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Year 2 LCRS > Pharmacology 3 > Flashcards

Pharmacology 3 Flashcards

1
Q

What does GABA stand for?

A

Gamma-Aminobutyric Acid

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2
Q

How is GABA synthesised and stored?

A

GABA is synthesised in GABA neurones from glutamate by enzyme glutamate decarboxylase.
GABA transporter proteins uptake GABA synthesised in the cytoplasm into vesicles where they are stored.

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3
Q

What is the difference between excitatory and inhibitory neurones based on carboxyl groups?

A

GABA (inhibitory) has one carboxyl group

Excitatory (such as glutamate and aspartate) have two carboxyl groups

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4
Q

What is the role of GABA transporter proteins?

A

They uptake GABA synthesised in the cytoplasm into vesicles where they are stored.

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5
Q

What are the four major functions of GABA bas on the areas of the brain with most GABA distribution?

A
  1. Motor activity - high [GABA] in the motor cortex, cerebellum, corpus striatum, and spinal chord
  2. Extrapyramidal activity - high [GABA] in the basal ganglia
  3. Emotional behaviour - high [GABA] in the limbic system
  4. Endocrine function - high [GABA] in the hypothalamus which exerts inhibitory control on hypothalamic neurones
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6
Q

What percentages of synapses in the CNS use GABA asa neurotransmitter?

A

30%

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7
Q

Most GABA neurones are short inhibitory neurones. What are the main long ones?

A
  • descending GABA striato-nigral tract

- GABAergic cerebellar tract

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8
Q

Describe the distribution of GABA receptors

A

GABA-alpha are found in post-synaptic neurones

GABA-beta are mainly found in pre-synaptic neurones (but also on some dopaminergic neurones)

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9
Q

Describe the nature of GABA-alpha and GABA-beta receptors

A
  • GABA-alpha are ionotropic, creating a Cl- ion channel to cause IPSPs.
  • GABA-beta are metabotropic to inhibit adenyl cyclase on pre-synaptic neurone, preventing further GABA release
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10
Q

What are the GABA-aplha agonists and antagonists?

A

Agonists:

  • GABA
  • Muscimol

Antagonists:
- Bicuculine
- Picrotoxin
both convulsants, only useful in experiements

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11
Q

What are the GABA-beta agonists and antagonists?

A

Agonists:

  • GABA
  • Baclofen (muscle relaxant and spasmolytic)

Antagonists:
- Saclofen

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12
Q

What drugs potentiate the action of GABA and how?

A
  • Benzodiazepines bind to the gamma subunit of the GABA-alpha receptor causing allosteric modification –> increased GABA-alpha activity by increasing the FREQUENCY of Cl- channel opening
  • Barbiturates bind to the beta subunit to increase the DURATION of Cl- channel opening.
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13
Q

How is GABA inactivated and metabolised?

A

Reuptake of GABA from synaptic cleft is done by neuronal and surrounding glial cells. Transporter systems are Na+ and ATP dependent, are so are saturable.

Metabolism happens through mitochondrial enzymes:
GABA –> succinic semialdehyde by GABA-transaminase.
succinic semialdehyde —> succinic acid by succinct semialdehyde dehydrogenase

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14
Q

What is the GABA shunt?

A

The fact that GABA is recycled in the mitochondria by the Kreb’s cycle:

Succinic acid generated by GABA metabolism enters the Kreb’s cycle, before it is converted to alpha-oxaloacetate –> glutamate –> GABA

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15
Q

What drugs inhibit GABA metabolism and how?

A
  • Sodium Valproate is an inhibitor of GABA-Transaminase and Succinic Semialdehyde Dehydrogenase
  • Vigabatin is an irreversible inhibitor of GABA-T so denovo synthesis must occur.
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16
Q

Describe the structure of the GABA-alpha receptor

A
  • 5 subunits

- 4 main proteins: GABA receptor protein, Barbiturate receptor protein, Benzodiazepine receptor protein, GABA modulin.

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17
Q

What is the MOA of benzodiazepines?

A
  1. Enhancement of Cl- channel opening by GABA - increased frequency of opening
  2. Reciprocated increase in affinity for GABA binding
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18
Q

What is the MOA of Barbiturates?

A
  1. Enhancement of GABA activity
  2. Unreciprocated increase in affinity for GABA binding
  3. In high concentrations can directly stimulate the Cl- channel
  4. A degree of glutamate antagonistic activity
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19
Q

What are the clinical uses of benzodiazepines and barbiturates?

A
  • General anaesthetic (only BARBs)
  • Anticonvulsants (diazepam, clonazepam, phenobarbital)
  • Anxiolytics - mild tranquillisers (both)
  • Anti-spastics (diazepam is a muscle relaxant)
  • Sedative (reduced mental/physical activity) and Hypnotic (induces sleep). Only difference between the two effects is dose. (both)
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20
Q

Name a barbiturate

A

Phenobarbital

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21
Q

What are the side-effects of barbiturates?

A
  • Low safety margin as can cause respiratory depression easily
  • Alters natural sleep by reducing REM sleep, leading to hangovers
  • Induces liver enzymes (increasing metabolism of co-administered drugs)
  • Tolerance can develop due to receptor down-regulation
  • Dependence can result in withdrawal
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22
Q

How is the hypnotic chloral hydrate activated?

A

Converted to trichloroethanal

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23
Q

What is the core structure of a benzodiazepine?

A

3-ringed tricyclic structure

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24
Q

Describe the metabolism of the benzodiazepines

A

in the liver:
DIAZEPAM (32h) is slowly converted to TEMAZEPAM (8h) which is converted to OXAZEPAM (8h) before metabolism to Glucoronide
NORADIAZEPAM (60h) is converted to OXAZEPAM before glucoronide

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25
Q

How do the pharmacokinetics of benzodiazepines determine use?

A

Oxazepam and Temezepam are rapidly metabolised (8h) and so are used as sedatives/hypnotics

Diazepam, Noradiazepam and Chlordiazepoxide (librium) are much longer-acting and so are used as anxiolytics for day-time activity.

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26
Q

What are the advantages in using benzodiazepines over barbiturates?

A
  • winner margin of safety
  • only have mild effect on REM
  • does not induce liver enzymes
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27
Q

What are the unwanted effects of benzodiapines?

A
  • Sedation (if intended for anxiolytic purpose)
  • Confusion and ataxia
  • Impaired manual skills
  • Potentiate other CNS depressants
  • Tolerance (less than barbiturates though)
  • Dependence
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28
Q

Name anxiolytics and hypnotics/sedatives that are not benzodiazepines nor barbiturates

A
  • Chloral hydrate
  • Zopliclone - short acting, works at BDZ receptor
  • Propranolol improves physical symptoms of anxiety
  • Buspirone is a 5HT(14) agonies with few side-effects but has a slow onset of action.
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29
Q

Describe the three main dopaminergic pathways in the brain?

A
  1. Mesocorticolimbic pathway: cell bodies from the ventral segmental area project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercle - involved in emotion.
  2. Nigrostriatal pathway: neuronal cell bodies from the substantia nigra pars compact project to the putamen and caudate nuclei, balancing control of movement
  3. Tuberoinfundibular system: short neurones from the arcuate nucleus in the hypothalamus, project to the medial eminence and pituitary gland to regulate hormone secretion.
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30
Q

Describe the synthesis of dopamine

A

Tyrosine –> DOPA by tyrosine hydroxylase (rate limiting)

DOPA –> Dopamine by DOPA decarboxylase

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31
Q

Describe the dopamine receptors

A
  • D1-like receptors (D1, D5) are excitatory metabotropic

- D2-like receptors (D2, D3, D4) are inhibitory metabotropic

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32
Q

Briefly describe the epidemiology of Parkinson’s disease

A
  • Mean age of onset at 65 years (although can affect younger humans)
  • Men more likely to develop than women (4:1) because oestrogen has protective effects
  • only 8% of cases are due to Genetic Familial Parkinson’s Disease
  • 92% is Idiopathic Parkinson’s Disease (combination of environment, oxidative stress and protein metabolism)
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33
Q

Describe the onset of symptoms in Parkinsons

A

Starts unilaterally before progressing bilateraly.

Symptoms worsen over time as it is a neurodegenerative disorder.

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34
Q

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

A

Motor (inc Cardinal four):

  1. Rest tremor
  2. Bradykineasa
  3. Rigidity
  4. Postural abnormalities
    - Micrographia
    - Lack of arm swing or blinking
    - Monotony of speech
    - Impassive face
    - Short, shuffling gait and loss of balance

Non-Motor:

  • depression
  • pain in limbs
  • taste/smell abnormalities
  • cognitive decline/dementia
  • autonomic dysfunction –> constipation, impotence and postural hypotension
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35
Q

Describe the pathophysiology of Parkinson’s Disease

A
  • loss of dopaminergic neurones (along with astrocytes) in the nigrostriatal pathway and the locus coeruleus
  • this causes a loss of cordate nucleus and putamen dopamine content –> less activation of the direct pathway (D1) and less inhibition of the indirect pathway (D2)
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36
Q

Describe the staging in Parkinson’s Disease

A

Staging based on where altered proteins are found in the brain.

  • Stage 1-2: altered proteins found in the brainstem
  • Stage 3: altered proteins found in the substantia nigra
  • Stage 4: proteins in the amygdala
  • Stage 5: the cortices
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37
Q

What are the three types/strategies of drugs that can be used to treat Parkinson’s Disease?

A
  • Dopamine replacement
  • Dopamine agonists
  • Inhibition of dopamine breakdown
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38
Q

Why can dopamine not be administered directly to treat Parkinson’s Disease?

A

It cannot cross the BBB, also would have lots of side-effects

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39
Q

What is the gold-standard treatment in Parkinson’s Disease?

A

L-Dopa

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40
Q

Describe the administration of L-Dopa to treat Parkinson’s Disease

A
  • administered with a peripheral dopamine-decarboxylase inhibitor
  • starting patient on a low dose, gradually increasing to the maximum (before side-effects are too severe)
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41
Q

Why does the effectiveness of L-Dopa decline as Parkinson’s Disease progresses?

A

L-Dopa needs functional neurones in order to be converted into Dopamine. As the disease processes, less dopaminergic neurones remain.

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42
Q

What drugs are often co-administered with L-Dopa?

A
  • Carbidopa and Benserazine are peripheral dopa-decarboxylase inhibitors, in order to prevent side-effects of peripheral dopamine
  • Domperidone is a dopamine antagonist (does not cross the BBB) to do the same thing, preventing nausea
  • Bromocriptine or Pergolide (dopamine agonists) when disease has progressed enough to make L-Dopa insufficient on its own
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43
Q

What are the side-effects of L-Dopa?

A

Acute:

  • Nausea (limited by Dopa-decarboxylase or dopamine agonists)
  • Hypotension
  • Schizophrenia-like syndrome: delusions, hallucinations etc due to increased DA in the mesocorticolimbic pathway

Chronic:

  • On-off syndrome due to varying concentrations of the drug in the body
  • Dyskinesias are uncontrollable movements due to the DRUG and not disease (excessive movement)
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44
Q

How can dopamine agonists treat Parkinson’s Disease?

A
  • Does not need dopaminergic neurones as can bind to D2 receptors directly
  • response is smoother and more sustained
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45
Q

Give examples of dopamine agonists

A

Bromocriptine and Pergolide

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46
Q

What are the side-effects of Bromocriptine and Pergolide?

A
  • Confusion
  • Dizziness
  • Hallucinations
  • Nausea/vomiting
  • (rarely) constipation, headaches and dyskinesias
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47
Q

Describe how dopamine is broken down

A
  • MAO-A/B is in the presynaptic neurone, used to recycle dopamine
  • COMT is in the post-synaptic and synapse also breaks down dopamine
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48
Q

Describe the drugs that inhibit the breakdown of dopamine, and how this treats Parkinson’s Disease

A
  • Deprenyl is selective for MAO-B (predominantly in the CNS). Increases dopamine in the striatum. Also reduces requirement of L-Dopa dose by 30-50 and so side-effects are reduced.
  • Resagiline is also an MAO inhibitor, with apparent anti-apoptotic effects
  • Tolocapone is a COMT inhibitor that is beneficial in the CNS for obvious reasons (more dopamine) and also periphery as normally L-Dopa is broken down by COMT in the periphery to 3-OMD, which competes for the same transport system into the brain as L-Dopa.
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49
Q

What are the types of schizophrenia?

A
  • Relapsing and remitting

- Chronic and progressive

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50
Q

Describe the heritability of schizophrenia

A
  • 10% risk with first degree relative

- 50% risk with monozygotic twins

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51
Q

What are the two theories attempting to explain the aetiology of Schizophrenia?

A
  • slow viral infection with auto-immune process

- developmental abnormalities –> anatomical changes in mesolimbic and mesocortiyal pathways

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52
Q

Describe the pathophysiology of Schizophrenia, and how this leads to positive and negative symptoms.

A
  • Excessive dopamine transmission in the mesolimbic pathway which mainly has D2 receptors, produces POSITIVE symptoms
  • Excessive dopamine transmission in the mesocortiyal pathway which mainly has D1 receptors produces NEGATIVE symptoms
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53
Q

What are the Positive and Negative symptoms of Schizophrenia?

A

Positive: hallucinations, delusions and thought disorders
Negative: withdrawal, flattening of emotional response

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54
Q

What property do all neuroleptic drugs have?

A

They are all antagonists at D2-like receptors. They therefore counteract the inhibition of the mesolimbic pathway, treating the positive symptoms.

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55
Q

What side effects are reduced by neuroleptic drugs due to:

a) unspecificity
b) excess D2 inhibition

A

a) - blocking 5-HT receptors can lead to weight gain
- blocking muscarninc receptors leads to typical effects
- blocking alpha-adrenoreceptors leads to orthostatic hypotension

b) - excess D2 inhibition in nigrostriatal pathway –> less inhibition of indirect pathway –> greater inhibition of movement –> extrapyramidal side effects such as acute dystonia and tar dive dyskinesias.
- D2 inhibition in tuberoinfundibulnar system –> less inhibition of prolactin release –> hyperprolactinaemia

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56
Q

What is the definition of a general anaesthetic?

A

A compound that induces a loss of consciousness at low concentrations, and a lack of responsiveness at higher concentrations.

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57
Q

What are the two types of general anaesthesia, and list the drugs belonging to each group.

A

Inhalation/Gaseous:

  • Nitrous Oxide
  • Diethyl Ether
  • Halothane
  • Enflurane

Intravenous:

  • Propofol
  • Etomidate
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58
Q

Which type of general anaesthetic is more potent?

A

Intravenous are MUCH more potent than inhaled GAs.

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59
Q

What are the two main neural effects of general anaesthetics due to the disruption of membrane proteins ?

A
  1. Reduced neuronal excitability

2. Altered synaptic function

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60
Q

What are the targets of Halothane and Enflurane, and how does this translate to its effects?

A
  1. Potentiate GABAa –> more general inhibition (ASF)
  2. Inhibit nAChR –> amnesia and analgesia (ASF)
  3. Open TREK K+ Channels (background k+ channels) (RNE)
61
Q

What is the target of NO as a General Anaesthetic, and how does this translate to its effects?

A
  • Blocks excitatory NMDA (glutamate) receptors –> reduced excitation
  • Blocks nAChR –> amnesia and analgesia
  • Blocks 5-HT3 receptors
62
Q

How does Propofol and Etomidate work?

A
  • more potent and more selective potentiators of GABAa –> increased neuronal inhibition
63
Q

How is the GABA receptor subunit important in the function of I.V general anaesthetics?

A

Propofol and Etomidate are more effective when beta subunits predominate.

  • beta3 subunits are found at synapses where the potentiation of GABA leads to the suppression of the reflex response
  • alpha3 subunits are found at extra-synaptic locations to induce amnesia
64
Q

What are the neuroanatomical sites of general anaesthetic action and how does that translate to GA effects?

A
  • Decreased excitation of the thalamocortical neurones and RAS leads to loss of consciousness
  • Depression of the reflex pathways in the spinal chord
  • Decreased excitation in the hippocampus and amygdala leads to amnesia.
65
Q

Describe the pharmacokinetics of gaseous general anaesthetics

A

Enters the blood through lungs, enters the brain, diffuses out of the brain, and exits via lungs.

  • The extent to which it dissolves in the blood is called the blood:gas partition coefficient.
  • The greater the blood:gass coefficient, the more water soluble, and less lipid soluble it is. It is therefore SLOWER to act and there is increased DIFFUSION TO LUNG to be excreted.
  • Conversely, the lower the blood:gass coefficient, the less water soluble it is, and the more lipid soluble it is. Therefore it is FASTER to act on the brain as there is increased DIFFUSION TO BRAIN.
66
Q

Why do we induce anaesthesia with an I.V general anaesthetic but maintain with gaseous GAs?

A

I.V general anaesthetics have a fast induction but cannot control anaesthesia quickly.
Inhaled anaesthesia is rapidly eliminated, so you can have more control over the level of anaesthesia.

67
Q

What are the targets of Local Anaesthetics?

A

Voltage-sensitive Sodium Channels

68
Q

What are the structural areas of a Local Anaesthetic? Name two examples of Local Anaesthetics with their structures

A

Three structural areas:

  1. Aromatic region
  2. Amide/Ester link
  3. Basic amine side-chain
  • Cocaine has the ester
  • Lidocaine has the amide
69
Q

Describe the pathways by which Local Anaesthetics can affect VSSC

A
  1. (Main) Hydrophilic pathway: UNIONISED LAs diffuse across the connective tissue sheath, and THROUGH the axon membrane. Once inside, it becomes IONISED and binds to the inside of the Na+ channel, stopping the influx of Na+. This pathway is USE -DEPENDENT
  2. (some highly lipid soluble) Hydrophobic pathway. UNIONISED LAs diffuse through connective tissue and INTO the neuronal membrane where it becomes IONISED and binds to the VSSC, dropping into a closed channel. Not use-dependent
70
Q

How do local anaesthetics affect resting membrane potential?

A

They don’t (as they don’t interact with Na+/K+ ATPase)

71
Q

What are the mechanisms by which local anaesthetics cause anaesthesia?

A
  1. Decreased neuronal conduction
  2. VSSC channel gating - holding it inactive
  3. Reducing surface tension of the neurone –> expansion of membrane –> non-specific stereochemical block
72
Q

What types of neurones do local anaesthetics target more?

A
  1. non-myelinated
  2. smaller diamatered axons

therefore applies to C-fibres and (alpha)(delta) fibres

73
Q

Why do local anaesthetics have less of an effect on infected tissue?

A

Infected tissue is more acidic.

More LA becomes ionised, decreased the amount of unionised LA available to act on neuronal membrane.

74
Q

What are the six routes of administration of local anaesthetics?

A
  1. Surface Anaesthesia (spray)
  2. Infiltration anaesthesia (subcutaneous)
  3. Intravenous regional anaesthesia
  4. Nerve block anaesthesia (given to nerve trunks)
  5. Spinal anaesthesia (in CSF)
  6. Epidural anaesthesia
75
Q

Describe how local anaesthetics are administered to deliver surface anaesthesia

A

Delivered to mucosal surfaces, such as mouth, bronchial tree, eyes, throat and nose.
Delivered by spray (or powder/ointment)
More anaesthesia is needed in higher concentrations –> likelihood of systemic toxicity

76
Q

Describe how local anaesthetics are administered to deliver Infiltration anaesthesia

A

Administered subcutaneously. Vasoconstrictors such as adrenaline are co-administered to keep LA from diffusing away quickly. Allows for a lower one and fewer side effects.

77
Q

Describe how local anaesthetics are administered to deliver Intravenous regional anaesthesia

A

Administered intravenously distal to a pressure cuff. Used in limb surgery. Systemic toxicity results if pressure cuff is released too early

78
Q

Describe how local anaesthetics are administered to deliver nerve block anaesthesia

A

This is when LA is administered close to nerve trunks such as for dental nerves. Used widely as can be given low doses close to the nerve. Co-administer a vasoconstrictor

79
Q

Describe how local anaesthetics are administered to deliver spinal anaesthesia

A

By intrathecal injection, delivering LA to the subarachnoid space (into CSF) which surrounds spinal chord and spinal roots (mainly roots as they are smaller)

80
Q

What are the side-effects of delivering spinal anaesthesia?

A
  • hypotension as LA can affect preganglionic sympathetic fibres (as their fibres are also quite narrow)
  • prolonged headache because LA mixes with the CSF and diffuses to the brain
81
Q

Describe how local anaesthetics are administered to deliver epidural anaesthesia

A

Achieved by administering LA to the fatty tissue surrounding spinal roots (in epidural space). Has a slower onset of action as has to diffuse through fatty tissue to reach spinal roots, and so a larger dose is needed. However, fewer side effects as does not penetrate meninges much, there are fewer hypotension and headache side-effects.

82
Q

Describe the differences and similarities of the pharmacokinetics of Cocaine and Lidocaine

A

Both are absorbed well by mucous membranes

  • Cociane is more plasma bound (90% compared to 70%)
  • Lidocaine is broken down via hepatic n-dealykation
  • Cocaine is broken down by liver and plasma non-specific esterases
  • therefore cocaine has half the plasma half-life (1h compared to 2h)
83
Q

What are the side effects of Lidocaine?

A

CNS: Central stimulation - restlessness, confusion, tremor (seemingly paradoxical - happens because inhibitory system is more sensitive to LA at first)
CVS: myocardial depression, vasodilation, reduced blood pressure

84
Q

What are the side-effects of Cocaine?

A

CNS: Excitation and euphoria (seemingly paradoxical - happens because inhibitory system is more sensitive to LA at first)
CVS: Increased CO, vasoconstriction and increases blood pressure. (also paradoxical - happens because cocaine increases endothelin 1 and decreases NO)

85
Q

When is chemotherapy used to treat colorectal cancer?

A

As an adjuvant to surgery. It is offered to all Duke stage C and above

86
Q

What is the standard chemotherapy regiment to treat colorectal cancer?

A
  • FUFA (5-Fluorouracil + Folinic Acid)

- Bevacizumab (if metastatic)

87
Q

Describe the MOA of FUFA

A
  • 5-Fluorouracil is an antimetabolite pyramidine analogue wide used in the treatment of solid tumours. Not only does it incorporate into DNA and RNA preventing translation and replication, it also inhibits thymidylate synthase and thus the production of THF (tetrahydroflorate) involved in DNA repair and synthesis.
  • Folinic acid makes 5-fluorouracil more effective. It is a tetrahydrofolic acid derivative that allows some purine and pyramidine synthesis to occur.
88
Q

Describe the MOA of Bevacizumab

A

It is a monoclonal antibody that binds to and inhibits VEGF, preventing it from binding to VEGFR. [It is given as combination treatment, none alone as associated with cardiovascular events and bleeding.]

89
Q

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

A

Used as a neoadjuvant (before surgery) as well as an adjuvant

90
Q

What is the standard chemotherapy regiment to treat non-small cell lung cancer?

A
  • Platinum therapy (cisplatin or carboplatin)

+ Etoposite or Gemcitibine

91
Q

What is the MOA of Cisplatin?

A

It is a pseudoalkylating agent that cross-links guanine residues forming adducts. DNA adducts prevent DNA replication and therefore cell division.

92
Q

What is the MOA of Etoposite

A

It is a type III topoisomerase inhibitor. It prevents DNA unwinding (as double helix cannot be cut) and thus replication.

93
Q

What is the MOA of Gemcitabine?

A

It is an anti-metabolite that:

  • inhibits ribonuclotide reductase
  • inhibits DNA polymeration
  • Incorporates into DNA causing side-chain termination
94
Q

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

A
  1. Platinum therapy (cisplatin)
  2. Taxane such as Docetaxel
  3. Vinca alkaloids such as Vinorelbine
  4. Erlotinib (if EGRF mutation) is a selective EGFR tyrosine kinase inhibitor
95
Q

What is the MOA of Taxanes and Vinca Alkaloids?

A
  • Vinca alkaloids inhibit microtubule assembly

- Taxanes inhibit microtubule disassembly

96
Q

What is the standard chemotherapy regiment to treat breast cancer?

A
  • Endocrine therapy such as Tamixofen
  • TAC regimen (Docataxel, Cyclophosphamide, and Doxorubicin)
  • Trastuzumab (if HER2+)
97
Q

What is the MOA of Doxorubicin?

A

It is a poison topoisomerase inhibitor used to treat (mainly) liquid tumours, but also breast cancer

98
Q

What is the MOA of Cyclophosphamide?

A

A nitrogen mustard that acts as an alkylating agent, forming covalent bonds, preventing DNA replication and RNA transcription

99
Q

What is the MOA of Trastuzumab?

A

It is a monoclonal antibody that binds to the extracellular region of the HER-2 receptor, preventing growth signalling.

100
Q

What are the three main types of bacterial wall types?

A
  • Gram- is where there is an inner membrane, a peptidoglycan layer, and an outer membrane (with LPS)
  • Gram+ is where there is cell membrane and an outer thick peptidoglycan layer
  • Mycolic is when it has an outer mycolic acid later, a peptidoglycan layer underneath, and a cell membrane.
101
Q

What are four stages of bacterial protein synthesis (that can be targeted by antibiotics)?

A
  1. Nucleic acid synthesis
  2. DNA replication
  3. RNA synthesis
  4. Protein synthesis
102
Q

What class of antibiotics inhibit bacterial nucleic acid synthesis and how?

A
  • Sulfonamides inhibit DHOp synthetase, preventing synthesis of DHOp from PABA (Paraaminobenzoate)
  • Trimethoprim inhibits enzyme DHF reductase. [DHOp is converted to DHF, which is then converted to THF] preventing synthesis of THF
103
Q

What class of antibiotics inhibit DNA replication, and how?

A
  • Fluoroquinolones inhibit DNA gyrase (a type II topoisomerase), and a type IV topoisomerase enzyme. Topoisomerase is needed to cut DNA strands, removing tension.
104
Q

What class of antibiotics inhibit RNA synthesis, and how?

A
  • Rifamycins inhibit bacterial RNA polymerase
105
Q

What class of antibiotics inhibit mRNA translation (protein synthesis)?

A
  • Macrolides (such as Eyrthromycin) inhibit prokaryotic ribosomes
  • Aminoglycosides, tetracyclins and chloramophenicol also do this.
106
Q

What are the four targets in bacterial wall synthesis for antibiotics?

A
  1. Peptidoglycan synthesis
  2. Peptidoglycan transportation
  3. Peptidoglycan Incorporation
  4. Cell wall stability
107
Q

What class of antibiotics inhibit Peptidoglycan synthesis, and how?

A
  • A peptide is created on N-acetyl Murmuric acid (NAM). N-acetyl Glucosamine (NAG) associates with NAM forming PtG.
  • Glycopeptides (such as vancomycin) binds to the pentapeptide preventing PtG synthesis
108
Q

What class of antibiotics inhibit Peptidoglycan transportation and how?

A
  • Peptidoglycan is transported across the cell membrane by a protein called bactoprenol.
  • Bacitracin inhibits bactoprenol regeneration, preventing further PtG transportation
109
Q

What class of antibiotics inhibit Peptidglycan incorporation, and how?

A
  • Peptidoglycan is incorporated into the cell wall when transpeptidase enzyme cross-links the PtG pentamers.
  • B-lactams bind covalently to the transpeptidase, inhibiting PtG incorporation.
110
Q

What family of drugs are beta-lactams?

A
  • Carbapenems
  • Cephalosporins
  • Penicillins
111
Q

What class of antibiotics inhibit cell wall stability, and how?

A
  • Lipopeptides disrupt Gram+ cell walls

- Polymyxins bind to LPS and disrupt Gram- cell membranes

112
Q

List the ways bacteria can become resistant to antibiotics

A
  1. Produce additional targets for the drug
  2. Hyperproduction of target
  3. Alteration in taget enzyme
  4. Alter drug permeation
  5. production of drug destruction enzymes
113
Q

Give an example of when bacteria have become resistant by the production of additional targets

A

Production of alternative DHF reductase enzymes, which is not inhibited by trimethoprim

114
Q

Give an example of when bacteria have become resistant by the hyperproduction of a taget

A

E.coli produce lots more of DHF reductase enzymes, making trimethoprim less effective

115
Q

Give an example of when bacteria have become resistant by the alteration in a target enzyme

A

Mutations in DNA gyrase are known to produce resistance against quinolones

116
Q

Give an example of when bacteria have become resistant by alterations in drug permetation

A

Gram- bacteria in particular can prevent intracellular access to the drug by reducing aquaporins and increasing efflux systems.

117
Q

Give an example of when bacteria have become resistant by the production of destruction enzymes

A

beta-lactameses hydrolyse the C-N bond of the beta-lactam ring. This makes the bacteria resistant to penicillin and amoxicillin.

118
Q

What antibiotics are beta-lactamase resistant?

A
  • Flucloxocillin

- Amoxicillin when given with clauvulanic acid

119
Q

Give examples of bacteria with mycolic walls

A

Mycobacteria tuberculosis and Mycobacteria leprae

120
Q

Describe the drug treatment of tuberculosis

A

6 months of antibiotics:

  • Isoniazid is a mycolic acid synthesis inhibitor
  • Rifampicin is a RNA polymerase inhibitor
121
Q

What are the classifications of a fungal infection?

A
  1. Superficial (outermost layer of skin)
  2. Dermatophyte (skin, hairs, or nails)
  3. Subcutaenous (innermost skin layers)
  4. Systemic (primarily respiratory tract)
122
Q

What are the types of anti-fungals, and how do they work?

A
  • Azoles (such as fluconazone) inhibts CYP450 dependent enzymes involved in membrane sterol synthesis
  • Polyenes (such as amphotericin) interacts with cell membrane sterols forming membrane channels. Used to treat systemic infections.
123
Q

What viruses cause viral hepatitis?

A

Hepatitis B Virus and Hepatitis C Virus

124
Q

What does the HBV capsid contain?

A
  • DNA

- Reverse transcriptase (one of the only non-retroviruses that use reverse transcriptase)

125
Q

What does the HCV capsid contain?

A
  • ssRNA

- RNA polymerase

126
Q

How is HBV treated? Describe the MOA of the durgs

A
  • Tenofovir is an adenosine nucleotide analogue that specifically targets reverse transcriptase
  • Peginterferon-alfa is a drug often co-administered
127
Q

How is HCV treated? Describe the MOA of the durgs

A
  • Ribavirin is a nucleoside analogue preventing RNA synthesis
  • Boceprevir is a protease inhibitor that is effective against Hep C genotype 1
  • Peginterferon-alfa is a drug often co-administered with the analogue
128
Q

What is the goal of HepC treatment today?

A

Cure the virus using a combination of drugs

129
Q

What are the steps of the HIV life-cycle that can be targeted by antivirals?

A
  1. Attachment and Entry
    2a. Replication
    2b. Integration
  2. Assembly and Release
130
Q

Describe the HIV process of attachment and entry and the drugs that can target the process

A

Viral membrane protein GP120 attaches to CD4 receptor, as well as either CCR5 or CXCR4 proteins on the T-cell
- Maraviroc blocks the CCR5 chemokine receptor

Viral GP41 penetrates the host cell membrane allowing endocytosis
- Enfuviritide binds to the GP41 transmembrane glycoprotein preventing endocytosis.

131
Q

Describe the HIV process of replication and the drugs that can target the process

A

Reverse transcriptase enzyme converts the viral ssRNA to dsDNA.

  • Efavirenz is a revere-transcriptase inhibitor
  • Zidovudine is a nucleoSIDE analogue requiring phosphorylation steps to be activated
  • Tenofovir is a nucleoTIDE analogue that targets RT
132
Q

Describe the HIV process of integreation and the drugs that can target the process

A

Enzyme integrase integrates viral dsDNA

- Raltegravir inhibits integrase

133
Q

Describe the HIV process of assembly and release and the drugs that can target the process

A

HIV protease cleaves Gag precursor protein which ecodes structural proteins.
- Saquinavir is a protease inhibitor, often administered with Ritonivir (a booster that blocks CYP450)

134
Q

Describe the types of Herpes Simplex Virus

A

They are viruses with dsDNA surrounded by a tegument and eclosed in a lipid bilayer

  • HSV-1 causes cold-sores
  • HSV-2 causes genital herpes
135
Q

What drug is often used to treat HSV infection?

A

Acyclovir - a nucleoside analogue

136
Q

Describe the influenza virus

A

It is a multipartite ssRNA virus that has envelope proteins neuraminidase and heamagglutinin. Neuraminidase aids the release of influenza into the cell.

137
Q

How is influenza virus treated?

A

Oseltamivir is a neuraminidase inhibitor

138
Q

Define eplilepsy

A

A physical condition with a tendency to recurrent and unprovoked seizures. It is a syndrome that includes a large number of disorders

139
Q

What is a seizure?

A

A paroxysmal manifestation of an abnormal and synchronously active set of cerebral neurones.

140
Q

What are the types of seizures?:

A

Partial/focal seizures:

  • complex (loss of consciousness)
  • simple (no loss in consciousness)

Generalised seizures:

  • absence
  • tonic
  • clonic
  • tonic-clonic
  • myo-clonic
  • atonic
  • secondary (started as a focal)
141
Q

How can seizures be divided by cause?

A
  • Idiopathic (genetic) includes mendelian and poly-genetic causes
  • Symptomatic (due to structural or metabolic) includes acquired and inherited
142
Q

What are the causes of symptomatic seizures?

A

Acquired:

  • trauma
  • infection
  • stroke
  • tumour

Inherited:

  • vascular malformation
  • metabolic disorder
  • cryptogenic disorder
143
Q

What are the factors influencing the decision to treat an epileptic?

A
  • number of seizures
  • seizure type and severity
  • cause of seizure
144
Q

What are the four mechanisms by which AED (Anticonvulsants) work?

A
  1. Potentiate GABA (BDZ, PB, VGB)
  2. Reduce glutamate mediated excitation
  3. Block action potential by Na+ channel depolarisation
  4. Interaction with neuronal ca2+ channels
145
Q

What are the pharmacokinetic variables influencing drug response?

A

Bioavailability:

  • age
  • gender
  • genetic makeup

Distribution:

  • muscle/fat
  • protein-binding
  • pregenancy
  • age

Metabolism:

  • Phase 1/2
  • enzymes

Excretion:

  • kidney failure
  • age

Drug interactions

  • hepatic inducer/inhibitor
  • interaction with other AED
146
Q

What drugs are used to treat partial seizures?

A
  • Carbamazepine
  • Lamotrigine
  • Levetiracetam
147
Q

What drugs are used to treat generalised epilepsy?

A
  • Valproate

- Levetiracetam

148
Q

What are the broad spectrum AEDs?

A
  • Lamotrigine
  • Valproate
  • Levetiracetam

Year 2 LCRS (5 decks)

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