Pharmacology Flashcards
1
Q
What are the neurotransmitters and receptors of the sympathetic nervous system?
A
Noradrenaline acting on α- and β-adrenoceptors.
2
Q
What are the neurotransmitters and receptors of the parasympathetic nervous system?
A
Acetylcholine (ACh) acting on muscarinic acetylcholine receptors (mAChR).
3
Q
What are the neurotransmitters and receptors of the somatic nervous system?
A
Acetylcholine acting on nicotinic acetylcholine receptors (nAChR)
4
Q
What are the requirements for a functioning nerve ending? Use noradrenaline as an example.
A
- Synthesis/storage of neurotransmitter (e.g. NA)
- Release (mediated by Ca2+ influx) of neurotransmitter
- Post-junctional/synaptic receptors in the target cell/organ (e.g. α- and β-adrenoceptors)
- Pre-junctional/synaptic receptors that can be activated by neurotransmitter coming out of the nerve
- Inactivation of neurotransmitter (e.g. for NA, via reuptake into nerve terminal, metabolism or extraneuronal uptake leading to inactivation.
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.
6
Q
What are the 2 different means by which neurotransmitter can be inactivated?
A
- Neuronal uptake, leading to metabolism
- Extraneuronal uptake, leading to metabolism
7
Q
True or false: drugs with identified peripheral actions can also have dramatic CNS effects?
A
True.
8
Q
Which two enzymes are capable of metabolising noradrenaline?
A
MAO and COMT
9
Q
Where is MAO found?
A
In pre- and post-junctional neurons.
10
Q
Where is COMT found?
A
In post-junctional neurons.
11
Q
Which class of adrenoceptor is found on the pre-junctional side of the synapse?
A
α-adrenoceptors
12
Q
What effect do amphetamines have on the noradrenergic system?
A
Displace noradrenaline from storage vesicles.
13
Q
What effect does cocaine have on the noradrenergic system?
A
Inhibits noradrenaline reuptake.
14
Q
Which systems is noradrenaline associated with in disease?
A
Mood and blood pressure.
15
Q
Which systems is acetylcholine associated with in disease?
A
Memory and learning.
16
Q
What must all drugs do before they can have any effect in the CNS?
A
Cross the blood brain barrier.
17
Q
Which two ways can drugs cross the blood brain barrier?
A
By being lipid soluble or exploiting active processes.
18
Q
Why may lipid-soluble drugs not remain in the CNS?
A
Because there are active export processes as well.
19
Q
Which key solutes need to get into the CNS?
A
- Amino acids
- Glucose
- Large and small ions
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.
21
Q
True or False: all CNS neurotransmitters are highly localised?
A
False: some are widespread, others highly localised.
22
Q
What are the 3 catecholamines?
A
Dopamine
Noradrenaline
Adrenaline
23
Q
What is the pathway for adrenaline synthesis?
A
- Tyrosine → L-DOPA (by tyrosine hydroxylase)
- L-DOPA → Dopamine (by DOPA decarboxylase(DDC))
- Dopamine → Noradrenaline (by dopamine-β-hydroxylase)
- Noradrenaline → Adrenaline (by PNMT)
24
Q
Where in the cell is tyrosine converted to L-DOPA?
A
On its passage into the intracellular space by Tyrosine hydroxylase.
25
Where in the cell is L-DOPA converted to Dopamine?
Intracellular space by Dopa decarboxylase
26
Where in the cell is Dopamine converted to Noradrenaline?
On its passage into the vesicle by dopamine-β-hydroxylase.
27
Where in the cell is Noradrenaline converted to Adrenaline?
In the vesicle by PNMT
28
Which pathway has a broader distribution: dopamine or noradrenaline?
Noradrenaline
29
True or false: Dopamine can act either as an excitatory or inhibitory neurotransmitter?
True
30
Which pathway is affected in Parkinson's disease?
Dopaminergic pathway
31
Which therapeutics are given to treat Parkinson's disease?
* L-DOPA and peripheral DDC inhibitor
* MAO B inhibitors
* Dopamine receptor agonists
* Muscarinic receptor antagonists
32
Which neurotransmitter is there a deficiency of in Huntington's disease?
GABA
33
Which therapeutics are given to treat Huntington's disease?
* GABA agonist Baclofen
* Dopamine antagonists Chlorpromazine
34
Which 3 major functionalities is dopamine involved in?
* Movement
* Behaviour
* Dependence
35
What happens to the dopamine system in Parkinson's disease?
Depletion of dopamine in basal ganglia.
36
What are the side effects of therapeutics used to treat Parkinson's disease?
Schizophrenia-like delusions, disorientation and insomnia.
37
What role does dopamine play in Schizophrenia?
Changes in dopamine-rich areas like the frontal cortex, basal ganglia and temporal lobe can lead to Schizophrenia.
38
Where in the brain does dopamine play a role in dependence?
Nucleus accumbens
Ventral tegmental area
39
How can neurotransmitter specificity be altered?
By interfering with synthesis and inactivation.
40
How can greater drug specificity be achieved?
By targeting receptor sub-types.
41
True or false: all neurotransmitters act postsynaptically?
False
42
What are postsynaptic receptors concerned with mostly?
AP generation
43
What are presynaptic receptors concerned with?
Modulation of release using autoreceptors and heteroreceptors at the nerve terminal.
44
What are the 4 different types of receptor in the neuron?
* Ligand-gated
* G-protein coupled
* Tyrosine kinase
* Cytoplasmic/Nuclear
45
Which receptor types are mostly concerned with neuronal function?
Ligand-gated and G-protein coupled
46
Which receptor types are mostly concerned with neuronal survival?
Tyrosine kinase and cytoplasmic/nuclear
47
Over what time course do ligand-gated receptors function?
Milliseconds
48
Over what time course do G-protein coupled receptors function?
Seconds
49
Over what time course do tyrosine kinase receptors function?
Minutes
50
Over what time course do cytoplasmic/nuclear receptors function?
Hours
51
True or False: A synapse can be both excitatory and inhibitory.
False. Can be either or, but **not both**.
52
Which neurotransmitters have the potential to be excitatory and inhibitory, depending on their receptor?
Dopamine and Serotonin
53
What are the 4 elements of generic chemical neurotransmission?
* Synthesis/Storage
* Vesicular content
* Release
* Ion channels
* Calcium influx
* Inactivation
* Uptake
* Metabolism
* Receptors
* Post-junctional
* Pre-junctional
54
What can disturbed motor function, such as that seen in epileptic seizures, be due to?
Too little inhibition or too much excitation.
55
What are the two ways in which excessive excitation of motor nerves can be treated?
1. Enhance inhibitory input by GABA
2. Reduce excitatory input by Glutamate
56
Which 3 drugs can be used to reduce excitatory input by glutamate?
Phenytoin
Ethosuximide
Felbemate
57
What does phenytoin do?
Limits excitatory nerve activation.
58
What does Ethosuximide do?
Inhibits T-type Ca2+ channels.
59
What does Felbemate do?
Inhibits NMDA receptor
60
Which drug can be used to enhance inhibitory input by GABA?
Benzodiazepines - enhance GABA receptor activity.
61
How do the benzodiazepines work?
They are allosteric modulators, enhancing the activity of the natural GABA signalling mechanisms to reduce nerve activity and provide muscle relaxation.
62
What is the common side effect of Phenytoin, Ethosuximide and Felbemate?
Reduce pain sensitivity.
63
What does an analgesic do?
Targets pain/sensory pathways
64
What does a local anaesthetic do?
Provides regionalised inhibition of pain/sensory pathways with **no** loss of consciousness.
65
What does a general anaesthetic do?
Depresses cortical processing of pain/sensory signals, resulting in a loss of consciousness. Not regionalised.
66
What are the different sites of drug action of anaesthetics/analgesics?
Peripheral nerves: local anaesthetics
Spinal cord and peripheral nerves: analgesics
Brain cortex and thalamus: general anaesthetics
67
What are local anaesthetics?
Drugs that reversibly block conduction of nerve impulses at the axonal membrane.
Weak bases that differ in onset, duration and toxicity
68
What are the 3 different classes of local anaesthetics? Give examples of each.
1. **Aminoesters:** procaine
2. **Aminoamides**: lignocaine, bupivicaine and ropivicaine
3. **Benzocaine**
69
Why are the aminoesters shorter acting?
Because they are hydrolysed by esterases.
70
Why are the aminoamides longer acting?
Because they must be metabolised by the liver.
71
Why is the clinical use of local anaesthetics considered safe? What are their potential side effects?
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
72
Describe the structure of the Na+ channel.
* 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
73
Where do local anaesthetics bind the Na+ channel?
On the internal side, at S6 in the IV transmembrane domain.
74
Where do toxins bind the Na+ channel?
Extracellular domains
75
What are the 2 proposed mechanisms of action of local anaesthetics? What are the characteristics of each?
1. **Hydrophobic:** fast onset, non-use-dependent
2. **Hydrophilic:** slow onset, use-dependent
76
Which local anaesthetic utilises the hydrophobic mechanism?
Benzocaine
77
Which local anaesthetics utilise the hydrophilic mechanism of action?
Aminoesters and aminoamides.
78
What is the hydrophobic mechanism of action for local anaesthetics?
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.*
79
What is the hydrophilic mechanism of action for local anaesthetics?
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.
80
Why is it the activity of the Na+ channel that dictates the ability of a drug to bind in the hydrophilic mechanism?
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.
81
What is the primary site of action of local anaesthetics?
Sensory afferents
82
What happens as the concentration of the local anaesthetic increases?
Motor neurons and autonomics will also be blocked.
83
What are the general properties of local anaesthetics?
* 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
84
Do local anaesthetics change the resting membrane potential?
**No.**
They stabilise the axon membrane.
85
Which form of the anaesthetic species is more active, charged or uncharged, in a basic medium?
Uncharged
86
Why is it important that the effect of local anaesthetics is more pronounced in a basic medium?
Because sites of inflammation are often more acidic.
87
Which topical local anaesthetics can be purchased over the counter?
1. Lozenge: throat drops - benzocaine
2. Gels: generally poor absorption across skin
88
What are the cardiovascular effects seen in local anaesthetic toxicity?
* Direct myocardial depression
* Depression of vasomotor centre
* Hypotension (except cocaine)
89
What are the CNS effects of local anaesthetics proportional to?
Blood level
90
Which CNS side effects are seen with increasing blood level of local anaesthetics?
1. Excitation
2. Tremor
3. Convulsion
4. Respiratory arrest
91
What type of reaction to local anaesthetics is not proportional to blood level?
Hypersensitivity (allergic) reactions
92
What is seen at the 4 different stages of anaesthesia seen in **general anaesthetics**?
**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
93
Which general anaesthetics are administered via inhalation?
* Desflurane
* Sevoflurane
* Isoflurane
94
Which general anaesthetics are administered intravenously?
Propofol
Thiopentone
95
What pharmacokinetic properties are important to consider with general anaesthetics?
* Dose and duration of action
* Absorption (inhalation)
* Distribution (Vd, t1/2)
* Biotransformation (metabolism)
* Elimination (How – kidneys/liver/lungs)
* Drug interactions
96
What are the two pharmacodynamic theories on the mechanism of action of **general anaesthetics**?
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)
97
What are the respiratory side effects of general anaesthetics?
All anaesthetics increase likelihood of:
Impaired ventilation
Depression of respiratory centre: retention of secretions
Obstruction of airways
98
What are the cardiovascular side effects of general anaesthetics?
All anaesthetics increase likelihood of
* Decreased vasomotor centre function
* Depress contractility
* Peripheral vasodilation
* Cardiac arrhythmias
* Inadequate response to fall in BP or CO
99
What parts of the chemical neurotransmission pathway can drugs interfere with?
* Synthesis
* Storage
* Release
* Inactivation
* Reuptake
* Metabolism
* Receptor
100
True or false: molecular and therapeutic mechanisms are always known.
False.
While molecular mechanisms may be known, therapeutic mechanisms may not always be known.
101
What effects do cocaine and amphetamine have on noradrenergic transmission?
Increase NA levels in the synaptic cleft.
102
What other systems do cocaine and amphetamines affect, other than the noradrenergic system?
Dopaminergic and serotonergic systems.
103
How do cocaine and amphetamines differ in their mechanism of action?
Cocaine blocks neuronal uptake, whereas amphetamine displaces monoamine out of the vesicle.
104
Which nerve types excessively discharge in epilepsy?
Motor nerves
105
What are the 2 different therapeutic approaches for epilepsy?
1. Limit excitatory nerve action
2. Enhance GABA receptor activity
106
Which drug is used to reduce excitatory input by glutamate?
Phenytoin
107
How does phenytoin work?
Inhibits Na+ channels on excitatory neurons
108
In which state must the Na+ channel be to allow phenytoin to bind?
Open - thus the action of phenytoin is enhanced during high frequency firing.
109
How do the benzodiazepines work?
Enhance GABA receptor activity, increasing inhibition and therefore decreasing activity of the motor nerve.
110
What type of a receptor is GABAA?
Ligand-gated receptor
111
Which neurotransmitters have been implicated in sedation and anxiety?
GABA (via GABAA receptor) and serotonin (via CNS pre-junctional receptors)
112
Which neurotransmitters have been implicated in anxiety?
Noradrenaline and neuropeptide Y
113
Which neurotransmitters have been implicated in sedation?
Histamine (H1 receptor)
114
Which neurotransmitter can also cause peripheral tachycardia?
Noradrenaline (hence, anxiety)
115
Which diseases or disorders are benzodiazepines used in?
* Epilepsy
* Anxiety
* Sleep disorders
* Premedication
* Sedation for medical procedures
* Acute alcohol withdrawal
116
What is insomnia?
Not being able to sleep when, or as well as one should.
117
What is anxiety?
Manifestation of “fear response” (marked sweating, tachycardia, chest pains, trembling, etc.) in an anticipatory manner, independent of external events.
118
What are two major symptoms/disorders for which sedative-hypnotic and anxiolytic agents are used?
Insomnia and anxiety
119
What can anxiety disorders be treated with? What effect does this have?
Beta-adrenoceptor antagonists
Block of physical signs of anxiety - sweating, tremor, tachycardia - with little effect on the CNS
120
Which disorders can benzodiazepines be used to treat?
Anxiety states and insomnia
121
What non-benzodiazepines can be used to as sedative-hypnotic and anxiolytic agents?
Beta-adrenoceptor antagonists (inhibit peripheral signs):
Busipirone
Zoplicone
Zolpidem
122
True or false: barbiturates are a general depressent.
True - they produce all levels of CNS depressions:
Mild sedation, surgical anaesthesia, coma and death.
123
Why are barbiturates considered exceedingly toxic?
Low therapeutic index
Induction of liver enzymes
Abrupt withdrawal could cause death
124
Although obsolete and no longer prescribed as an anxiolytic agent, when are barbiturates used?
In controlled situations, such as an anaesthetic and anticonvulsant
125
Why are benzodiazepines considered better than barbiturates?
Wider therapeutic index and:
Less depression of respiratory and cardiovascular centres
Less dependence
Considered safe in overdose
126
What do benzodiazepines elicit?
* 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
Which channels do benzodiazepines open?
Cl- channels
128
What effect do benzodiazepines have on Cl- channels?
* 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
Compared to benzodiazepines, what effect do barbiturates have on the GABA receptor?
* Bind GABA receptor, prolong opening of channel
* Increase sensitivity and maximum response
* The plateau/ceiling is much higher (dangerous and fatal)
130
How do benzodiazepines modulate the GABA receptor?
Allosteric modulation - they increase the affinity of the receptor for GABA.
131
What are the advantages of allosteric modulators?
* 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
What are the disadvantages of benzodiazepines?
* 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
What are the 2 short-acting benzodiazepines?
Oxazepam and Temazepam
134
What are the 2 medium-/long-acting benzodiazepines?
Clonazepam and diazepam
135
True or false: the more potent of two drugs is clinically superior.
* False.
* A more potent of two drugs is not necessarily clinically superior.
136
When is low potency a disadvantage?
Only if the dose is so large that it is awkward to administer.
137
True or false: potency has little clinical significance for a given therapeutic effect.
True
138
What is pharmacological efficacy?
The strength of the receptor activation:
* Full agonists: high efficacy
* Partial agonists: low efficacy
139
What is clinical efficacy?
The strength of the beneficial effect
140
How are benzodiazepines different to barbiturates in their mechanism of action?
* 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
Which pharmacodynamic effect is seen with benzodiazepines?
They increase the potency of GABA
142
Which pharmacodynamic effect is seen with barbiturates?
They increase the efficacy of GABA
143
What is the reason for increased toxicity of barbiturates compared to benzodiazepines in overdose?
The direct gating or opening of the chloride ion channel.
144
What are some non-benzodiazepine hypnotics?
**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
What is a non-benzodiazepine anxiolytic?
**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
What is Parkinson's disease?
* Chronic, progressive degradation of dopamine from substantia nigra to corpus striatum
* Disorder of muscle movement
147
Degradation of which areas of dopamine neurons occur in Parkinson's disease?
Substantia nigra to corpus striatum
148
What are the motor signs and symptoms of Parkinson's disease?
* Tremor
* Rigidity of limbs
* Bradykinesia
* Impairment of postural reflexes
* Facial
* Impassive, no blinking
* Speech
* Monotonous, hypophonic
* Movement
* Decreased manual dexterity
149
What are the non-motor signs and symptoms of Parkinson's disease?
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
What is present at post-mortem in Parkinson's disease?
Lewy bodies
151
When can Parkinson's disease first be diagnosed?
After the disease has progressed to 80% of its stage.
152
True or false: asymmetric striatal dopamine degradation is common in Parkinson's disease.
True
153
Is management of Parksinson's disease more palliative or curative?
Palliative
154
What are the 4 potential mechanisms for restoration of dopamine deficiency?
1. Increase DA synthesis
2. Increase DA release
3. DA receptor agonists
4. Reduce DA metabolism
155
How can dopaminergic/cholinergic balance in the striatum be restored?
Using cholinergic antagonists
156
How does dopaminergic transmission in the CNS work?
See image
157
Why can't dopamine be ingested or injected?
Because it doesn't cross the BBB. If ingested, it will induce vomiting.
158
How is Noradrenaline synthesised from L-Dopa?
L-Dopa→Dopamine (by DOPA-decarboxylase)→NA (by Dopamine beta-hydroxylase)
159
What are the 3 possible pathways for dopamine?
1. Breakdown by MAO and COMT
2. Packaged into vesicles and used at synapse
3. Synthesised into Noradrenaline by dopamine beta-hydroxylase
160
What happens to over 90% of L-dopa?
Metabolised in the peripheral tissues or gut.
161
Which drug is used to increase dopamine synthesis?
Levodopa (L-DOPA)
162
Why is a large dose of Levodopa required?
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
What is levodopa formulated with to help prevent the peripheral side effects?
Peripheral dopamine decarboxylase inhibitors:
* Carbidopa
* Benserazide
164
What does Levodopa require to function?
Some functional dopaminergic neurons.
165
Why is there debate as to when start patients on Levodopa?
* 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
What are the effects of Levodopa?
Reduces rigidity, tremors and other symptoms.
167
Why does the effectiveness of Levodopa decline with time?
Continued degeneration of dopaminergic nerves
Increase dose or incorporate other drugs
168
What are the peripheral adverse effects of Levodopa?
* Anorexia, nausea & vomiting
* Tachycardia & ventricular dysrhythmias
* Orthostatic hypotension
* Pupil dilation (avoid in patients with glaucoma)
169
What are the central adverse effects of Levodopa?
* Visual & auditory hallucinations, abnormal motor movements
* Mood changes, depression, anxiety
170
Which drugs can Levodopa interact with?
* Vitamin B6
* MAO (type A) inhibitors
* Inhalational anaesthetics
* Anticonvulsants & neuroleptics
171
Which dopamine agonists can be used to treat Parkinson's disease?
Bromocriptine and carbergoline:
Can be used as monotherapy to improve bradykinesia and rigidity
May be preferred in younger patients
172
When is Pergolide used in Parkinson's disease?
Only as an adjunct to L-Dopa
173
What are the side effects of dopamine agonists?
* Similar to L-DOPA but hallucinations, confusion, delirium, nausea and hypotension more common
* Dyskinesia less prominent
* Arrhythmias, myocardial infarction
174
What are some other dopaminergic drugs for the treatment of Parkinson's disease?
* 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
What are MAOB inhibitors?
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
What are COMT inhibitors?
* Reduce metabolism of L-Dopa
* Adjunct to L-DOPA
* Increase CNS levels of L-DOPA
177
What is Amantadine?
* 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
Describe the CNS microanatomy of the extrapyramidal motor system.
See image.
179
How can dopaminergic-cholinergic imbalance be restored?
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
How is alpha-synuclein involved with Parkinson's disease?
* 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
How are mitochondria implicated in Parkinson's disease?
* 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
How are smoking and drinking implicated in Parkinson's disease?
Epidemiological studies have linked cigarette smoking and coffee drinking to a lower incidence of Parkinson's disease. Unknown why.
183
How is MPTP implicated in Parkinson's disease?
* 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
What is drug dependence?
State where drug use becomes compulsive taking precedence over other needs.
185
What is drug abuse?
Use of illicit substances (or illicit use of legal substances) characterised by recurrent and clinically significant adverse consequences.
186
Why are drugs abused?
Rewarding effect of the psychoactive drug
Habituation or adaptation
187
What are some examples of opioids?
Morphine and heroin
188
What are the effects of opioids?
Euphoria
189
What are some examples of CNS depressents?
Alcohol and diazepam
190
What are the effects of CNS depressents?
Reduced anxiety
191
What are some examples of CNS stimulants?
Cocaine, amphetamine and MDMA
192
What are the effects of CNS stimulants?
Increased energy
193
What are some examples of cannabinoids?
D-9-THC
194
What are the effects of cannabinoids?
Altered perception
195
What are some examples of hallucinogens?
LSD
196
What are the effects of hallucinogens?
Altered perception
197
What effect do drugs of dependence have on the reward pathways?
Increase dopamine in the nucleus accumbens
198
What are the key transmitters modulating dopaminergic transmission?
* Acetylcholine, Serotonin, Noradrenaline
* GABA, Glutamate
* Opioids
199
What do amphetamines (CNS stimulant) do in the CNS?
Releases dopamine, noradrenaline and 5-HT in the CNS
Increase NA in periphery
200
What are the effects of amphetamines?
Mood elevation, euphoria
Increase locomotor activity
201
What effect do amphetamines have on physical and mental performance?
* Postpone fatigue
* Improve confidence
* Speedy performance but less accuracy
202
What happens in amphetamine overdose?
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
What is amphetamine dependence related to?
Dopaminergic actions in nuclear accumbens
204
Which group of people are particularly susceptible to amphetamine dependence?
depressives, lonely people
205
What is the appetite suppressant effects of amphetamines related to?
5HT effect
206
Which systems to cocaine and MDMA have relative selectivity for?
Dopamine, noradrenaline and 5-HT
207
What does ecstasy (methylene dioxy met amphetamine) do to neurotransmitters?
Releases dopamine & serotonin
208
What are the effects of ecstasy?
Stimulant and hallucinogenic effects
209
Is ecstasy more effective than amphetamines/LSD?
No.
less effective than amphetamine / LSD
210
What psychological effects are seen with ecstasy?
Feeling of closeness, empathy, love and heightened self-awarness
211
What are the negative effects of ecstasy?
* Psychological dependence
* Increase heart rate, blood pressure
* Disrupted thermoregulation (chills - sweating)
* Potential degeneration of 5-HT & DA neurons
* Affects mood, memory, sleep & appetite
212
What are the effects of LSD (lysergic acid diethylamide)?
Visual, auditory & tactile hallucinations
Sensory modalities confused
Thought processes disturbed but aware drug-induced
213
What happens with tolerance in LSD?
Need to increase dose to get same effect
Cross tolerance with other psychotomimetics
214
What pharmacological effect does LSD have?
Agonist at 5-HT2 receptors
Activates autoreceptors on 5-HT neurones in Raphe.
215
What are the psychological effects of caffeine?
* 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
Which drug class does caffeine belong to?
Methylxanthine
217
What pharmacological effect does caffeine have?
Adenosine antagonist, phosphodiesterase inhibitor
Affects transmission beyond NA, DA & 5-HT
218
What is dependence on caffeine like in humans?
No strong reinforcing effect in animals, social aspect in humans
Physical: weekend headache
219
What are the subjective effects of ∆9 THC?
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
What are the effects of ∆9 THC influenced by?
Both by the characteristics of the drug and the individual
221
What are the pharmacological effects of ∆9 THC?
* Acts on cannabinoid receptors
* Activated by endogenous anandamide
* G protein-coupled receptors: inhibition of adenylate cyclase » inhibition of transmission
222
What are the central effects of CB1-central cannabinoid receptor stimulation?
* Impaired short term memory and motor coordination
* Catelepsy
* Analgesia
* Anti-emetic
* Increased appetite
223
What are the central effects of CB2-central cannabinoid receptor stimulation?
* Tachycardia, sympathetic
* Vasodilatation
* Reduced intraoccular pressure
* Bronchodilatation
224
What are the behavioural effects of ethanol?
Increased self-consciousness, euphoria
Less often morose, withdrawn
Usually loud, outgoing
At higher doses aggression, mood swings
225
What are the motor effects of ethanol?
Loss of motor coordination
Slurred speech
226
What are the tissue effects of ethanol?
Cardiovascular protection – red wine?
Liver damage, neurodegeneration, foetal impairment
227
How does ethanol act pharmacologically?
Inhibit glutamate receptors via NMDA channel
Inhibit Ca2+ channel opening
Enhance GABA action
Reversal by flumazenil
GABAA receptors
228
What happens in increased tolerance of ethanol?
Enhanced clearance – switches on liver enzymes and is broken down more quickly, thus more is needed for the same effect
229
What happens in physical dependence on ethanol?
Anxiety, insomnia, nausea, dizziness, delusions, hallucinations
Tremor, agitation, hyperactive reflexes, convulsions, delirium
Anorexia, vomiting, postural hypotension, sweating, hyperpyrexia
230
How is drug use and abuse subjective?
Because it's influenced both by the characteristics of the drug and the individual
231
What were the 1st generation of antidepressents?
Tricyclic antidepressants
Monoamine Oxidase (MAO) inhibitors
232
What were the 2nd generation of antidepressents?
Selective serotonin uptake inhibitors (SSRIs)
Selective serotonin/noradrenaline uptake inhibitors (SSNRI)
233
What are the 3rd generation of antidepressents?
Novel monoaminergic drugs
Non-monoaminergic drugs
234
What are the pharmacological actions of tricyclic antidepressents?
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
How is the selectivity for tricyclic antidepressents?
Poor
236
What are the tricyclic antidepressents structurally similar to?
Phenothiazines used to treat schizophrenia
237
What are the 3 major tricyclic antidepressents?
Imipramine
Amitryptiline
Doxepin
238
What are the clinical effects of tricyclic antidepressents?
Takes weeks to develop despite pharmacological effects manifest in hrs.
Adaptive changes in neuronal function likely underly antidepressant activity
239
What is the therapeutic window of tricyclic antidepressents like?
Narrow - limited efficacy
240
What is the half life of the tricyclic antidepressents like?
Longish half-lives
Gradual accumulation possible
Sedation, anticholinergic, postural hypotension, weight gain
Confusion, mania, cardiac dysrhythmias, rarely seizures
241
What is the pharmacological action of MAO inhibitors?
Increase levels of 5-HT, NA and DA
Delayed antidepressant effect
242
What are the irreversible MAO inhibitors?
Phenelzine
Ttranylcypromine
243
What is the cheese reaction?
Reaction to irreversible MAO inhibitors results in foods containing tyramine precipitating into hypertensive crisis.
244
What are the reversible MAO inhibitors?
Moclobemide
245
What selectivity is Moclobemide?
MAO A selective
246
Why is Maclobemide less likely to cause the cheese reaction?
Because it competes
247
What are the side effects of reversible MAO inhibitors (maclobemide)?
Postural hypotension, dizziness, nausea, insomnia
248
What are the 3 selective serotonin reuptake inhibitors (SSRI)?
Fluoxetine
Paroxetine
Sertraline
249
What are SSRI selective for?
5-HT uptake
250
What is the advantage of SSRsI?
Few adrenergic, histaminergic and cholinergic actions
High therapeutic index
Minimal toxicity unless combined with other drugs
251
What are the side effects of SSRIs?
Nausea
Insomnia
Agitation
Weight change
Loss of libido
252
What is Venlaflaxine?
Selective serotonin and noradrenaline uptake inhibitor
253
What are the advantages of Venlafaxine?
Minimal dopamine effects
Minimal receptor effects
