limbs and face. Can occur within 2 years of treatment. Disappear if reduce dose but clinical symptoms reappear.
On-off effects: Rapid fluctuations in clinical state. Off periods may last from minutes to hours. Occurs more with L-DOPA

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49
Q

What are the actions of Dopamine Agonists?

A
  • Act on D2 receptors
  • Bromocriptine, Pergolide, Ropinerol
  • Longer duration of action than L-DOPA
  • Smoother and more sustained response
  • Actions independent of dopaminergic neurons
  • Incidence of dyskinesias is less
  • Can be used in conjunction with L-DOPA
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50
Q

What are the adverse effects of dopamine agonists?

A

Common- confusion, dizziness, nausea/vomiting, hallucinations
Rare- Constipation, headache, dyskinesias

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51
Q

What is Deprenyl (selegiline)?

A

MAO INHIBITOR

  • Selective for MAO-B, predominates in dopaminergic areas of CNS. Actions are without peripheral side effects of non-slective MAO-I’s
  • Can be given alone in the early stages of disease
  • Or in combination with L-DOPA, reduce the dose of L-DOPA by 30-50%
  • Rare side effects: hypotension, nausea/vomiting, confusion and agitation
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52
Q

What is Resagiline?

A

MAO INHIBITOR

- Shown to have neuroprotective properties by inhibiting apoptosis- Promotes anti-apoptosis genes

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53
Q

Give examples of Catechol-O-Methyl transferase (COMT) inhibitors

A

Tolocapone (CNS and peripheral)

Entacapone (Peripheral)

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54
Q

What does COMT do in the CNS and peripheral?

A

CNS- Prevents breakdown of dopamine
Peripheral: COMT in the periphery converts L-DOPA to 3-0-methyl DOPA (3-OMD).
3-OMD and L-DOPA compete for the same transport system across the blood brain barrier

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55
Q

What is the mode of action of COMT inhibitors?

A

They stop 3-OMD formation.
This increases the penetration of L-DOPA across the blood brain barrier.
This increases brain concentrations, where it is converted to dopamine. L-DOPA dosage can therefore be reduced.
- Has cardiovascular side effects

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56
Q

What are the positive and negative symptoms of schizophrenia?

A

Positive: Hallucinations, delusions, disorganised thoughts
Negative:
- Reduced speech (even when encouraged to interact- alogia)
- Lack of emotion and facial expression
- Diminished ability to begin and sustain activities (avolition)
- Social withdrawal (associality)

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57
Q

Once Schizophrenia has been diagnoses, what are the four main outcomes?

A

1) The illness resolves completely, with or without treatment and never returns
2) The illness recurs repeatedly with full recovery after each episode
3) The illness recurs repeatedly, but recovery is incomplete and a persistent defective state develops, becoming more pronounced with each successive relapse
4) The illness pursues a downhill course from the beginning

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58
Q

How is dopamine involved in the positive and negative symptoms of Schizophrenia?

A
  • Excessive dopamine transmission in the mesolimbic and striatal region lead to positive symptoms. Mediated through D2 receptors
  • Dopamine deficit in pre-frontal region leads to the negative symptoms. Mediated by D1 receptors
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59
Q

What is the mechanism of action of antipsychotics?

A
  • All neuroleptic drugs are antagonists at dopamine ‘D2 like’ receptors
  • Most neuroleptics block other receptors e.g. 5-HT, thus accounting for some of their effects
  • Drugs treat positive symptoms, not negative one
  • Delayed effects, takes weeks to work
  • Initially, neuroleptics induce an increase in DA synthesis and neuronal activity. This declines with time.
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60
Q

How do neuroleptics act as an anti-emetic agent?

A
  • Blocking dopamine receptors in the chemoreceptor trigger zone.
    Neuroleptic Phenothiazine is effective at controlling vomiting and nausea induced by drugs, renal failure
  • Many neuroleptics have blocking action at histamine receptors. This is effective at controlling motion sickness.
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61
Q

What causes the side effects of antipsychotics?

A

Extrapyramidal side effects.

Blockade of dopamine receptors in the nigrostriatal system can induce ‘Parkinson’ like side effects

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62
Q

What are the side effects of antipsychotics?

A

Acute dystonia: Involuntary movements- muscle spasm, protruding tongue, fixed upward gaze, neck spasm etc. Often accompanies by Parkinson’s features. Reversible with drug withdrawal or anti-cholinergics.
Tardive dyskinesias: Involuntary movements, often involving the face and tongue but also limb and trunk. Made worse by drug withdrawal or anti-cholinergics
Blocking alpha-adrenoceptors: causes orthostatic hypotension
Blocking 5-HT receptors: weight gain
Blockade of cholinergic muscarinic receptors: Typical peripheral anti-muscarinic side effects e.g. blurring of vision, increased intra-ocular pressure, dry mouth, constipation, urinary retention

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63
Q

What are the endocrine effects of antipsychotics?

A
  • Dopamine is involved in the tuberoinfundibular system and acts to inhibit prolactin secretion via the D2 receptors
  • Antipsychotics increase serum prolactin concentrations which can lead to breast swelling (in men and women) and sometimes lactation in women
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64
Q

What are local anaesthetics?

A

Drugs which reversibly block neuronal conduction when applied locally
- They are weak bases (pKa 8-9)

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65
Q

What are the effects of local anaesthetics?

A

1) Prevent generation and conduction of action potentials
2) Do NOT influence resting membrane potential
3) May also influence
- Channel gating
- Surface tension
4) Selectively block
- Small diameter fibres
- Non-myelinated fibres

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66
Q

How is surface anaesthesia administered?

A
  • LA applied to mucosal surface (mouth, bronchial tree)
  • Spray (or powder)
  • High concentration is needed which can lead to systemic toxicity
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67
Q

How is infiltration anaesthesia administered?

A
  • LA applied directly into tissues- sensory nerve terminals
  • Minor surgery
  • Adrenaline co-injection to reduce side effects and increase duration of action (NOT given at extremities as could lead to ischaemic damage)
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68
Q

How is intravenous regional anaesthesia administered?

A
  • LA injected intravenously, distal to a pressure cuff
  • Useful in limb surgery
  • Diffuses into surrounding tissue rapidly
  • Potential for systemic toxicity if cuff is released prematurely
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69
Q

How is nerve block anaesthesia administered?

A
  • LA injected close to the nerve drugs e.g. dental anaesthesia around dental nerve
  • Widely used, low doses. Slow onset
  • Co-injection vasoconstrictor (e.g. Felypressin)
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70
Q

How is spinal anaesthesia administered?

A
  • LA injected into the sub-arachnoid space and has effects on the spinal roots
  • ‘Intra-thecal’ injection
  • Abdominal, pelvic or lower limb surgery
  • Risks include a drop in blood pressure
  • Unwanted effects- prolonged headache if LA accesses the brain
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71
Q

How is epidural anaesthesia administered?

A
  • LA injected into the fatty tissue of the epidural space, has effect on spinal roots
  • Used in abdominal, pelvic and lower limb surgery. Also for painless childbirth.
  • Slower onset, need to use higher doses so systemic toxicity is more likely
  • Effects on blood pressure less likely as the area is more restricted
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72
Q

What are the properities of lidocaine (local anaesthetic)

A 
Type: Amide 
Absorption by mucous membranes: Good
Plasma protein binding: 70% 
Metabolism: Hepatic N-dealkylation 
Plasma half life: 2 hours
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73
Q

What are the properties of cocaine (local anaesthetic)?

A 
Type: Ester 
Absorption by mucous membranes: Good
Plasma protein binding: 90% 
Metabolism: Liver and plasma but non-specific esterases
Plasma half life: 1 hour
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74
Q

What are the unwanted effects of lidocaine?

A 
CNS:
- Stimulation 
- Restlessness, confusion 
- Tremor
- These symptoms are paradoxical as are unexpected
CVS: 
- Myocardial depression 
- Vasodilation 
- Hypotension 
- Due to the Na+ channel blockade
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75
Q

What are the unwanted effects of cocaine?

A 
CNS:
- Euphoria 
- Excitation 
CVS:
- Increased cardiac output 
- Vasoconstriction 
- Increased blood pressure
  • All symptoms due to sympathetic actions
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76
Q

Why is general anaesthesia clinically desirable?

A
  • Loss of consciousness (low concentrations e.g. isoflurane 100um)
  • Suppression of reflex responses (high concentrations e.g. isoflurane 300um)
  • Relief of pain (analgesia)
  • Muscle relaxation
  • Amnesia
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77
Q

What are the gaseous general anaesthetics?

A
  • Nitrous oxide
  • Diethyl ether
  • Halothane
  • Enflurane
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78
Q

What are the intravenous general anaesthetics?

A
  • Propofol

- Etomidate

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79
Q

What is the Meyer/Overton Correlation?

A

The potency of a general anaesthetic increases in proportion to its oil: water partition coefficient
- The more lipid soluble the agent, the more effective it is

80
Q

How do intravenous general anaesthetic agents produce their actions?

A

Alter synaptic function via GABA-a receptors which are predominant in the brain

  • The anaesthetic binds to the outside of the receptor, facilitating opening leading to increased inhibition
  • The Beta-3 subunit is important for anaesthetic effects- suppression of reflex responses
  • Alpha-5 subunit is important for amnesia effects
81
Q

What is the mechanism of action of inhalation general anaesthetic agents?

A
  • Potentiate GABAa receptor function (and glycine receptors). Less potent than intravenous anaesthetics and show no subunit selectivity
  • Inhibits nicotinic acetylcholine receptors
  • Facilitate TREK (background leak) potassium opening- important for suppression of reflex responses
82
Q

How do general anaesthetics produce their actions on molecular targets?

A
  • Reduced neuronal excitability

- Altered synaptic function

83
Q

How do general anaesthetics produce loss of consciousness?

A
  • Depress excitability of thalamocortical neurons

- Influences reticular activating neurons

84
Q

How do general anaesthetics produce suppression of reflex responses?

A
  • Depression of reflex pathways in the spinal cord
85
Q

How do general anaesthetics produce amnesia?

A

Decreased synaptic transmission in hippocampus/amygdala

86
Q

Why is the blood-gas partition co-efficient important with regards to general anaesthetics?

A
  • The high the coefficient, the better the anaesthetic dissolves in blood, the slower it crosses into the brain
  • A desired agent has a low coefficient for quicker induction of anaesthesia as well as fast recovery. The longer the inhaled anaesthetic remains in gaseous form, it can enter and leave the brain quickly, and be excreted via the lungs.
87
Q

How do intravenous anaesthetics reach the brain?

A
  • Inject directly into blood, therefore need to be water soluble
  • After it dissolves, there is slow movement of the anaesthetic agent from the blood to the brain as the brain is lipid based.
88
Q

What are the benefits of inhalation and intravenous anaesthetics?

A 
Inhalation:
- Rapidly eliminated 
- Rapid control of the depth of anaesthesia 
Intravenous 
- Fast induction 
- Less coughing/excitatory phenomena
89
Q

What general anaesthetic drug is used for the induction of loss of consciousness?

90
Q

What general anaesthetic drug is used for the maintenance of suppression of reflex responses?

91
Q

What general anaesthetic drug is used for the relief of pain (analgesia)

A

Opioid

e.g. IV Fentanyl

92
Q

What general anaesthetic drug is used for muscle relaxation?

A

Neuromuscular blocking drugs

e.g. Suxamethonium

93
Q

What general anaesthetic drug is used for amnesia?

A

Benzodiazepines

e.g. IV Midazolsam

94
Q

What is the cancer cell phenotype?

A
  • Disregard of signals to stop proliferating
  • Disregard of signals to differentiate
  • Capacity for sustained proliferation
  • Evasion of apoptosis
  • Ability to invade
  • Ability to promote angiogenesis
95
Q

What increases the risk of colorectal cancer?

A
  • Inflammation
  • Meat consumption
  • Smoking
96
Q

What decreases the risk of colorectal cancer?

A

High fibre diets
Folic acid intake
NSAID use

97
Q

What non-pharmacological treatment is available for colorectal cancer?

A

Endoscopic polypectomy and colonoscopy

98
Q

How is adjuvant chemotherapy used in colorectal cancer?

A
  • Offered to all Duke’s Stage C patients following surgery
    Standard treatment:
    1) 5-fluorouracil & folinic acid (FUFA)
    2) Bevacizumab
99
Q

What is 5-fluorouracil and why is it effective in colorectal cancer?

A
  • Antimetabolite pyrimidine analogue
  • Interferes with thymidylate synthase
  • Effective as it inhibits DNA synthesis and repair therefore cells are unable to divide
100
Q

What is Bevacizumab and why is it effective in colorectal cancer?

A
  • Monoclonal antibody
  • Inhibits vascular endothelial growth factor (VEGF)
  • Effective as it inhibits angiogenesis- strangling tumour blood supply
101
Q

What is the non-pharmacological treatment of non-small cell lung cancer?

A
  • Surgery involved lobectomy or pneumonectomy

- Often combined with adjuvant chemotherapy and/or radiotherapy

102
Q

How is chemotherapy used to treat non-small cell lung cancer?

A
  • Given to post surgery patients with stage 2 and above NSCLC
    Standard treatment:
    Platinum therapy PT & other agent e.g.
    1) Cisplatin & Etoposide
    2) Carboplatin & Gemcitabine
103
Q

What is Cisplatin and why is it effective in chemotherapy for non-small cell lung cancer?

A
  • Alkylating (-like) agent that crosslinks DNA guanine residues forming adducts
  • Effective as it inhibits DNA synthesis and repair therefore cells are unable to divide
104
Q

What is Etoposide and why is it effective in chemotherapy for non-small cell lung cancer?

A
  • Inhibitor of the topoisomerase (Ti) type II enzyme

- Inhibits DNA synthesis and repair so cells are unable to divide

105
Q

What is Gemcitabine and why is it effective in chemotherapy for non-small cell lung cancer?

A
  • An anti metabolite which:
    1) Inhibits ribonucleotide reductase
    2) Inhibits DNA polymerase
    3) Incorporates into DNA causing chain termination
  • Effective as it inhibits DNA synthesis and repair so cells are unable to divide
106
Q

How is advanced non-small cell lung cancer treated with chemotherapy?

A
  • Platinum therapy in combination with
    1) Taxane e.g. Docetazel
    2) Vinca alkaloid e.g. Vinorelbine
  • EGFR mutations: Erlotinib is recommended
107
Q

How do docetaxel and vinorelbine act in chemotherapy for advance non-small cell lung cancer?

A

Doxetaxel: Prevents microtubule disassembly
Vinorelbine: Inhibit microtubule assembly
- Effective as spindle formation is inhibit so cells can not divide

108
Q

What is Erlotinib and why is effective in chemotherapy for advance non-small cell lung cancer?

A
  • Selective inhibitor of EGFR tyrosine kinase

- Prevents intracellular actions of EGFR and reduces cell proliferation

109
Q

What are the non-pharmacological treatments of breast cancer?

A

Lumpectomy in combination with radiotherapy for mastectomy and surgical reconstruction

110
Q

What are the treatment options breast cancer chemotherapy?

A

1) Hormone therapy- cornerstones of treatment
2) The TAC regimen- Doxetacel, Doxorubin & Cyclophosphamide. Recommended for early node-positive breast cancer
3) Trastuzumab

111
Q

What are cyclophosphamide and doxorubucin and how do they work in chemotherapy for breast cancer?

A

TAC regimen
Cyclophosphamide- Nitrogen mustard that forms covalent bonds with RNA and RNA preventing replication and transcription
Doxorubicin- ‘Poison’ topoisomerase by intercalating DNA
- Effective as they inhibit DNA synthesis and replication so cells unable to divide

112
Q

How is Trastuzumab used in chemotherapy for breast cancer?

A
  • For HER-2 enriched breast cancer
  • Monoclonal antibody that binds to extracellular region of the HER-2/neureceptor
  • Effective as it prevents the intracellular actions of HER-2 and reduces cell proliferation
113
Q

Which cytotoxic drugs act as nucleic acid inhibitors?

A

Antimetabolites

  • 5-fluorouracil inhibits nucleic acid synthesis
  • Gemcitabine inhibits DNA polymerase
114
Q

Which cytotoxic drugs act as DNA replication inhibitors?

A

Topoisomerase inhibitors:
- Etoposide inhibits the type I and type II topoisomerases respectively
DNA intercalators:
- Doxorubicin intercalates DNA and poisons type II toposomerase
Alkylating agents:
- The nitrogen mustards (Cyclophosphamide) form covalent bonds with DNA
- The platinum compounds (Cisplatin) form DNA adducts

115
Q

Which cytotoxic drugs act as microtubule inhibitors?

A

Vinca alkaloids:
- Vinorelbine inhibits microtubule assembly
Taxanes:
- Docetaxel inhibits microtubule disassembly

116
Q

Which cytotoxic drugs act as tyrosine kinase receptor inhibitors?

A

Antibodies:
- Bevacizumab binds to VEGF
- Trastuzumab binds to the HER-2 receptor
Small molecules:
- Erlotinib inhibits the epithelial growth factor receptor (EGFR)

117
Q

What are the membrane properties of gram positive bacteria?

A
  • Prominent peptidoglucan cell wall

- Staphylococcus Aureus

118
Q

What are the membrane properties of Gram negative bacteria?

A

Other membrane with lipolysaccharide

119
Q

What are the membrane properties of mycolic bacteria?

A

Outer mycolic acid layer

120
Q

What are the steps of prokaryotic protein synthesis?

A

1) Nucleic acid synthesis
2) DNA replication
3) RNA synthesis
4) Protein synthesis

121
Q

What is produced in nucleic acid synthesis for prokaryotes?

A
  • Dihydropterate (DHOp)
    Produced from paraaminobenzoate (PABA) and converted into dihydofolate (DHF)
  • Tetrahydrofolate (THF)
    Produed from DHF by DHF reductase. THF is important in DNA synthesis
122
Q

What is the function of DNA gyrase in DNA replication in prokaryotes?

A

Produces Topoisomerase- releases tension

123
Q

What is the function of RNA polymerase in RNA synthesis in prokaryotes?

A

Produces RNA from DNA template

- Differs from eukaryotic RNA polymerase

124
Q

What protein synthesis inhibitors act in nucleic acid synthesis?

A
  • Sulphonamides: inhibits DHOp synthase

- Trimethoprim: inhibits DHF reductase

125
Q

What protein synthesis inhibitors act in DNA replication?

A

Quinolones (e.g. Ciprofloxacin) - inhibits DNA gyrase and topoisomerase IV

126
Q

What protein synthesis inhibitors act in RNA synthesis?

A

Rifamycins (e.g. Rifampicin) inhibits bacterial RNA polymerase

127
Q

What protein synthesis inhibitors inhibit ribosomes?

A
  • Aminoglucosides (e.g. Gentamicin
  • Chloramphenicol
  • Macrolides (Erythromycin
  • Tetracyclines
128
Q

What are the steps of bacterial wall synthesis?

A

1) Petigoglycan (PtG) synthesis
2) PtG transportation
3) PtH incorporation

129
Q

What happens during peptidoglycan synthesis?

A
  • A pentapeptide is created on N-acetyl murmarmic acid (NAM)
  • N-acetyl glucoasmine (NAG) associates with NAM forming PtG
130
Q

What happens during PtG transportation?

A

PtG is transported across the membrane by bactoprenol

131
Q

What happens during PtG incorporation?

A

PtG is incorporated into the cell wall when transpeptidase enzyme cross-links PtG pentapeptides

132
Q

What bacterial wall inhibitors act on PtG synthesis?

A

Glycopeptides (e.g. Vancomycin)

- Binds to pentapeptide preventing PtG synthesis

133
Q

What bacterial wall inhibitors act on PtG transportation?

A

Bacitracin inhibits bactroprenol regeneration which prevent PtG transportation

134
Q

What bacterial wall inhibitors affect PtG incorporation?

A 
Beta-lactam bind covalently to transpeptidase which inibits PtG incorporation into cell wall Beta-lactas
E.g.
- Carpenems 
- Cephalosporins 
- Penicillins
135
Q

What bacterial wall inhibitors affect cell wall stability?

A
  • Lipopeptide: (e.g. daptomycin) disrupts Gram negative cell walls
  • Polymyxins: binds to LPS and disrupts Gram negative cell membranes
136
Q

What is the mechanisms of action of Trimethoprim?

A

Inhibit DHF reductase (bacteriostatic)

Acts on urinary tract infections: E.coli

137
Q

How does resistance to Trimethoprim occur?

A

1) Additional target- bacteria produces another DHF reductase which is unaffected by drug
2) Hyperproduction- bacteria significantly increase levels of DHF reductase

138
Q

What is the mechanism of action of Quinolones?

A

Inhibits DNA gyrase and topoisomerase IV (bactericidal)

  • Mainly targets gram negative bacteria
  • Fluoroquinolones have moderate activity against gram positive bacteria
139
Q

How does resistance against Quinolones occur?

A

1) Alterations in target enzymes- spontaneous mutations in genes encoding DNA gyrase and topoisomerase IV
3) Alterations in drug permeation: Reducations in aquaporins and increased efflux systems

140
Q

What is the mechanism of action of Cephalosporins?

A 
Inhibit transpeptidase (bactericidal) 
- Targets both Gram negative and positive
- 2nd gen= greater activity with gram positive 
- 3rd gen= greater activity with gram negative 
4th and 5th gen= drug resistant bacteria and MRSA
141
Q

How is resistance against Cephalosporins achieved?

A

Destruction enzymes: Beta-lactamases hydrolyse C-N bond of the Beta-lactam ring

142
Q

What is the mechanism of action of penicillins?

A

Inhibits transpeptidase (bactericidal)

  • Penicillins G & V target Gram +ve
  • Flucloxacillin & Temocillin- Beta lactamase reistant
  • Amoxicillin has gram -ve activity. Co-administered with Clavulanic acid
143
Q

How is penicillin resistance achieved?

A

Destruction enzymes: Beta-lactamases hydroline C-N bond of the beta-lactam ring

144
Q

What is Isoniazid?

A

Anti-mycobacterial

  • Mycolic acid synthesis inhibitor
  • Key drug for tuberculosis
145
Q

What is Rimfamipicin?

A

Anti-mycobacterial

  • RNA polymerase inhibitor
  • Key drug for tuberbuculosis
  • Also indicated for Leprosy
146
Q

How can fungal infections be classified?

A

Classified in terms of tissue/organs

1) Superficial- skin, hair or nails
2) Dermatophyte- skin, hair or nails
3) Subcutaneous- innermost skin layers
4) Systemic- primarily respiratory tract

147
Q

What are the most common categories of anti-fungals?

A

Azoles: FLuconazole
Polyenes: Amphotericin

148
Q

What is the mechanism of action of azoles?

A
  • Inhibit cytochrome P540-dependent enzymes involved in membrane sterol synthesis
  • Fluconazole (oral) used for candidiasis and systemic infections
149
Q

What is the mechanism of action of polyenes?

A
  • Interact with cell membrane sterols forming membrane channels
  • Bind to egosterol and creates pores
  • Amphotericin (I-V) is used for systemic infections
150
Q

What is the life cycle of HIV?

A

1) Attachment and entry
2) Replication and integration
3) Assembly and release

151
Q

What happens during attachment and entry of HIV?

A
  • Viral membrane proteins interact with macrophage membrane receptors
  • Viral caspid endocytosis
152
Q

What happens during replication and integration of HIV?

A
  • Within cytoplasm- reverse transcriptase enzyme converts viral RNA to DNA
  • DNA is transported into the nucleus and integrated into host DNA
153
Q

What happens during assembly and release of HIV?

A
  • Host cell’s machinery is utilised to produce viral RNA and essential proteins
  • Virus is assembled within the cell. A mature virion is released
  • HIV glycoprotein (GP)120 attaches to CD4 receptor
  • GP120 binds to either CCR5 or CXCR4
  • GP41 penetrates host cell membrane and viral caspid enters
154
Q

With HIV entry inhibitors affect attachment and entry?

A
  • Enfuvirtide: Binds to HIV GP41 transmembrane glycoprotein

- Maraviroc: Blocks CCR5 chemokine receptor

155
Q

Which HIV inhibitors affect replication?

A

1) Nucleoside reverse transcriptase inhibitors
- Activated by 3 step phosphorylation e.g. Zidovudine
2) Nucleotide RT inhibitors
- Fewer phosphorylation steps required e.g. Tenofovir
3) Non-nucleoside RT inhibitors
- No phosphorylation required
- Not incorporated into DNA e.g. Efavirenz

156
Q

Which HIV inhibitors affect integration?

A

DNA integration: viral integrase inserts viral DNA into host DNA
Integrase inhibitor: Raltegravir

157
Q

What HIV inhibitors affect assembly and release?

A

Here, Gag precursor encodes all structural proteins
- HIV protease cleaves Gag precursor protein
Protease inhibitors:
- Saguinavir- 1st gen
- Low dose Ritonavir reduces PI metabolism which is co-administered as a ‘booster’

158
Q

How is Hepatitis B treated?

A

Tenofovir

- Nucleotide analogue, given with Peginterferon- alpha

159
Q

How is Hepatitis C treated?

A

Ribavarin & Pegeninterferon alpha:
- Ribavirin is a nucleoside analogue that prevents viral RNA synthesis
Boceprevir:
- Protease inhibitor
- Most effective against Hepatitis C genotype 1

160
Q

What is the virology of HPV?

A
  • Double stranded DNA
  • Surrounded by tegument and enclosed in a lipid bilayer
  • HSV-1 leads to cold-sores
  • HSV-2 leads to genital herpes
161
Q

How is HPV treated

A

Nucleoside analogues

e.g. Aciclovir

162
Q

What is the virology of Influenza and what does it affect?

A
  • Mutlipartite singel stranded RNA virus
  • Envolope protein neuraminidase and releases
  • Affects nose, throat and bronchi
163
Q

How is Influenza treated?

A

Neuraminiase inhibitor

- E.g. Oseltamivir

164
Q

What is epilepsy?

A

A condition defined as a tendency to recurrent, unprovoked seizures

165
Q

What are epileptic seizures?

A

Manifestation of an abnormal and excessive synchronised discharge of a set of cerebral neurones
- Can be classified as focal or generalised

166
Q

What causes symptomatic (structural or metabolic) epilepsy?

A

Acquired: Tumour, stroke, infection, head injury
Inherited: Malformation of cortical development, Vascular malformations, metabolic

167
Q

What are the different types of seizures?

A
  • Generalised tonic clonic seizure
  • Absence seizure
  • Focal/partial seizure (temporal lobe type but can arise from any part of the cortex)
168
Q

What are the benefits and harms of anti-epileptic drug (AED) therapy?

A

Benefit: Seizure suppression
Harm: Psychosocial consequences. Idiosyncratic and dose-related ADRs

169
Q

What factors influence the decision to treat epilepsy?

A
  • Number of seizures at presentation
  • Seizure type and severity
  • Cause of seizure
170
Q

What are the mechanisms of action of AED therapy?

A

Most anti-epileptic drugs act by one or more of these mechanisms

1) Enhancing GABA mediated inhibition
2) Inhibiting fast excitatory neurotransmission, principally that mediated by the excitatory neutransmitter glutamate
3) Inhibiting neuronal action potentials by blocking voltage-gated sodium channels
4) Neuronal calcium channels

171
Q

What drugs enhance GABA inhibition?

A

BZPs
Phenobarbital
VGB
Valproate

172
Q

What drugs reduce glutamate mediated excitation (pre-synaptic)

A

TPM
GPT
Levetiracetam

173
Q

What drugs reduce glutamate-mediated excitation (post-synaptic)

A

TPM

Parampanel

174
Q

What pharmacokinetic variables influence drug response?

A
  • Bio-availability: age, gender, generic formulations
  • Distribution: Vd(muscle,fat), Protein binding
  • Metabolism: biotransformation
  • Excretion: renal disease, age
  • Drug interactions: induction/inhibition of liver enzymes
175
Q

What drugs are used for partial epilepsy?

A

Carbamazepine
Lamotrigine
Levetiracetam

176
Q

What drugs are used for generalised epilepsy?

A

Valproate

Levetiracetam

177
Q

What broad spectrum drugs are used in both generalised and partial epilepsy?

A

Valproate, Levetiracetam, Lamotrigine

Ethosuximide is used in childhood absence epilepsy only

178
Q

What is the hepatic metabolism of Phenytoin?

A

Oxidation, followed by hydroxylation then conjugation and renal excretion of non-active metabolites

179
Q

What are the indications of phenytoin use?

A

Partial and secondary generalised seizures and status epilepticus

180
Q

What is the mechanism of of Phenytoin?

A

Blockade of voltage-gated Na channels

181
Q

What are the adverse drug reactions of phenytoin?

A
  • Hypersensitivity: rash, hepatitis, nephritis
    Dose related: Ataxia, dizziness, sedation diplopia
    Chronic: Gingival hypertrophy, folate deficiency, megaloblastic anaemia, Vit K deficiency, depression, hirsuitism, peripheral neuropathy, oestomalacia
182
Q

How do other drug affect Phenytoin?

A
  • Amiodarone, Isoniazid: potent inhibitors of PHT metabolism, cause increased PHT levels
  • Aspirin: displaces PHT from protein binding
  • Valproate: displaces PHT from protein binding and also inhibit PHT metabolism.
183
Q

How does Phenytoin affect other drugs?

A
  • Warfarin- increases clearance of warfarin with chronic use
  • LTG, corticosteroids, cyclosprin, some cancer-cytotoxics levels all lowered
  • Oestrogen containing OCP efficacy reduced
184
Q

What are the indications for Carbamazepine use?

A

Partial and secondary generalised seizures

185
Q

What is the mechanism of action of Carbamazepine?

A

Blockade of voltage-gated Na channels

186
Q

What is the metabolism of Carbamazepine?

A

Hepatic oxidation then conjugation.

CBZ is a potent hepatic enzyme inducer

187
Q

What are the adverse drug reactions of Carbamazepine?

A
  • Hypersensitivity: rash, hepatitis, nephritis
    Dose related: Ataxia, dizziness, sedation, diplopia
    Chronic: Vit K deficiency, depression, impotence, osteomalacia, hyponatraemia
188
Q

How do other drugs affect Carbamezepine?

A
  • PHT, PB induce CBZ metabolism
  • Macrolide antibiotics inhibit CBZ metabolism
  • Calcium channel blockers can double CBZ levels
  • Fluoxetine can increase CBZ levels
189
Q

How does Carbamamezepine affect other drugs?

A
  • Reduces levels of a wide variety of AEDs
  • OCP-inform patients
  • Warfarin
190
Q

What are the indications of Valproate use?

A

Partial or generalised epilepsy

- Enhances GABA

191
Q

What are the adverse drug reactions of Valproate?

A

Severe hepatic toxicity, pancreatitis, drowsiness, encephalopathy, tremor, hair thinning and loss, weight gain, PCOS

192
Q

How does Valproate affect other drugs?

A
  • VPA is potent inhibitor of both oxidation and glucuronidation
  • PHT, PB, LTG levels increased
  • CBZ-epoxide levels increased
193
Q

How do other drugs affect Valproate?

A
  • Levels reduced by hepatic enzyme inducers (PHT, PB, CBZ)
  • Antacids may impair absorption
  • Some NSAIDs, aspirin, phenylbutazone displace VPA from its albumin binding sites- can result in toxicity
194
Q

What causes antibiotic resistance?

A
  • Unnecessary prescription
  • Livestock farming
  • Lack of regulation
  • Lack of development
195
Q

What are the different mechanisms of antibiotic resistance?

A
  • Additional target
  • Hyperproduction
  • Alterations in target enzymes
  • Alterations in drug permeation
  • Production of destruction enzymes

Year 2: LCRS (8 decks)

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