Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Pharmacology 3 > Nervous System > Flashcards

Nervous System Flashcards

1
Q

What is the Parasympathetic System?

A

The parasympathetic nervous system is one of the two main divisions of the autonomic nervous system (ANS). Its general function is to control homeostasis and the body’s rest-and-digest response.

Regulated through Acetylcholine Receptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the sub-types of Acetylcholine Receptors?

A

Acetylcholine receptors can be divided into two subtypes:
Nicotinic (ligand-gated ion channel) and Muscarinic (g-protein coupled)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Explain the synthesis step of Acetylcholine

A

Choline is taken up into the nerve terminal by a specific transporter. Choline is acetylated by Choline acetyltransferase (ChAT).

Rate-limiting process in ACh synthesis is the choline transport, which is determined by the extracellular concentration and hence is linked to the rate at which ACh is released.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the function of Hemicholinium?

A

Competitive
Blocks the transport of choline into the nerve terminals.

By blocking the rate-limiting process, transport of choline, you will inhibit ACh synthesis.

It has no therapeutic use given that this will work systemically and will inhibit production everywhere

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Explain the process of storing ACh

A

Proton pump moves protons into the vesicle in an ATP-dependent manner, creating a proton gradient.

VAChT uses this proton gradient to pump ACh molecules into the vesicle in exchange for protons that are moved out of the vesicles

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the action of Vesamicol?

A

Non-Competitive and Reversible

Blocks the intracellular transporter (VAChT) responsible for uptake into synaptic vesicles

Reduces release of ACh

Little therapeutic use but valuable experimental tool

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Explain the release of ACh

A

ACh is released by exocytosis from pre-synaptic nerve terminals following the depolarisation of the nerve by an action potential. This stimulates the entry of calcium via voltage-gated ion channels.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the action of Tetrodotoxin?

A

Blocks voltage-gated Na+ channels, thus preventing an action potential from being generated.

This blocks the action-potential dependent release of neurotransmitter from nerve-terminals

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is the action of Botulinum toxin (BOTOX)?

A

Causes the degradation of (SNARE) proteins that cause vesicles to dock on to the membrane. Thus there is no docking, and the vesicles are unable to release its content

The effectiveness of this toxin is not about its pharmacology but about its locality

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What can botulinum toxin be used to treat?

A
  • Persistent and disabling eye spasm
  • Excessive exterior muscle tone
  • Bladder over activity
  • Squint (injection into extra ocular muscles)
  • Excessive salivary secretion or sweating
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are non-depolarising blocking agents?

A

Competitive Receptor Antagonist for the ACh Receptors of the endplate

Blocks numerous numbers of receptors, and given that transmission is all-or-nothing, the binding of ACh is not enough to elicit a response

They also block facilitator presynaptic autoreceptors, and thus inhibit the release of ACh during repetitive stimulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the action of Suxamethonium

A

It is a depolarising blocker.

It activates the nicotinic receptor and cause a small amount of sustained depolarisation at the endplate, that ultimately cause the nicotinic receptors to inactivate (i.e. the pore do not open in response to the binding of agonist - H gates)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are anticholinesterases?

A

Drugs that prolong the existence of acetylcholine after it is released from cholinergic nerve endings by inhibiting acetylcholinesterase

They are broken down by cholinesterase and so it has short duration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are the side effects of anticholinesterases?

A
  • Bradycardia
  • Potassium release
  • Raised intraocular pressure
  • Prolonged paralysis in individuals with low plasma cholinesterase levels
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is Myasthenia Gravis?

A

An autoimmune disease characterised by fluctuating, sometimes fatal, muscle weakness

Result of an autoimmune attack against nAChR at the NMJ, so the muscles are less likely to respond to the ACh. ACh release is normal but its effect on the post-synaptic membrane is reduced

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the action of Neostigmine?

A

Inhibits the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission.

Approved treatment for Myasthenia Gravis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are the effects of Parasympathetic activation?

A
  • Dilation of veins and arterioles
  • Decreased heart rate and force of contraction
  • Bronchi contraction
  • Constriction of pupils
  • Contraction of Ciliary Muscles
  • Contraction of GI tract
  • Increase secretion of the salivary glands
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are the actions of directly acting mAChR agonists?

A

They have mainly muscarinic effect at end effectors. Any nicotinic effect at the ganglia can amplify the muscarinic effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Give two examples of directly acting mAChR agonists

A

Muscarine and Pilocarpine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Describe the key structures of ACh as an agonist

A

The key features of the ACh molecule is the quaternary ammonium group, which bears a positive charge, and the ester group, which bears a partial negative charge and is susceptible to rapid hydrolysis by cholinesterase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Explain the structure/function relationship of different mAChR agonists

A
  • Methacholine (addition of methyl to ACh): methyl group makes it less susceptible to AChesterase and more lenient to muscarinic
  • Carbachol: amine group added to ACh makes it harder to break down by AChesterase but has more specificity for nicotinic
  • Bethanecol: has both amine and methyl group which makes it resilient to being broken down
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the therapeutic uses of cholinomimetics?

A
  1. Glaucoma (Pilocarpine)
  2. Intestinal and Urinary Bladder Atony (Bethanecol and Neostigmine)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Give two examples of muscarinic antagonists

A
  • Atropine
  • Hyoscine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What are the effects of muscarinic antagonists?

A
  1. Decreased motility of gastrointestinal system - atony and constipation
  2. Pupil dilation, Paralysis of accommodation and Increased intraocular pressure
  3. Tachycardia - used to treat bradycardia
  4. Decreases bladder motor activity
  5. Decreased activity of exocrine glands - dry eyes, mouth and skin
  6. Bronchodilation and reduced mucous secretions
  7. Excitatory effects of the central nervous system
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What are the therapeutic uses of mAChR antagonists?

A
  1. Asthma (Ipratropium)
  2. Acute myocardial infarction with sinus bradycardia (Atropine or derivatives)
  3. Pre-anaesthetic medication (Atropine or derivatives)
  4. Ophthalmological Uses (Atropine or shorter acting derivatives used topically (e.g. tropicamide))
  5. Parkinson’s Disease (Atropine derivatives (e.g. benztropine))
  6. Treatment of Poisoning of cholinomimetics (Atropine or derivatives)
  7. Urinary Incontinence (Oxybutynin, tolterodine and darifenacin)
  8. Peptic Ulcers (Pirenzipine)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Explain the termination of ACh Action

A

Two enzymes are involved: Acetylcholinesterase and Butyrylcholinesterase

AChE is a serine hydrolase, essential for the deactivation of ACh. Highly selective for ACh and substances with a similar structure

Butyrylcholinesterase is a general esterase and has a wide distribution in mammals. Hydrolyses faster than ACh and other esters such as suxamethonium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Give three examples of Reversible Inhibitors of cholinesterases

A
  • Physostigmine
  • Neostigmine
  • Carbaril
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Give three examples of irreversible inhibitors of cholinesterases

A
  • Insecticides
  • Ecothiphate
  • Military Nerve Gases
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What are the therapeutic uses of cholinesterase inhibitors?

A

1 Glaucoma (Physostigmine, echothiphate)
- Normally could not be given systemically because of the CNS effects, but can avoid side effects by local administration to tissue, such as eye

2 Intestinal atony, Urinary bladder atony (Neostigmine)
3 Intoxication by antimuscarinic drugs (Physostigmine )

4 Reversal of non-depolarising block at NMJ (Physostigmine, neostigmine)

5 Alleviating cognitive decline in Alzheimer’s Disease ( tacrine, donepezil)

6 Myasthenia Gravis (Edrophonium is used as diagnostic, neostigmine has longer action for treatment )

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is the sympathetic nervous system?

A

The sympathetic nervous system (SNS) is one of two main divisions of the autonomic nervous system (ANS). Its general action is to mobilize the body’s fight-or-flight response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What receptors ar involved in sympathetic pathway?

A
  • Nicotinic Acetylcholine Receptors
  • Adrenoceptors
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What are the classes of Adrenoceptors?

A

Can be divided into two classes based on agonist potencies
- alpha ( noradrenaline > adrenaline > isoprenaline)
- beta (isoprenaline > adrenaline > noradrenaline)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What are the subclasses of adrenoceptors?

A

Determine by antagonist selectivity

alpha 1 and alpha 2
beta 1, beta 2 and beta 3.

All of these receptors are 7 transmembrane domain G protein-coupled receptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What is alpha 1’s signalling pathway?

A

Coupled through Gq/11 to phospholipase C which facilitates the conversion of PIP2 to DAG and IP3.

Produce their effect through the release of intracellular Ca2+

Cause smooth muscle contraction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What is the signalling pathway of alpha2?

A

Coupled through Gi/Go to inhibit adenylyl cyclase and reduce cAMP as well as inhibit Ca2+ channels and activated K+ channels

Inhibition of transmitter release

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What is the signalling pathway of all three of the beta-adrenoceptors?

A

Coupled through Gs to stimulate adenylyl cyclase and increase cAMP

Heart Muscle contraction, smooth muscle relaxation and lipolysis/thermogenesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

Explain the synthesis and Storage of Noradrenaline

A

L-Tyrosine is converted into L-DOPA using tyrosine hydroxylase –> Main control point for noradrenaline synthesis
L-DOPE is converted into dopamine using DOPA decarboxylase
Dopamine is finally converted into noradrenaline using Dopamine beta-hydroxylase

Taken up into vesicles

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

Explain the release of noradrenaline

A

Action potential will cause the depolarization of the nerve terminal. This causes an influx of Ca2+.

Thus calcium-dependent exocytosis will cause the vesicles to fuse and release the noradrenaline. It can then act on the receptors to produce its effect.

NA can act on a pre-synaptic receptor (alpha 2) to regulate its own release –> negative feedback regulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Explain the termination of NA action

A

Two main Catecholamine-metabolising enzymes are located within the cell

Uptake 1: Neuronal uptake (75% of released NA). NA taken back up into the cell by the NET. Once in cell, susceptible to degradation by Monoamine oxidase (MOA)

Uptake 2: Extra-Neuronal Uptake. Surrounding cells take up NA. This is to limit its spread. This has a low affinity so it will also transport similar compounds. Once taken up, can be broken down by Catechol-O-methyl-transferase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

WHat is the action of alpha-methyl tyrosine?

A

Inhibits tyrosine hydroxylase

USed experimentally however is no longer used clinically

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

What is the action of Carbidopa?

A

It is a hydrazine derivative of dopa, which inhibits dopa decarboxylase

Dopamine cannot cross the barrier so carbidopa is given at the same time of L-DOPA to prevent the peripheral conversion so that it can get into brain and then convert

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What is the action of methyl-DOPA?

A

it is taken up by noradrenergic neurons, which convert it to the false transmitter α-methylnoradrenaline. This substance cannot be deaminated by MOA, so it will accumulate and displace NA.

Reduction in NA release

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

What is the action of Reserpine?

A

Potently blocks the transport of noradrenaline and other amines into storage vesicles by blocking the VMAT.

Therefore, Noradrenaline accumulates instead in the cytoplasm and is degraded by MAO

Reduced levels of noradrenaline

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

What is the action of guanethidine?

A

It blocks the impulse conduction in the nerve cells, reducing release of NA

It also accumulates in vesicles and displaces NA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

How do Tyramine, Amphetamine and Ephedrine work?

A

They all are structurally similar to noradrenaline and, although much less potent, have quantitatively similar effects.

Structural similarity means that they can be taken up into cell in uptake 1. Recognised by vesicle and taken in. Will displace NA. NA can then exit via reverse uptake 1 and can then be used on the synapse

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

How does cocaine and tricyclic antidepressants works?

A

They block uptake 1 of NA. This will thus increase concentration of NA in synaptic cleft

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

Give examples of alpha 1 anatgonists

A

1 Phenoxybenzamine: targets alpha-AR and uptake 1. Results in vasodilation (non-sel; irrev)
2. Phentolamine: Targets alpha-AR. Results in vasodilation (non-sel; rev)
3. Prazosin: Targets alpha1-AR. Results in vasodilation
4. Labetalol and Carvedilol: Targets a mixture of alpha1 and beta adrenoceptors. Causes reduced BP and SVR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

Give examples of Beta antagonists

A

Propanolol: Targets B1 and B2. Causes Negative Inotropy

Metoprolol: Targets B1. Causes Negative Inotropy

Nebivolol: Targets B1 and Increases NO. Results in Negative Inotropy and vasodilation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

What is anxiety?

A

It is a neurosis, an exaggeration of normal behaviour, however, diagnosing the difference between “normal” and “pathological” srares of anxiety is difficult to draw

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

How can anxiety manifest?

A
  1. Verbal complaint
  2. Somatic and autonomic effects - restlessness, agitation, increased sweating and tachycardia
  3. Interference with normal “productive” activities
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

Explain the fear response pathway

A

Results from activation of the hypothalamic-pituitary-adrenal axis (HPA)

  1. Increased excitability in amygdala triggers hypothalamic corticotropin-releasing factor (CRF)
  2. CRF stimulates pituitary to release adrenocorticotrophic hormone (ACTH)
  3. ACTH triggers glucocorticoid release (cortisol) from the adrenal cortex
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

What role do hippocampus and amygdala play in HPA?

A

Hippocampus exerts negative feedback on the hypothalamus thereby suppressing cortisol release

Amygdala exerts positive feedback on the hypothalamus thereby increasing cortisol release

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

How does anxiety arise?

A

Chronic exposure to circulating cortisol can lead to the inhibition of hippocampal activity reduces negative influence

May involve cell death in the hippocampus

Anxiety can be related to either increased activity in amygdala or decreased hippocampal activity

54
Q

How do drugs acting on the serotonin (5-HT) pathway work?

A

5- HT released by a group of neurons that cluster together in the raphe nuclei

5-HT1A receptors are expressed on the soma and dendrites of 5-HT-containing neurons, where they function as inhibitory autoreceptors

Activation might result in reduced excitability

55
Q

Why do SSRIs and buspirone have delayed anxiolytic effects?

A

Induce slow desensitisation of somato-dendritic 5-HT1A autoreceptors, resulting in heightened excitation of serotonergic neurons and enhanced 5-HT release

56
Q

What is the effect of Buspirone?

A

5-HT1A partial agonist

Slow desensitisation of somato-dendritic 5-HT1A receptors

Increase serotonin release

57
Q

What are benzodiazepines?

A

Composed of a seven-membered ring fused to an aromatic ring. Four main substituent groups (R1 - R4) can be modified without loss activity

58
Q

What are the pharmacological effects of benzodiazepines?

A
  1. Reduction of anxiety and aggression
  2. Sedation and induction of sleep
  3. Reduction in muscle tone and co-ordination
  4. Anticonvulsant effects
59
Q

What is the mechanism of action of benzodiazepines?

A

Act selectively on GABAA receptors, which mediate inhibitory synaptic transmission throughout the CNS.

They act as positive allosteric modulators to facilitate the opening of GABA-activated chloride channels thus enhancing the response to GABA

Does not alter individual conductance or open time

60
Q

How does the subunit of the GABAA receptor affect benzodiazepine effects?

A

GABAA receptors containing α1,2,3 or 5 are sensitive to benzodiazepines while those with α4 and α6 are not

Due to a difference in arginine at position 101 which stops sensitivity. Usually histidine in α1,2,3 and 5.

61
Q

What is the relationship between α1 and benzodiazepines?

A

Benzodiazepines given to transgenic mice with a point mutation (arginine at point 101 in α1 subunit) are still anxiolytic but no longer sedative

Observation suggest it is possible to develop subunit selective drugs

62
Q

What is the action of Flumazenil?

A

Flumazenil a competitive inhibitor that blocks the effect of BDZs and are useful for treating acute overdose

63
Q

What are the toxic effects of acute overdose of benzodiazepines?

A

Prolonged sleep but little serious depression of respiration it cardiovascular function unless with alcohol where respiratory depression can be life-threatening

64
Q

What can be said about tolerance to BDZs?

A

Of little importance because BDZs do not induce hepatic microsomal enzymes

Tissue tolerance does occur due to receptor change

65
Q

Describe the pharmacokinetics of BDZs?

A
  • Well absorbed from the gut and bind strongly to plasma proteins
  • Accumulate in fat due to high lipid solubility
  • Subject to phase 1 and 2 metabolism –> phase 1 metabolism by CYP450 biotransform molecules to retain activity
  • Therefore, duration of action of different benzodiazepines can be long, medium or short depending active oxidative metabolites formed
66
Q

What drugs can be used to treat insomnia?

A
  • benzodiazepines (e.g. temazepam) and related drugs (e.g. zolpidem, zopiclone, which also act at the benzodiazepine binding site)
  • chloral hydrate and triclofos, which were used formerly in children, but this is seldom justified
  • sedating antihistamines (e.g. promethazine), which cause drowsiness are less suitable for treating insomnia. They can impair performance the next day
67
Q

What are affective disorders?

A

Characterised by changes in mood, including depression and/or mania

68
Q

What are the two forms of depression syndrome?

A
  • Bipolar depressive syndrome: patient oscillates between depression and mania. Suggest a biochemical imbalance
  • Unipolar depressive syndrome: Depression without associated mania
69
Q

What brains are involved in mood (and, by inference, depression)?

A
  • Frontal cortex and Hippocampus: memory impairment, worthlessness, hopelessness, guilt and doom
  • Hypothalamus: sleep, appetite and energy impairment
  • Nucleus accumbens and Amygdala: anhedonia, anxiety, reduced motivation
70
Q

What is the monoamine theory of depression?

A

States that depression is due to a functional deficit of monoamine (serotonin (5-hydroxytryptamine), noradrenaline and dopamine)

Mania is regarded as the opposite mechanism i.e. a functional excess of these neurotransmitters

71
Q

What is the evidence in support of the monoamine hypothesis of depression?

A
  1. TCAs and SSRIs block NA and/or 5-HT re-uptake and alleviate depression
  2. MAOIs increase stores of NA and 5-HT and alleviate depression
  3. Reserpine depletes stores of NA and 5-HT and depresses mood
  4. ECT increases CNS responses to 5-HT and NA and alleviates depression
72
Q

What is the negative affective bias?

A

People suffering from depression tend to perceive events in a negative way, focus on the negative information and recall information in a negative rather than positive manner

73
Q

What issues arise from animal models?

A

There is no known animal condition corresponding to the inherited form of depression in humans

Procedures involving mild stress produce behavioural states in animals that mimic aspects of human depression

However, no model for drug-resistant depression

74
Q

What drug effects are inconsistent with the monoamine theory of depression?

A
  1. Amphetamine releases NA and blocks it re-uptake but has no effect on depression
  2. Cocaine blocks NA re-uptake but has no effect on depression
  3. L-DOPA increases NA synthesis but has no effect on mood
  4. Methysergide, a 5-HT antagonist, has no effect on mood
75
Q

What problem exists with the monoamine hypothesis?

A
  1. Primary biochemical actions of drugs are very rapid but antidepressant effects usually take 2-4 weeks to develop
  2. Current antidepressant drugs do not improve symptoms in all patients
76
Q

Explain the neuroendocrine mechanism of depression

A

A similar mechanism to that of anxiety

Depressed patients have high concentrations of CRF and cortisol that have demonstrated to induce many of depression associated symptom

77
Q

What is the general mechanism of antidepressants?

A

Act through the 5-HT and noradrenergic systems are suggested to trigger intracellular second messenger pathways that activate cAMP response element binding (CREB) protein, a transcriptional activator

Leads to production of growth factors such as BDNF which can reverse effects of cortisol on hippocampus by stimulating neurogenesis

78
Q

How do Tricyclic Antidepressant drugs work?

A

Block the uptake of amines by nerve terminals, by competition for the binding site of the amine transporters

Inhibit NA and 5-HT uptake but have much less effect on dopamine uptake

79
Q

Describe the pharmacokinetics of TCAs

A

Metabolites of this drug retain pharmacological activity (with altered selectivity) extending the duration of action on the molecular targets and also contributing to slow rate of elimination

Metabolism involves hydroxylation steps mediated by CYP2D6

80
Q

Explain the individual variation in response to TCAs

A

There are more than 80 allelic variants of CYP2D6 which display a range of catalytic activity

These difference contribute to individual variation in response to TCAs

81
Q

What are the unwanted effects of TCAs

A
  1. Acute effects include sedation, confusion and motor in-coordination but these wear off after one to two weeks as antidepressant effects develop.
  2. Atropine-like autonomic side effects related to mAChR block: - dry mouth, blurred vision etc.
  3. Postural hypotension probably related to block of alpha-adrenoceptors in the vasomotor centre located in the brainstem.
  4. Sedation associated with histamine H1 receptor block.
82
Q

What are MAOIs?

A

These drugs cause irreversible inhibition of the enzyme and do not distinguish between the two main isozymes

Ex. phenelzine, tranylcypromine and iproniazid

83
Q

What are monoamine oxidases?

A

Monoamine oxidase is found in nearly all tissues, and exists in two similar molecular forms coded by separate genes:

  • MAO-A: substrate preference for 5-HT and noradrenaline (target for antidepressant MAOIs)
  • MAO-B: substrate preference for phenylethylamine and dopamine
84
Q

What is the function of MAOs?

A
  • Within nerve terminals, MAO regulates the free intraneuronal concentration of noradrenaline or 5-HT. Not involved in the inactivation of released transmitter
  • In gut wall, it is important in the inactivation of endogenous and ingested amines such as tyramine that would otherwise produce unwanted effects
85
Q

How do MAOIs work?

A

MAOIs are substrate analogues with a phenylethylamine-like structure, and most contain a reactive group (e.g. hydrazine, propargylamine, cyclopropylamine) that enables the inhibitor to bind covalently to the enzyme, resulting in a non-competitive and long-lasting inhibition

Increases in monoamine but do not alter the amount of synaptically released neurotransmitter

86
Q

What is the cheese - effect?

A

MAO inhibition allows tyramine to be absorbed, and also enhances its sympathomimetic effect, as discussed earlier.

The result is acute hypertension, giving rise to a severe throbbing headache and occasionally even to intracranial haemorrhage

87
Q

What are the advantages and disadvantages of SSRIs?

A

Advantage: No anticholinergic or cardiovascular side effects. No weight gain and Low acute toxicity

Drawbacks: Nause, anorexia, insomnia and increased aggression

88
Q

How do Noradrenaline and Serotonin Specific Antidepressant work

A

Act to block both 5-HT and NA reuptake with equal high affinity

89
Q

How does Mirtazepine work?

A

Increases 5-HT and NA by inhibiting presynaptic alpha2 adrenoceptors (thereby blocking inhibitory feedback of transmitter release) and enhances 5-HT action through 5-HT1A receptors

90
Q

What is the mechanism of action of Ketamine?

A

Ketamine is an NMDA glutamate receptor (NMDAR) antagonist

It selectively blocks NMDARs expressed on GABAergic inhibitory interneurons

The resulting disinhibition of pyramidal neurons and enhanced release of glutamate activates post-synaptic AMPARs promoting enhanced BDNF release, activation of the tropomyosin receptor kinase B (TrkB) receptor and subsequent protein synthesis via activation of mechanistic target of rapamycin complex 1 (mTORC1)

91
Q

Define Epilepsy

A

Epilepsy is a very common disorder, characterised by seizures, which take various forms and result from episodic neuronal discharges, the form of the seizure depending on the part of the brain affected

92
Q

What are seizures?

A

Seizures are associated with episodic high-frequency discharges of impulses by a group of neurons (sometimes referred to as focus) in the brain. This local abnormal discharge can spread to other regions of the brain

93
Q

What are the types of epilepsy?

A
  • Partial (focus) seizures
  • Generalised seizures
94
Q

What are Partial (focal) seizures?

A

seizures are those in which the discharge begins locally and often remains localized

EGG shows high-frequency asynchronous discharge spreading out from a local focus

95
Q

What are the symptoms of partial seizures?

A

involuntary muscle contraction, abnormal sensory experiences or autonomic discharge, or effects on mood and behaviour

In complex partial seizures, loss of consciousness may occur if the discharge spreads to regions of the brain stem reticular formation

96
Q

What are generalised seizures?

A

involve the whole brain, including the reticular system, thus producing abnormal electrical activity throughout both hemispheres

Often involve immediate loss of consciousness

97
Q

What are the two categories of generalised seizures?

A
  1. Tonic-clonic: inital contraction of whole musculature and respiration stops. Followed by a series of violent, synchronous jerks
  2. Absence: patiently abruptly ceases what they are doing and stares vacantly with little or no motor disturbance. Result of oscillatory feedback between cortex and thalamus
98
Q

How does a seizure start?

A

Seizure initiation is characterized by two concurrent events:
1) high-frequency bursts of action potentials, 2) hypersynchronization of a neuronal population

99
Q

Explain what happens during a seizure

A

Neurons involved in epileptic discharge display Paroxysmal Depolarising Shift (PDS)

Membrane Potential suddenly decreases by about 30 mV and remains depolarised for up to a few seconds before returning to normal

Following PDS, there is a burst of action potential resulting in a spike discharge visible on EEG

100
Q

What is the kindling model?

A

Brief low-intensity electrical stimulation of certain regions of the limbic system repeated daily for several days

Response gradually increases until very low levels of stimulation will evoke a full seizure

101
Q

What are the three main mechanisms of action of anti-seizure drugs?

A
  1. Enhancement of GABA Action
  2. Inhibition of sodium channel function
  3. Inhibition of calcium channel function
102
Q

Explain the mechanism of anticonvulsant drugs that enhance GABA action

A

Enhance the activation of GABAA receptors, thus facilitating the GABA-mediated opening of chloride channels

Ex. Phenobarbital and Benzodiazepines

103
Q

Explain the mechanism of anticonvulsant drugs that inhibit sodium channel function

A

They affect membrane excitability by an action on voltage-dependent sodium channels, which carry the inward membrane current necessary for the generation of an action potential

They show use dependence. Depolarisation of neuron increase no. of inactivated receptors which drugs can bind to prevent AP

Ex. Carbamazepine, phenytoin, and lamotrigine

104
Q

Explain the mechanism of anticonvulsant drugs that inhibit calcium channel function

A

Treat absence seizures by blocking T-type low-voltage-activated calcium channels

This is important in determining the rhythmic discharge of thalamic neurons associated with absence seizures

Ex. Ethosuximide and valproate

105
Q

What is the interaction profile of Carbamazepine?

A

Powerful inducer of hepatic microsomal enzymes, and thus accelerates the metabolism of drugs like phenytoin, oral contraceptives, warfarin and corticosteroids

106
Q

What is the pharmacodynamics of phenytoin?

A

Well absorbed when given orally, and about 80%–90% of the plasma content is bound to albumin.

Salicylates, phenylbutazone and valproate, inhibit this binding competitively

This increases the free phenytoin concentration but also increases hepatic clearance of phenytoin, so may enhance or reduce the effect of the phenytoin in an unpredictable way

107
Q

What is the mechanism of action of Valproate?

A
  • Causes a significant increase in the GABA content of the brain
  • Weak inhibitor of the enzyme system that inactivates GABA (GABA transaminase and succinic semialdehyde dehydrogenase)
  • Inhibits sodium channels (less so than phenytoin)
  • Inhibits T-type calcium channels –> effective against absence seizures

Effective in many kinds of epilepsy

108
Q

What are the side effects of Valproate?

A

Contra-indicated in women of childbearing age because it is a potent teratogen causing spina bifida and other neural tube defects

109
Q

What is Dravet Syndrome?

A

Dravet Syndrome is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever

90% of cases are caused by De Novo (non-sense) mutations in SCN1A (this is a spontaneous mutation that has not been inherited)

110
Q

What is Parkinson’s Disease (PD)?

A

A disease characterised by impaired voluntary movement

111
Q

What are the symptoms of PD?

A
  • Tremor at rest
  • Abnormal posture
  • Bradykinesia (slow initiation of movement)
  • Muscle rigidity (resistance to movement)
112
Q

How is voluntary movement normally controlled?

A

Controlled by signals from motor cortex that travel down pathways in the brainstem and spinal cord, called pyramidal tract, to alpha-motor neurones in the ventral horn of the spinal cord

Signals fine-tuned by input from extrapyramidal regions to give smooth voluntary region

113
Q

What is the structure of the basal ganglia?

A
  • Globus pallidus (which has defined internal (GPi) and external (GPe) regions)
  • Subthalamic nucleus (STN)
  • Substantia nigra.
    1. Pars reticulata (SNr, ventral)
    2. Pars compacta (SNc, dorsal)
114
Q

What is the pathophysiology of PD?

A

It is a neurodegenerative disease resulting in the progressive loss of dopamine (DA)-releasing neurones that originate in the substantia nigra

The loss of these DA-releasing neurones prevents the basal ganglia from fine-tuning the output from the motor cortex that controls voluntary movement

115
Q

What is the defining feature of PD?

A

The appearance of “Lewy bodies” in the substantia nigra.

These are small spherical inclusion with a primary component of synucleins

Not known whether these are a cause of the disease or a protective response

116
Q

What is the Oxidative Stress theory?

A

Oxidative stress refers to the excessive production of “reactive oxygen species” when oxidative phosphorylation is compromised

DA SNc neurons have high metabolic demands which leaves little reserve when additional demands associated with disease arise.

ROS lead to cell damage and thus death

117
Q

What may cause the high metabolic demands of the DA SNc neurons?

A
  • the need to remove high cytosolic calcium entry during autonomous pacemaking of DA SNc neurons
  • the massive, complex, unmyelinated axonal arbours of DA SNc neurons,
118
Q

What is MPTP and how is it used?

A

MPTP is a designer drug that when metabolised by MAO-B produces a toxic metabolite, MPP+.

MPP+ is transported via transporter into DA cells and inhibits mitochondria complex I

Results in production of neurotoxic ROS. Model for PD

119
Q

What is Rotenone?

A

A commonly used pesticide

Acts by inhibiting mitochondrial complex I, can induce Parkinson’s-like symptoms in animal models

Unlike MPTP, this model is associated with appearance of Lewy Bodies

120
Q

What is alpha-synuclein?

A

It is also thought that the accumulation of synuclein protein that forms Lewy bodies promotes the excessive production of ROS

121
Q

What is the action of alpha-synuclein?

A

Defects in dopamine packaging and release resulting from genetic variants in alpha-synuclein and its subsequent aggregation into Lewy bodies may lead to excessive amounts of cytoplasmic dopamine which when metabolised produces the ROS that promote cell death

122
Q

Describe the structure of the basal ganglia

A

In the normal brain,
Cortical motor areas project to the striatum to form an excitatory synapse with GABA neurons.
These neurones give rise to two pathways that connect the striatum to the globus pallidus interna (GPi) and the substantia nigra reticulata (SNr)

GPi and SNr form the major output pathway of the basal ganglia.

The GPi / SNr exert a tonic GABA- mediated inhibitory influence on brainstem and thalamo-cortical neurones in the ventral thalamus involved in modulating motor activity.

123
Q

Describe the direct pathway of the basal ganglia

A

Neurones project directly from the striatum to the GPi / SNr.

They have D1 receptors and provide a direct GABA-mediated inhibitory effect on the neurones of the GPi / SNr

124
Q

Describe the indirect pathway of the basal ganglia

A

Striatal neurones connect the putamen to the GPi / SNr through synaptic connections in the GPe and the subthalamic nucleus (STN).

These striatal neurones contain D2 receptors and are inhibitory, releasing GABA onto the neurones of the GPe and STN.

Neurones in the STN project to the GPi and SNr where they are excitatory releasing glutamate as a neurotransmitter.

125
Q

What are the final consequences of both basal ganglia pathways?

A
  • Indirect pathway causes excitation of GPi / SNr
  • Direct pathway causes inhibition of GPi / SNr

The balance between the two pathways determines the output of the basal ganglia.

126
Q

Explain how the dysfunction of the basal ganglia leads to PD

A

In Parkinson’s disease there is an increase in the activity of the output pathways resulting in excessive inhibition of the thalamo-cortical and brainstem motor systems.

Loss of dopamine results in reduced inhibition of GPi / SNr by direct pathway and increased excitation by indirect pathway

127
Q

How can PD be treated?

A
  1. Facilitation of the synthesis and release of endogenous dopamine
  2. Direct acting dopaminergic receptor agonists.
  3. Inhibitors of dopamine metabolism.

However, none prevent progressive loss of dopamine

128
Q

What is L-DOPA?

A

Metabolic precursor of dopamine and is the most effective drug for treatment of Parkinson’s disease.

Requires transport across the blood-brain barrier where it is then transported into dopaminergic neurones and converted to dopamine by dopa decarboxylase.

129
Q

What issues arise with L-DOPA?

A

The plasma half-life is short (1-3 hours) due to extensive metabolism in the gut wall, plasma and peripheral tissues by peripheral dopa decarboxylase

Dopamine itself cannot cross the blood-brain barrier thus only ~1% of the administered dose of L-dopa reaches the brain.

130
Q

What methods can be used to increase effectiveness of oral L-DOPA?

A
  • Co-administration of dopa decarboxylase (lower doses used)
  • Carbidopa : act equally through both pathways. Rapidly alleviates symptoms
  • Selegiline: MOAI selective for MAO-B. Prevents degradation dopamine
  • Entacapone: Inhibitor of catachol-O-methyl transferase (degrades dopamine)
  • Dopamine receptor agonist (bromocriptine): Act on cells that have not degraded
  • AntiCHergic agets (benztropine): increased activity of ACh neurons causes some activity

Typically DA inhibits ACh

131
Q

What is L-dopa-induced dyskinesia?

A

Motor complication associated with L-DOPA therapy

Associated with high L-DOPA plasma levels that result in involuntary writhing movements

Excessive inhibition of neurones in the indirect pathway (Striatum – GPe). This causes disinhibition of the GPe, subsequent over-inhibition of the STN and a consequent reduced excitatory drive to the GPi / SNr

132
Q

What is the On-Off effect?

A

As the disease progresses the benefits of L-dopa wear off before the next dose

Patients fluctuate between an “ON” response (good anti-parkinson effect) and an “OFF” response (poor control of symptoms).

Thus, higher and more frequent doses are required to control rigidity and bradykinesia but these also cause more severe dyskinesia

Pharmacology 3 (6 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions