Nervous System Flashcards

Question

What are the therapeutic uses of mAChR antagonists?

Answer 1

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)

Answer 2

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

Answer 3

- Physostigmine - Neostigmine - Carbaril

Answer 4

- Insecticides - Ecothiphate - Military Nerve Gases

Answer 5

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 )

Answer 6

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

Answer 7

- Nicotinic Acetylcholine Receptors - Adrenoceptors

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

Coupled through Gs to stimulate adenylyl cyclase and increase cAMP Heart Muscle contraction, smooth muscle relaxation and lipolysis/thermogenesis

Answer 13

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

Answer 14

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

Answer 15

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

Answer 16

Inhibits tyrosine hydroxylase USed experimentally however is no longer used clinically

Answer 17

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

Answer 18

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

Answer 19

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

Answer 20

It blocks the impulse conduction in the nerve cells, reducing release of NA It also accumulates in vesicles and displaces NA

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

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

Answer 26

1. Verbal complaint 2. Somatic and autonomic effects - restlessness, agitation, increased sweating and tachycardia 3. Interference with normal "productive" activities

Answer 27

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

Answer 28

Hippocampus exerts negative feedback on the hypothalamus thereby suppressing cortisol release Amygdala exerts positive feedback on the hypothalamus thereby increasing cortisol release

Answer 29

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

Answer 30

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

Answer 31

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

Answer 32

5-HT1A partial agonist Slow desensitisation of somato-dendritic 5-HT1A receptors Increase serotonin release

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

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.

Answer 37

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

Answer 38

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

Answer 39

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

Answer 40

Of little importance because BDZs do not induce hepatic microsomal enzymes Tissue tolerance does occur due to receptor change

Answer 41

- 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

Answer 42

- 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

Answer 43

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

Answer 44

- Bipolar depressive syndrome: patient oscillates between depression and mania. Suggest a biochemical imbalance - Unipolar depressive syndrome: Depression without associated mania

Answer 45

- 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

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

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

Answer 50

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

Answer 51

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

Answer 52

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

Answer 53

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

Answer 54

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

Answer 55

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

Answer 56

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

Answer 57

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.

Answer 58

These drugs cause irreversible inhibition of the enzyme and do not distinguish between the two main isozymes Ex. phenelzine, tranylcypromine and iproniazid

Answer 59

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

Answer 60

- 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

Answer 61

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

Answer 62

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

Answer 63

Advantage: No anticholinergic or cardiovascular side effects. No weight gain and Low acute toxicity Drawbacks: Nause, anorexia, insomnia and increased aggression

Answer 64

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

Answer 65

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

Answer 66

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)

Answer 67

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

Answer 68

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

Answer 69

- Partial (focus) seizures - Generalised seizures

Answer 70

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

Answer 71

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

Answer 72

involve the whole brain, including the reticular system, thus producing abnormal electrical activity throughout both hemispheres Often involve immediate loss of consciousness

Answer 73

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

Answer 74

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

Answer 75

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

Answer 76

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

Answer 77

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

Answer 78

Enhance the activation of GABAA receptors, thus facilitating the GABA-mediated opening of chloride channels Ex. Phenobarbital and Benzodiazepines

Answer 79

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

Answer 80

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

Answer 81

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

Answer 82

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

Answer 83

- 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

Answer 84

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

Answer 85

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)

Answer 86

A disease characterised by impaired voluntary movement

Answer 87

- Tremor at rest - Abnormal posture - Bradykinesia (slow initiation of movement) - Muscle rigidity (resistance to movement)

Answer 88

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

Answer 89

- 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)

Answer 90

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

Answer 91

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

Answer 92

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

Answer 93

- 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,

Answer 94

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

Answer 95

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

Answer 96

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

Answer 97

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

Answer 98

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.

Answer 99

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

Answer 100

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.

Answer 101

- 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.

Answer 102

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

Answer 103

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

Answer 104

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.

Answer 105

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.

Answer 106

- 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

Answer 107

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

Answer 108

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

Nervous System Flashcards

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