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MD1 Neuroscience > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What are the neurotransmitters and receptors of the sympathetic nervous system?

A

Noradrenaline acting on α- and β-adrenoceptors.

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2
Q

What are the neurotransmitters and receptors of the parasympathetic nervous system?

A

Acetylcholine (ACh) acting on muscarinic acetylcholine receptors (mAChR).

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3
Q

What are the neurotransmitters and receptors of the somatic nervous system?

A

Acetylcholine acting on nicotinic acetylcholine receptors (nAChR)

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4
Q

What are the requirements for a functioning nerve ending? Use noradrenaline as an example.

A
  1. Synthesis/storage of neurotransmitter (e.g. NA)
  2. Release (mediated by Ca2+ influx) of neurotransmitter
  3. Post-junctional/synaptic receptors in the target cell/organ (e.g. α- and β-adrenoceptors)
  4. Pre-junctional/synaptic receptors that can be activated by neurotransmitter coming out of the nerve
  5. Inactivation of neurotransmitter (e.g. for NA, via reuptake into nerve terminal, metabolism or extraneuronal uptake leading to inactivation.
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5
Q

What is an example of an autoregulatory mechanism within noradrenergic transmission?

A

Pre-junctional receptors that can be activated to by noradrenaline coming out of the nerve, inducing reuptake of NA back into the nerve terminal.

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6
Q

What are the 2 different means by which neurotransmitter can be inactivated?

A
  1. Neuronal uptake, leading to metabolism
  2. Extraneuronal uptake, leading to metabolism
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7
Q

True or false: drugs with identified peripheral actions can also have dramatic CNS effects?

A

True.

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8
Q

Which two enzymes are capable of metabolising noradrenaline?

A

MAO and COMT

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9
Q

Where is MAO found?

A

In pre- and post-junctional neurons.

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10
Q

Where is COMT found?

A

In post-junctional neurons.

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11
Q

Which class of adrenoceptor is found on the pre-junctional side of the synapse?

A

α-adrenoceptors

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12
Q

What effect do amphetamines have on the noradrenergic system?

A

Displace noradrenaline from storage vesicles.

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13
Q

What effect does cocaine have on the noradrenergic system?

A

Inhibits noradrenaline reuptake.

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14
Q

Which systems is noradrenaline associated with in disease?

A

Mood and blood pressure.

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15
Q

Which systems is acetylcholine associated with in disease?

A

Memory and learning.

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16
Q

What must all drugs do before they can have any effect in the CNS?

A

Cross the blood brain barrier.

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17
Q

Which two ways can drugs cross the blood brain barrier?

A

By being lipid soluble or exploiting active processes.

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18
Q

Why may lipid-soluble drugs not remain in the CNS?

A

Because there are active export processes as well.

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19
Q

Which key solutes need to get into the CNS?

A
  • Amino acids
  • Glucose
  • Large and small ions
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20
Q

How are amphetamines able to enter the brain?

A

Because they look like amino acids and therefore can exploit the amino acid transporter.

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21
Q

True or False: all CNS neurotransmitters are highly localised?

A

False: some are widespread, others highly localised.

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22
Q

What are the 3 catecholamines?

A

Dopamine

Noradrenaline

Adrenaline

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23
Q

What is the pathway for adrenaline synthesis?

A
  1. Tyrosine → L-DOPA (by tyrosine hydroxylase)
  2. L-DOPA → Dopamine (by DOPA decarboxylase(DDC))
  3. Dopamine → Noradrenaline (by dopamine-β-hydroxylase)
  4. Noradrenaline → Adrenaline (by PNMT)
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24
Q

Where in the cell is tyrosine converted to L-DOPA?

A

On its passage into the intracellular space by Tyrosine hydroxylase.

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25
Q

Where in the cell is L-DOPA converted to Dopamine?

A

Intracellular space by Dopa decarboxylase

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26
Q

Where in the cell is Dopamine converted to Noradrenaline?

A

On its passage into the vesicle by dopamine-β-hydroxylase.

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27
Q

Where in the cell is Noradrenaline converted to Adrenaline?

A

In the vesicle by PNMT

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28
Q

Which pathway has a broader distribution: dopamine or noradrenaline?

A

Noradrenaline

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29
Q

True or false: Dopamine can act either as an excitatory or inhibitory neurotransmitter?

A

True

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30
Q

Which pathway is affected in Parkinson’s disease?

A

Dopaminergic pathway

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31
Q

Which therapeutics are given to treat Parkinson’s disease?

A
  • L-DOPA and peripheral DDC inhibitor
    • MAO B inhibitors
    • Dopamine receptor agonists
    • Muscarinic receptor antagonists
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32
Q

Which neurotransmitter is there a deficiency of in Huntington’s disease?

A

GABA

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33
Q

Which therapeutics are given to treat Huntington’s disease?

A
  • GABA agonist Baclofen
  • Dopamine antagonists Chlorpromazine
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34
Q

Which 3 major functionalities is dopamine involved in?

A
  • Movement
  • Behaviour
  • Dependence
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35
Q

What happens to the dopamine system in Parkinson’s disease?

A

Depletion of dopamine in basal ganglia.

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36
Q

What are the side effects of therapeutics used to treat Parkinson’s disease?

A

Schizophrenia-like delusions, disorientation and insomnia.

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37
Q

What role does dopamine play in Schizophrenia?

A

Changes in dopamine-rich areas like the frontal cortex, basal ganglia and temporal lobe can lead to Schizophrenia.

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38
Q

Where in the brain does dopamine play a role in dependence?

A

Nucleus accumbens

Ventral tegmental area

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39
Q

How can neurotransmitter specificity be altered?

A

By interfering with synthesis and inactivation.

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40
Q

How can greater drug specificity be achieved?

A

By targeting receptor sub-types.

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41
Q

True or false: all neurotransmitters act postsynaptically?

A

False

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42
Q

What are postsynaptic receptors concerned with mostly?

A

AP generation

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43
Q

What are presynaptic receptors concerned with?

A

Modulation of release using autoreceptors and heteroreceptors at the nerve terminal.

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44
Q

What are the 4 different types of receptor in the neuron?

A
  • Ligand-gated
  • G-protein coupled
  • Tyrosine kinase
  • Cytoplasmic/Nuclear
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45
Q

Which receptor types are mostly concerned with neuronal function?

A

Ligand-gated and G-protein coupled

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46
Q

Which receptor types are mostly concerned with neuronal survival?

A

Tyrosine kinase and cytoplasmic/nuclear

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47
Q

Over what time course do ligand-gated receptors function?

A

Milliseconds

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48
Q

Over what time course do G-protein coupled receptors function?

A

Seconds

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49
Q

Over what time course do tyrosine kinase receptors function?

A

Minutes

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50
Q

Over what time course do cytoplasmic/nuclear receptors function?

A

Hours

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51
Q

True or False: A synapse can be both excitatory and inhibitory.

A

False. Can be either or, but not both.

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52
Q

Which neurotransmitters have the potential to be excitatory and inhibitory, depending on their receptor?

A

Dopamine and Serotonin

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53
Q

What are the 4 elements of generic chemical neurotransmission?

A
  • Synthesis/Storage
    • Vesicular content
  • Release
    • Ion channels
    • Calcium influx
  • Inactivation
    • Uptake
    • Metabolism
  • Receptors
    • Post-junctional
    • Pre-junctional
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54
Q

What can disturbed motor function, such as that seen in epileptic seizures, be due to?

A

Too little inhibition or too much excitation.

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55
Q

What are the two ways in which excessive excitation of motor nerves can be treated?

A
  1. Enhance inhibitory input by GABA
  2. Reduce excitatory input by Glutamate
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56
Q

Which 3 drugs can be used to reduce excitatory input by glutamate?

A

Phenytoin

Ethosuximide

Felbemate

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57
Q

What does phenytoin do?

A

Limits excitatory nerve activation.

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58
Q

What does Ethosuximide do?

A

Inhibits T-type Ca2+ channels.

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59
Q

What does Felbemate do?

A

Inhibits NMDA receptor

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60
Q

Which drug can be used to enhance inhibitory input by GABA?

A

Benzodiazepines - enhance GABA receptor activity.

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61
Q

How do the benzodiazepines work?

A

They are allosteric modulators, enhancing the activity of the natural GABA signalling mechanisms to reduce nerve activity and provide muscle relaxation.

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62
Q

What is the common side effect of Phenytoin, Ethosuximide and Felbemate?

A

Reduce pain sensitivity.

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63
Q

What does an analgesic do?

A

Targets pain/sensory pathways

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64
Q

What does a local anaesthetic do?

A

Provides regionalised inhibition of pain/sensory pathways with no loss of consciousness.

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65
Q

What does a general anaesthetic do?

A

Depresses cortical processing of pain/sensory signals, resulting in a loss of consciousness. Not regionalised.

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66
Q

What are the different sites of drug action of anaesthetics/analgesics?

A

Peripheral nerves: local anaesthetics

Spinal cord and peripheral nerves: analgesics

Brain cortex and thalamus: general anaesthetics

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67
Q

What are local anaesthetics?

A

Drugs that reversibly block conduction of nerve impulses at the axonal membrane.

Weak bases that differ in onset, duration and toxicity

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68
Q

What are the 3 different classes of local anaesthetics? Give examples of each.

A
  1. Aminoesters: procaine
  2. Aminoamides: lignocaine, bupivicaine and ropivicaine
  3. Benzocaine
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69
Q

Why are the aminoesters shorter acting?

A

Because they are hydrolysed by esterases.

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70
Q

Why are the aminoamides longer acting?

A

Because they must be metabolised by the liver.

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71
Q

Why is the clinical use of local anaesthetics considered safe? What are their potential side effects?

A
  1. They selectively bind to Na+ channel
  2. Reversible binding with no nerve damage
  3. Will affect all nerves/excitable tissue
    1. Peripheral motor nerves - sensory loss by paralysis
    2. Autonomic nerves - hypotension but CNS convulsions, coma
    3. Heart - anti-dysrhythmic but cardiac arrest
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72
Q

Describe the structure of the Na+ channel.

A
  • 2 sub-units
    • Large alpha sub-unit
      • 4 domains
      • 6 transmembrane segments
      • These fold up to form a pore
    • 2 beta subunits
      • Hold 4 alpha domains together
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73
Q

Where do local anaesthetics bind the Na+ channel?

A

On the internal side, at S6 in the IV transmembrane domain.

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74
Q

Where do toxins bind the Na+ channel?

A

Extracellular domains

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75
Q

What are the 2 proposed mechanisms of action of local anaesthetics? What are the characteristics of each?

A
  1. Hydrophobic: fast onset, non-use-dependent
  2. Hydrophilic: slow onset, use-dependent
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76
Q

Which local anaesthetic utilises the hydrophobic mechanism?

A

Benzocaine

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77
Q

Which local anaesthetics utilise the hydrophilic mechanism of action?

A

Aminoesters and aminoamides.

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78
Q

What is the hydrophobic mechanism of action for local anaesthetics?

A

When the sodium channel opens, benzocaine can travel through into the pore from the extracellular space and block the channel, preventing complete depolarisation. This explains how benzocaine works but not how the charged forms (Aminoesters) work.

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79
Q

What is the hydrophilic mechanism of action for local anaesthetics?

A

Uncharged Benzocaine diffuses across the membrane (B-).

Benzocaine becomes charged (BH+)

Charged form binds Na+ channel from the inside when the activation gate is open.

Can only bind in the closed and open states.

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80
Q

Why is it the activity of the Na+ channel that dictates the ability of a drug to bind in the hydrophilic mechanism?

A

If it’s binding from the inside, it can only do this when the activation gate is open. Only in the closed and open states can the drug bind. In the inactive states it cannot have an effect.

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81
Q

What is the primary site of action of local anaesthetics?

A

Sensory afferents

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82
Q

What happens as the concentration of the local anaesthetic increases?

A

Motor neurons and autonomics will also be blocked.

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83
Q

What are the general properties of local anaesthetics?

A
  • Prevent propagation of nerve AP
  • Stabilise the axon membrane
  • Small fibres are more sensitive (Sensory > ANS > Motor)
  • Effect more pronounced in a basic medium
  • Greater effect at high frequency
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84
Q

Do local anaesthetics change the resting membrane potential?

A

No.

They stabilise the axon membrane.

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85
Q

Which form of the anaesthetic species is more active, charged or uncharged, in a basic medium?

A

Uncharged

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86
Q

Why is it important that the effect of local anaesthetics is more pronounced in a basic medium?

A

Because sites of inflammation are often more acidic.

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87
Q

Which topical local anaesthetics can be purchased over the counter?

A
  1. Lozenge: throat drops - benzocaine
  2. Gels: generally poor absorption across skin
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88
Q

What are the cardiovascular effects seen in local anaesthetic toxicity?

A
  • Direct myocardial depression
  • Depression of vasomotor centre
  • Hypotension (except cocaine)
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89
Q

What are the CNS effects of local anaesthetics proportional to?

A

Blood level

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90
Q

Which CNS side effects are seen with increasing blood level of local anaesthetics?

A
  1. Excitation
  2. Tremor
  3. Convulsion
  4. Respiratory arrest
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91
Q

What type of reaction to local anaesthetics is not proportional to blood level?

A

Hypersensitivity (allergic) reactions

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92
Q

What is seen at the 4 different stages of anaesthesia seen in general anaesthetics?

A

Stage 1

  • Amnesia
  • Euphoria

Stage II “Excitement”

  • Excitement
  • Delirium
  • Resistance to handling

Stage III “Surgical anaesthesia”

  • Unconsciousness
  • Regular respiration
  • Decreasing eye movement

Stage IV “Medullary depression”

  • Respiratory arrest
  • Cardiac depression and arrest
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93
Q

Which general anaesthetics are administered via inhalation?

A
  • Desflurane
  • Sevoflurane
  • Isoflurane
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94
Q

Which general anaesthetics are administered intravenously?

A

Propofol

Thiopentone

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95
Q

What pharmacokinetic properties are important to consider with general anaesthetics?

A
  • Dose and duration of action
  • Absorption (inhalation)
  • Distribution (Vd, t1/2)
  • Biotransformation (metabolism)
  • Elimination (How – kidneys/liver/lungs)
  • Drug interactions
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96
Q

What are the two pharmacodynamic theories on the mechanism of action of general anaesthetics?

A
  1. Lipid theory (outdated)
    1. Close correlation between anaesthetic potency and lipid solubility
    2. Meyer-Overton: anaesthesia is caused by volume expansion of membrane lipids
      1. Effect can be reversed by pressure
  2. Receptor interaction
    1. Inhibit excitatory receptors (glutamate, NMDA)
    2. Enhance effects on inhibitory receptors (GABA, glycine)
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97
Q

What are the respiratory side effects of general anaesthetics?

A

All anaesthetics increase likelihood of:

Impaired ventilation

Depression of respiratory centre: retention of secretions

Obstruction of airways

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98
Q

What are the cardiovascular side effects of general anaesthetics?

A

All anaesthetics increase likelihood of

  • Decreased vasomotor centre function
  • Depress contractility
  • Peripheral vasodilation
  • Cardiac arrhythmias
  • Inadequate response to fall in BP or CO
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99
Q

What parts of the chemical neurotransmission pathway can drugs interfere with?

A
  • Synthesis
  • Storage
  • Release
  • Inactivation
    • Reuptake
    • Metabolism
  • Receptor
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100
Q

True or false: molecular and therapeutic mechanisms are always known.

A

False.

While molecular mechanisms may be known, therapeutic mechanisms may not always be known.

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101
Q

What effects do cocaine and amphetamine have on noradrenergic transmission?

A

Increase NA levels in the synaptic cleft.

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102
Q

What other systems do cocaine and amphetamines affect, other than the noradrenergic system?

A

Dopaminergic and serotonergic systems.

103
Q

How do cocaine and amphetamines differ in their mechanism of action?

A

Cocaine blocks neuronal uptake, whereas amphetamine displaces monoamine out of the vesicle.

104
Q

Which nerve types excessively discharge in epilepsy?

A

Motor nerves

105
Q

What are the 2 different therapeutic approaches for epilepsy?

A
  1. Limit excitatory nerve action
  2. Enhance GABA receptor activity
106
Q

Which drug is used to reduce excitatory input by glutamate?

A

Phenytoin

107
Q

How does phenytoin work?

A

Inhibits Na+ channels on excitatory neurons

108
Q

In which state must the Na+ channel be to allow phenytoin to bind?

A

Open - thus the action of phenytoin is enhanced during high frequency firing.

109
Q

How do the benzodiazepines work?

A

Enhance GABA receptor activity, increasing inhibition and therefore decreasing activity of the motor nerve.

110
Q

What type of a receptor is GABAA?

A

Ligand-gated receptor

111
Q

Which neurotransmitters have been implicated in sedation and anxiety?

A

GABA (via GABAA receptor) and serotonin (via CNS pre-junctional receptors)

112
Q

Which neurotransmitters have been implicated in anxiety?

A

Noradrenaline and neuropeptide Y

113
Q

Which neurotransmitters have been implicated in sedation?

A

Histamine (H1 receptor)

114
Q

Which neurotransmitter can also cause peripheral tachycardia?

A

Noradrenaline (hence, anxiety)

115
Q

Which diseases or disorders are benzodiazepines used in?

A
  • Epilepsy
  • Anxiety
  • Sleep disorders
  • Premedication
    • Sedation for medical procedures
  • Acute alcohol withdrawal
116
Q

What is insomnia?

A

Not being able to sleep when, or as well as one should.

117
Q

What is anxiety?

A

Manifestation of “fear response” (marked sweating, tachycardia, chest pains, trembling, etc.) in an anticipatory manner, independent of external events.

118
Q

What are two major symptoms/disorders for which sedative-hypnotic and anxiolytic agents are used?

A

Insomnia and anxiety

119
Q

What can anxiety disorders be treated with? What effect does this have?

A

Beta-adrenoceptor antagonists

Block of physical signs of anxiety - sweating, tremor, tachycardia - with little effect on the CNS

120
Q

Which disorders can benzodiazepines be used to treat?

A

Anxiety states and insomnia

121
Q

What non-benzodiazepines can be used to as sedative-hypnotic and anxiolytic agents?

A

Beta-adrenoceptor antagonists (inhibit peripheral signs):

Busipirone

Zoplicone

Zolpidem

122
Q

True or false: barbiturates are a general depressent.

A

True - they produce all levels of CNS depressions:

Mild sedation, surgical anaesthesia, coma and death.

123
Q

Why are barbiturates considered exceedingly toxic?

A

Low therapeutic index

Induction of liver enzymes

Abrupt withdrawal could cause death

124
Q

Although obsolete and no longer prescribed as an anxiolytic agent, when are barbiturates used?

A

In controlled situations, such as an anaesthetic and anticonvulsant

125
Q

Why are benzodiazepines considered better than barbiturates?

A

Wider therapeutic index and:

Less depression of respiratory and cardiovascular centres

Less dependence

Considered safe in overdose

126
Q

What do benzodiazepines elicit?

A
  • Sedation and induction of sleep
    • Reduce time to fall asleep
    • Increase duration of sleep
  • Reduction of anxiety and aggression
  • Reduction of muscle tone
    • Anticonvulsant but reduce coordination
  • Obliterate memory
    • Used as premedicant
127
Q

Which channels do benzodiazepines open?

A

Cl- channels

128
Q

What effect do benzodiazepines have on Cl- channels?

A
  • Increase frequency, no change in conductance or mean open time
  • Increase sensitivity of receptor with no change in maximum response
  • Results in a ceiling/plateau for maximum response
129
Q

Compared to benzodiazepines, what effect do barbiturates have on the GABA receptor?

A
  • Bind GABA receptor, prolong opening of channel
  • Increase sensitivity and maximum response
  • The plateau/ceiling is much higher (dangerous and fatal)
130
Q

How do benzodiazepines modulate the GABA receptor?

A

Allosteric modulation - they increase the affinity of the receptor for GABA.

131
Q

What are the advantages of allosteric modulators?

A
  • Ceiling of effect of inhibitors - increased therapeutic window
  • Positive modulation of endogenous agonist effect rather than continuous effect of exogenous agonist - physiological regulation continues
  • Great receptor subtype selectivity possible
132
Q

What are the disadvantages of benzodiazepines?

A
  • Tolerance: Gradual escalation of dose needed
  • Dependence: Signs of physical and psychological withdrawal (Nausea, tremor, also anxiety, depression, insomnia) - Gradual dose reduction required
  • The pharmacokinetic profile determines use: Active orally but differ in their duration of action - Generation of active and inactive metabolites
133
Q

What are the 2 short-acting benzodiazepines?

A

Oxazepam and Temazepam

134
Q

What are the 2 medium-/long-acting benzodiazepines?

A

Clonazepam and diazepam

135
Q

True or false: the more potent of two drugs is clinically superior.

A
  • False.
  • A more potent of two drugs is not necessarily clinically superior.
136
Q

When is low potency a disadvantage?

A

Only if the dose is so large that it is awkward to administer.

137
Q

True or false: potency has little clinical significance for a given therapeutic effect.

A

True

138
Q

What is pharmacological efficacy?

A

The strength of the receptor activation:

  • Full agonists: high efficacy
  • Partial agonists: low efficacy
139
Q

What is clinical efficacy?

A

The strength of the beneficial effect

140
Q

How are benzodiazepines different to barbiturates in their mechanism of action?

A
  • Benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor.
  • Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor.
141
Q

Which pharmacodynamic effect is seen with benzodiazepines?

A

They increase the potency of GABA

142
Q

Which pharmacodynamic effect is seen with barbiturates?

A

They increase the efficacy of GABA

143
Q

What is the reason for increased toxicity of barbiturates compared to benzodiazepines in overdose?

A

The direct gating or opening of the chloride ion channel.

144
Q

What are some non-benzodiazepine hypnotics?

A

Zolpidem

  • Short-term acting treatment of insomnia
  • Although non-benzodiazepine binds benzodiazepine site - Reversed by BDZ antagonist Flumazenil
  • Very little anti-convulsant activity
  • Short duration of action (t1/2 = 4hrs)

Zopiclone

  • Short-term treatment of insomnia
  • Profile similar to BDZ although structurally unrelated - binds separate site at GABAA receptor
145
Q

What is a non-benzodiazepine anxiolytic?

A

Buspirone

  • Partial agonist at 5HT1A receptors
    • Inhibitory autoreceptors regulating transmitter release
  • Slow onset - up to 2 weeks
  • Little dependence
  • Side effects: Nausea, dizziness, headache
146
Q

What is Parkinson’s disease?

A
  • Chronic, progressive degradation of dopamine from substantia nigra to corpus striatum
  • Disorder of muscle movement
147
Q

Degradation of which areas of dopamine neurons occur in Parkinson’s disease?

A

Substantia nigra to corpus striatum

148
Q

What are the motor signs and symptoms of Parkinson’s disease?

A
  • Tremor
  • Rigidity of limbs
  • Bradykinesia
  • Impairment of postural reflexes
  • Facial
    • Impassive, no blinking
  • Speech
    • Monotonous, hypophonic
  • Movement
    • Decreased manual dexterity
149
Q

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

A

Cognitive deficiencies

Depression (due to having the illness as well as altered dopamine levels)

Raised anxiety levels

Olfactory deficiencies (sense of smell leaves first)

Sleep disturbances

Fatigue

Pain

Bowel and bladder problems

Sexual dysfunction

150
Q

What is present at post-mortem in Parkinson’s disease?

A

Lewy bodies

151
Q

When can Parkinson’s disease first be diagnosed?

A

After the disease has progressed to 80% of its stage.

152
Q

True or false: asymmetric striatal dopamine degradation is common in Parkinson’s disease.

A

True

153
Q

Is management of Parksinson’s disease more palliative or curative?

A

Palliative

154
Q

What are the 4 potential mechanisms for restoration of dopamine deficiency?

A
  1. Increase DA synthesis
  2. Increase DA release
  3. DA receptor agonists
  4. Reduce DA metabolism
155
Q

How can dopaminergic/cholinergic balance in the striatum be restored?

A

Using cholinergic antagonists

156
Q

How does dopaminergic transmission in the CNS work?

A

See image

157
Q

Why can’t dopamine be ingested or injected?

A

Because it doesn’t cross the BBB. If ingested, it will induce vomiting.

158
Q

How is Noradrenaline synthesised from L-Dopa?

A

L-Dopa→Dopamine (by DOPA-decarboxylase)→NA (by Dopamine beta-hydroxylase)

159
Q

What are the 3 possible pathways for dopamine?

A
  1. Breakdown by MAO and COMT
  2. Packaged into vesicles and used at synapse
  3. Synthesised into Noradrenaline by dopamine beta-hydroxylase
160
Q

What happens to over 90% of L-dopa?

A

Metabolised in the peripheral tissues or gut.

161
Q

Which drug is used to increase dopamine synthesis?

A

Levodopa (L-DOPA)

162
Q

Why is a large dose of Levodopa required?

A

Because over 90% is metabolised in the periphery and there is peripheral conversion into dopamine and noradrenaline, causing nausea, vomiting, orthostatic hypotension and cardiac dysrhythmias.

163
Q

What is levodopa formulated with to help prevent the peripheral side effects?

A

Peripheral dopamine decarboxylase inhibitors:

  • Carbidopa
  • Benserazide
164
Q

What does Levodopa require to function?

A

Some functional dopaminergic neurons.

165
Q

Why is there debate as to when start patients on Levodopa?

A
  • Flooding the system with dopamine leads to increase in the rate of degradation of the dopaminergic neurons.
  • Mechanism unknown, except that iron is required for dopamine to be made. However, dietary antioxidants are ineffective.
166
Q

What are the effects of Levodopa?

A

Reduces rigidity, tremors and other symptoms.

167
Q

Why does the effectiveness of Levodopa decline with time?

A

Continued degeneration of dopaminergic nerves

Increase dose or incorporate other drugs

168
Q

What are the peripheral adverse effects of Levodopa?

A
  • Anorexia, nausea & vomiting
  • Tachycardia & ventricular dysrhythmias
  • Orthostatic hypotension
  • Pupil dilation (avoid in patients with glaucoma)
169
Q

What are the central adverse effects of Levodopa?

A
  • Visual & auditory hallucinations, abnormal motor movements
  • Mood changes, depression, anxiety
170
Q

Which drugs can Levodopa interact with?

A
  • Vitamin B6
  • MAO (type A) inhibitors
  • Inhalational anaesthetics
  • Anticonvulsants & neuroleptics
171
Q

Which dopamine agonists can be used to treat Parkinson’s disease?

A

Bromocriptine and carbergoline:

Can be used as monotherapy to improve bradykinesia and rigidity

May be preferred in younger patients

172
Q

When is Pergolide used in Parkinson’s disease?

A

Only as an adjunct to L-Dopa

173
Q

What are the side effects of dopamine agonists?

A
  • Similar to L-DOPA but hallucinations, confusion, delirium, nausea and hypotension more common
  • Dyskinesia less prominent
  • Arrhythmias, myocardial infarction
174
Q

What are some other dopaminergic drugs for the treatment of Parkinson’s disease?

A
  • DDC inhibitors to prevent peripheral metabolism of L-DOPA
  • Entacapone to inhibit breakdown of L-DOPA by COMT + DDC inhibitors
  • Selegiline to prevent inactivation of dopamine by MAO + DDC inhibitors.
175
Q

What are MAOB inhibitors?

A

Reduce metabolism of dopamine

No hypertensive crises like MAOA inhibitors

At recommended doses, selectivity is relative

Early use may delay disease progression

Reduced formation of free radicals

176
Q

What are COMT inhibitors?

A
  • Reduce metabolism of L-Dopa
  • Adjunct to L-DOPA
    • Increase CNS levels of L-DOPA
177
Q

What is Amantadine?

A
  • Antiviral used in influenza - observed to reduce rigidity and bradykinesia
  • Enhances release of dopamine
  • Less efficacious than L-DOPA and more rapid tolerance
  • Adverse effects
    • Restlessness, agitation, confusion & hallucinations
    • Orthostatic hypotension, urinary retention, dry mouth
  • Has anticholinergic activity
178
Q

Describe the CNS microanatomy of the extrapyramidal motor system.

A

See image.

179
Q

How can dopaminergic-cholinergic imbalance be restored?

A

Muscarinic receptor antagonists

  • Adjunct to L-DOPA only: modest effect on tremor, little effect on rigidity and bradykinesia
  • Bezhexol, benztropine, biperiden, orphenadrine: individuals may respond more favourably to one drug

Adverse effects:

  • Classic anti-muscarinic side effects
    • Reduced Salivation, Lacrimation, Urination, Defacation
    • Dry mouth, dry skin, blurred vision, constipation, urinary hesitancy, nausea, vomiting
    • Memory impairment, confusion, worsening of dyskinesias
180
Q

How is alpha-synuclein involved with Parkinson’s disease?

A
  • Thread-like fibrils of stuck-together copies of this protein are found in Lewy body deposits inside neurons in affected brain areas.
  • Mutating or overproducing can cause Parkinson’s disease
  • Small oligomers, not larger fibrils, are the real toxic drivers of the disease
181
Q

How are mitochondria implicated in Parkinson’s disease?

A
  • Tiny oxygen reactors that produce chemical energy within cells
  • When damaged by toxins they can undergo biochemical meltdown, releasing harmful oxygen-based molecules.
  • Several mitochondria-related genes can cause Parkinson’s disease when mutated
182
Q

How are smoking and drinking implicated in Parkinson’s disease?

A

Epidemiological studies have linked cigarette smoking and coffee drinking to a lower incidence of Parkinson’s disease. Unknown why.

183
Q

How is MPTP implicated in Parkinson’s disease?

A
  • Discovery of MPTP triggered by outbreak of Parkinson’s disease symptoms in a group of relatively young drug abusers
  • MPTP contamination of a batch of a meperidine analogue ‘designer drug’
  • Systemic administration of MPTP to humans and primates causes parkinson-like symptoms and selective degeneration of substantia nigra (s.n. pars compacta)
  • Depletes DA terminals
  • Lipid-soluble, crosses the blood-brain barrier
184
Q

What is drug dependence?

A

State where drug use becomes compulsive taking precedence over other needs.

185
Q

What is drug abuse?

A

Use of illicit substances (or illicit use of legal substances) characterised by recurrent and clinically significant adverse consequences.

186
Q

Why are drugs abused?

A

Rewarding effect of the psychoactive drug

Habituation or adaptation

187
Q

What are some examples of opioids?

A

Morphine and heroin

188
Q

What are the effects of opioids?

A

Euphoria

189
Q

What are some examples of CNS depressents?

A

Alcohol and diazepam

190
Q

What are the effects of CNS depressents?

A

Reduced anxiety

191
Q

What are some examples of CNS stimulants?

A

Cocaine, amphetamine and MDMA

192
Q

What are the effects of CNS stimulants?

A

Increased energy

193
Q

What are some examples of cannabinoids?

A

D-9-THC

194
Q

What are the effects of cannabinoids?

A

Altered perception

195
Q

What are some examples of hallucinogens?

A

LSD

196
Q

What are the effects of hallucinogens?

A

Altered perception

197
Q

What effect do drugs of dependence have on the reward pathways?

A

Increase dopamine in the nucleus accumbens

198
Q

What are the key transmitters modulating dopaminergic transmission?

A
  • Acetylcholine, Serotonin, Noradrenaline
  • GABA, Glutamate
  • Opioids
199
Q

What do amphetamines (CNS stimulant) do in the CNS?

A

Releases dopamine, noradrenaline and 5-HT in the CNS

Increase NA in periphery

200
Q

What are the effects of amphetamines?

A

Mood elevation, euphoria

Increase locomotor activity

201
Q

What effect do amphetamines have on physical and mental performance?

A
  • Postpone fatigue
  • Improve confidence
  • Speedy performance but less accuracy
202
Q

What happens in amphetamine overdose?

A

Anxiety, nervous & physical tension

Tremors, confusion, dizziness, time passes quickly

It’s the peripheral effects that kill you.

Hyperthermia, tachycardia, increased blood pressure, vascular collapse – death

Amphetamine psychosis – hallucinations

203
Q

What is amphetamine dependence related to?

A

Dopaminergic actions in nuclear accumbens

204
Q

Which group of people are particularly susceptible to amphetamine dependence?

A

depressives, lonely people

205
Q

What is the appetite suppressant effects of amphetamines related to?

A

5HT effect

206
Q

Which systems to cocaine and MDMA have relative selectivity for?

A

Dopamine, noradrenaline and 5-HT

207
Q

What does ecstasy (methylene dioxy met amphetamine) do to neurotransmitters?

A

Releases dopamine & serotonin

208
Q

What are the effects of ecstasy?

A

Stimulant and hallucinogenic effects

209
Q

Is ecstasy more effective than amphetamines/LSD?

A

No.

less effective than amphetamine / LSD

210
Q

What psychological effects are seen with ecstasy?

A

Feeling of closeness, empathy, love and heightened self-awarness

211
Q

What are the negative effects of ecstasy?

A
  • Psychological dependence
  • Increase heart rate, blood pressure
  • Disrupted thermoregulation (chills - sweating)
    • Potential degeneration of 5-HT & DA neurons
  • Affects mood, memory, sleep & appetite
212
Q

What are the effects of LSD (lysergic acid diethylamide)?

A

Visual, auditory & tactile hallucinations

Sensory modalities confused

Thought processes disturbed but aware drug-induced

213
Q

What happens with tolerance in LSD?

A

Need to increase dose to get same effect

Cross tolerance with other psychotomimetics

214
Q

What pharmacological effect does LSD have?

A

Agonist at 5-HT2 receptors

Activates autoreceptors on 5-HT neurones in Raphe.

215
Q

What are the psychological effects of caffeine?

A
  • Increases alertness, well-being, no euphoria - delays onset of sleep
  • Postpone boredom, fatigue, inattentiveness
  • Enhanced intellectual/motor performance
  • If reduced by fatigue/boredom
  • High doses – anxiety, tension & tremors
  • Stimulates mental activity
216
Q

Which drug class does caffeine belong to?

A

Methylxanthine

217
Q

What pharmacological effect does caffeine have?

A

Adenosine antagonist, phosphodiesterase inhibitor

Affects transmission beyond NA, DA & 5-HT

218
Q

What is dependence on caffeine like in humans?

A

No strong reinforcing effect in animals, social aspect in humans

Physical: weekend headache

219
Q

What are the subjective effects of ∆9 THC?

A

Sharpened sensory awareness, increased intensity of sounds and sights - Similar to LSD but less pronounced

Relaxation, feeling of well being - Like alcohol but without aggression

220
Q

What are the effects of ∆9 THC influenced by?

A

Both by the characteristics of the drug and the individual

221
Q

What are the pharmacological effects of ∆9 THC?

A
  • Acts on cannabinoid receptors
  • Activated by endogenous anandamide
  • G protein-coupled receptors: inhibition of adenylate cyclase » inhibition of transmission
222
Q

What are the central effects of CB1-central cannabinoid receptor stimulation?

A
  • Impaired short term memory and motor coordination
  • Catelepsy
  • Analgesia
  • Anti-emetic
  • Increased appetite
223
Q

What are the central effects of CB2-central cannabinoid receptor stimulation?

A
  • Tachycardia, sympathetic
  • Vasodilatation
  • Reduced intraoccular pressure
  • Bronchodilatation
224
Q

What are the behavioural effects of ethanol?

A

Increased self-consciousness, euphoria

Less often morose, withdrawn

Usually loud, outgoing

At higher doses aggression, mood swings

225
Q

What are the motor effects of ethanol?

A

Loss of motor coordination

Slurred speech

226
Q

What are the tissue effects of ethanol?

A

Cardiovascular protection – red wine?

Liver damage, neurodegeneration, foetal impairment

227
Q

How does ethanol act pharmacologically?

A

Inhibit glutamate receptors via NMDA channel

Inhibit Ca2+ channel opening

Enhance GABA action

Reversal by flumazenil

GABAA receptors

228
Q

What happens in increased tolerance of ethanol?

A

Enhanced clearance – switches on liver enzymes and is broken down more quickly, thus more is needed for the same effect

229
Q

What happens in physical dependence on ethanol?

A

Anxiety, insomnia, nausea, dizziness, delusions, hallucinations

Tremor, agitation, hyperactive reflexes, convulsions, delirium

Anorexia, vomiting, postural hypotension, sweating, hyperpyrexia

230
Q

How is drug use and abuse subjective?

A

Because it’s influenced both by the characteristics of the drug and the individual

231
Q

What were the 1st generation of antidepressents?

A

Tricyclic antidepressants

Monoamine Oxidase (MAO) inhibitors

232
Q

What were the 2nd generation of antidepressents?

A

Selective serotonin uptake inhibitors (SSRIs)

Selective serotonin/noradrenaline uptake inhibitors (SSNRI)

233
Q

What are the 3rd generation of antidepressents?

A

Novel monoaminergic drugs

Non-monoaminergic drugs

234
Q

What are the pharmacological actions of tricyclic antidepressents?

A

Inhibit neuronal uptake of noradrenaline and serotonin

Antagonise a-adrenoceptors, muscarinic receptors, histamine receptors and serotonin receptors

Quinidine-like membrane stabilising action at very high concentrations

235
Q

How is the selectivity for tricyclic antidepressents?

A

Poor

236
Q

What are the tricyclic antidepressents structurally similar to?

A

Phenothiazines used to treat schizophrenia

237
Q

What are the 3 major tricyclic antidepressents?

A

Imipramine

Amitryptiline

Doxepin

238
Q

What are the clinical effects of tricyclic antidepressents?

A

Takes weeks to develop despite pharmacological effects manifest in hrs.

Adaptive changes in neuronal function likely underly antidepressant activity

239
Q

What is the therapeutic window of tricyclic antidepressents like?

A

Narrow - limited efficacy

240
Q

What is the half life of the tricyclic antidepressents like?

A

Longish half-lives

Gradual accumulation possible

Sedation, anticholinergic, postural hypotension, weight gain

Confusion, mania, cardiac dysrhythmias, rarely seizures

241
Q

What is the pharmacological action of MAO inhibitors?

A

Increase levels of 5-HT, NA and DA

Delayed antidepressant effect

242
Q

What are the irreversible MAO inhibitors?

A

Phenelzine
Ttranylcypromine

243
Q

What is the cheese reaction?

A

Reaction to irreversible MAO inhibitors results in foods containing tyramine precipitating into hypertensive crisis.

244
Q

What are the reversible MAO inhibitors?

A

Moclobemide

245
Q

What selectivity is Moclobemide?

A

MAO A selective

246
Q

Why is Maclobemide less likely to cause the cheese reaction?

A

Because it competes

247
Q

What are the side effects of reversible MAO inhibitors (maclobemide)?

A

Postural hypotension, dizziness, nausea, insomnia

248
Q

What are the 3 selective serotonin reuptake inhibitors (SSRI)?

A

Fluoxetine

Paroxetine

Sertraline

249
Q

What are SSRI selective for?

A

5-HT uptake

250
Q

What is the advantage of SSRsI?

A

Few adrenergic, histaminergic and cholinergic actions

High therapeutic index

Minimal toxicity unless combined with other drugs

251
Q

What are the side effects of SSRIs?

A

Nausea

Insomnia

Agitation

Weight change

Loss of libido

252
Q

What is Venlaflaxine?

A

Selective serotonin and noradrenaline uptake inhibitor

253
Q

What are the advantages of Venlafaxine?

A

Minimal dopamine effects

Minimal receptor effects

MD1 Neuroscience (23 decks)

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