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Fundamentals of Pharmacology > Autonomic Pharmacology > Flashcards

Autonomic Pharmacology Flashcards

1
Q

what processes are regulated by the autonomic nervous system?

A

Smooth muscle tone
Cardiac rate and force
Secretion (exo/endocrine)
certain metabolic processes

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2
Q

What neurotransmitters are released from sympathetic post ganglionic neurones?

A

Noradrenaline

ATP

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3
Q

What neurotransmitters are released from parasympathetic post ganglionic neurones?

A

ACh

Nitrous Oxide

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4
Q

how can we interfere with adrenergic pharmacology?

A

By interrupting the synthesis of adrenaline and noradrenaline.

Drugs that inhibit enzymes that help create intermediates in their synthesis.

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5
Q

What is the rate limiting step in noradrenaline synthesis?

A

Tyrosine Hydroxylase

Modifying this allows us to have the greatest control on the rest of the metabolic synthesis so this is often the target for drugs

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6
Q

What drug inhibits tyrosine hydroxylase?

A

alpha-methyltryosine

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7
Q

What drug inhibits DOPA decarboxylase?

A

Carbidopa

drug used to treat Parkinson’s disease

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8
Q

Where are adrenaline and noradrenaline stored in the body?

A

Stored in subcellular membrane limited particles (chromaffin granules) within the adrenal glands.

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9
Q

what is the main enzyme that packages noradrenaline into vesicles?

A

VMAT - Vesicular monoamine transporter

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10
Q

what drug inhibits the VMAT transporter?

A

Reserpine
Inhibits VMAT

Not in use today due to having many side effects.

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11
Q

what are varicosities?

A

Point at which neurotransmitters are released from their vesicles

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12
Q

How are neurotransmitters released from sympathetic nerves by exocytosis?

A

Arrival of action potential causes depolarisation of varicosity
This results in opening of voltage-gated Ca2+ channels Ca2+ entry causes an increase in the concentration of free Ca2+ in the varicosity
This activates Ca2+-sensitive proteins that initiate the process of exocytosis

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13
Q

explain the autoinhibition of noradrenaline release?

A

Noradrenaline, released from sympathetic varicosities, can act locally on presynaptic receptors to inhibit its own release, and also that of ATP

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14
Q

What other mediators can affect noradrenaline release?

A

ACh - inhibits release via muscarinic receptors, facilitates nicotinic receptors

Adenosine - Inhibits release (A1 receptors)

Opioids - Inhibits release (u-receptors)

Angiotensin II - facilitates release via AT1 receptors

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15
Q

What is morphine??

A

Important analgesic with important autonomic side effects - constipation, pupillary dilation.

These autonomic side effects are through the prejunctional inhibition of neurotransmitter release

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16
Q

how is noradrenaline terminated after release?

A
  1. uptake into sympathetic nerve terminals or other cells.

2. Degradation by intracellular enzymes

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17
Q

What are the processes used in uptake of noradrenaline for its termination?

A

Neuronal

Non-neuronal

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18
Q

How does neuronal uptake 1 work?

A

due to the secondary active transporter NAT.

High affinity for noradrenaline, and relatively selective.

Cotransports Na, Cl and catecholamine.

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19
Q

What drugs inhibit neuronal uptake transporters?

A

cocaine
Tricyclic antidepressants (desipramine)
Phenoxybenzamine

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20
Q

What effect do NAT inhibitors have?

A

enhance sympathetic activity,
Desipramine:
major action on CNS.
adverse effects - tachycardia, dysrhythmia

Cocaine:
euphoria and excitement (CNS action)
acts as a local anaesthetic
Tachycardia and increased BP

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21
Q

What are the autonomic effects of taking cocaine?

A

increased heart rate
Increased blood pressure
Local vasocontriction (could lead to infarction)

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22
Q

How are catecholamines degraded?

A 
via intracellular enzymes
monamine oxidase (MAO)
Catechol-O-methyl transferase (COMT)
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23
Q

What are monoamine oxidase inhibitors used for and how do they work?

A

Used to treat depression

They work by blocking MAO irreversibly leading to increased noradrenaline, dopamine and 5-HT in the brain and peripheral tissues

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24
Q

What are COMT inhibitors used for?

A

Treatment of Parkinson’s disease

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25
Q

what do noradrenergic neuron blocking drugs do?

A

inhibit noradrenaline release from sympathetic nerve terminals.

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26
Q

What are indirectly acting sympathetic amines?

A

eg. amphetamine, ephedrine, tyramine

act by displacing noradrenaline which leaks out via NAT.

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27
Q

What receptors detect noradrenaline from the sympathetic nervous system?

A

Adrenoreceptors:
Alpha
Beta

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28
Q

what is the agonist potency order for the alpha adrenoreceptors comparing noradrenaline, adrenaline and isoprenaline?

A

Alpha 1:
Noradrenaline > adrenaline&raquo_space; isoprenaline

Alpha 2:
Adrenaline > Noradrenaline&raquo_space; Isoprenaline

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29
Q

what is the agonist potency order for the beta adrenoreceptors comparing noradrenaline, adrenaline and isoprenaline?

A

Beta 1:
isoprenaline > noradrenaline > adrenaline

Beta 2isoprenaline > adrenaline > noradrenaline

Beta 3:
isoprenaline > noradrenaline = adrenaline

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30
Q

what is the structure of adrenoreceptors?

A

All adrenergic receptors are part of the family of G proteincoupled receptors (metabotropic receptors)

Recruit intracellular proteins, known as G proteins, in order to produce their cellular effects

Integral membrane protein

Single polypeptide chain: 400 - 500 amino acids

Extracellular N-terminus, intracellular C-terminus

7 transmembrane α helices

Binding site buried within a cleft between the α helices

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31
Q

How do alpha 1 adrenoreceptors lead to downstream signalling?

A

Noradrenaline binds to its alpha 1 receptor.
A change takes place in the Gq-protein where GDP is converted to GTP.
This leads to the alpha subunit of the G-protein dissociating from the beta-gamma complex.
The alpha subunit can diffuse in the membrane to interact with its target protein phospholipase C.
Phospholipase C acts on PIP2 membrane phospholipid which produces IP3 and DAG.
IP3 binds to the IP3 receptors on the surface of the ER and opens Ca ion channels leading to Ca release.

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32
Q

How do alpha 2 adrenoreceptors lead to downstream signalling?

A

Noradrenaline binds to its alpha 2 receptor.
A change takes place in the Gi-protein where GDP is converted to GTP.
This leads to the alpha subunit of the G-protein dissociating from the beta-gamma complex.
The alpha subunit can diffuse in the membrane to interact with its target protein adenyl cyclase.
The Gi-protein inhibits adenyl cyclase
which leads to decreased cAMP levels
thus less activity of PKA
hence decreased phosphorylation of intracellular proteins.
produces effects of inhibition of neurotransmitter release.

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33
Q

give an example of an alpha 2 adrenoreceptor antagonist?

A

Yohimbine - used for treatment of sexual dysfunction.

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34
Q

How do beta adrenoreceptors lead to downstream signalling?

A

Noradrenaline binds to the beta adrenoreceptors.
This recruits Gs-protein
The Gs (G-protein) is converted from its GDP to GTP form
The alpha subunit dissociates and goes to activate the protein adenyl cyclase.
This leads to:
increased cAMP levels
increased activity of PKA
increased phosphorylation of intracellular proteins.
Produces the effect of relaxation of smooth muscle.

35
Q

How can we target organs for drugs?

A

The 5 adrenoreceptors act upon different organs.

36
Q

What is the function of adrenoreceptors on the heart?

A 
Beta 1 adrenoreceptors:
SAN - increased heart rate
AVN - increased conduction velocity
Atria - increased contractility 
Ventricles - increased contractility and enhance automaticity.
37
Q

what adrenoreceptors are found in blood vessels and what are their affects on the smooth muscle.

A 
alpha 1 (2) - constriction
Beta 2 - dilation
38
Q

what adrenoreceptors are found in bronchi and what are their affects on the smooth muscle.

A

Beta 2 - dilation

39
Q

what adrenoreceptors are found in GIT and what are their affects on the smooth muscle.

A

Alpha 1, alpha 2 - contraction of sphincters

Beta 2 - relax

40
Q

what adrenoreceptors are found in uterus and what are their affects on the smooth muscle.

A

alpha 1 - contract

beta 2 - relax

41
Q

what adrenoreceptors are found in bladder and what are their affects on the smooth muscle.

A

Beta 3

42
Q

What would be the effect of agonists (noradrenaline, adrenaline and isprenaline) on the cardiovascular system?

A

Noradrenaline - increased peripheral resistance to increase blood pressure

43
Q

What are some adrenoreceptors agonists?

A

α1 - phenylephrine

α2 - clonidine
β1 - dobutamine
β2 - salbutamol - terbutaline - salmeterol
β3 -mirabegron

44
Q

What are some adrenoreceptor antagonists?

A

α1 - prazosin - doxazosin

α2 - yohimbine - idazoxan

β1 - atenolol - metoprolol

β2 - butoxamine

45
Q

What is the function of adrenaline as an adrenoreceptor agonist?

A

activates both the alpha and beta agonist

used in cardiac arrest (to help restore cardiac rhythm)

46
Q

What is the function of Dobutamine as an adrenoreceptor agonist?

A

Selective B1 receptor agonist.

Used in cardiogenic shock (acute heart failure)

47
Q

What is the function of Salbutamol as an adrenoreceptor agonist?

A

Selective B2 receptor agonist

Used in asthma

48
Q

What is the function of Mirabegron as an adrenoreceptor agonist?

A

Selective B3 receptor agonist.

Treatment of overactive bladder syndrome (OAB)

49
Q

What is the function of Phenylephrine as an adrenoreceptor agonist?

A

Selective alpha 1 receptor agonist

Used for nasal decongestion

50
Q

What are some uses of alpha adrenoreceptor antagonists?

A

Hypertension
Benign prostatic hypertrophy
Phaeochromocytoma

51
Q

What are some uses of beta adrenoreceptor antagonists?

A

Cariovascular (hypertension, angina)

Glaucoma

52
Q

What are the adverse effects of Beta adrenoreceptors antagonists

A 
Bronchoconstriction
worsening of cardiac failure
bradycardia 
heart block
hypoglycaemia
physical fatigue
cold extremities
bad dreams
53
Q

What are cholinergic nerves?

A

Nerves that release acetylcholine and are found in all divisions of the nervous system

54
Q

What divisions of the nervous system release acetylcholine?

A 
Somatic motor nerves
parasympathetic pre and post ganglionic neurones
sympathetic preganglionic neurones
Enteric
CNS
55
Q

What is a major pathway to drug discovery?

A

Toxins!!
Berries of deadly nightshade - dilate pupils
Calabar bean - Potentiates the effects of the parasympathetic stimulation.

56
Q

What is muscarine?

A

Active compound that mimicked the activation of the parasympathetic nervous system found in poisonous fungi (fly agaric)

57
Q

What is cholinergic transmission?

A

Nerves which use acetylcholine as a neurotransmitter

58
Q

how is acetylcholine supplied?

A

Choline comes from the diet and liver since nerves cannot make enough choline.
Uptake into nerve endings via high affinity carrier Na dependent transport proteins..

59
Q

What is Hemicholinum?

A

A competitive inhibitor of the choline carrier.

60
Q

How is acetylcholine synthesised?

A

Choline + acetylCoA catalysed by choline acetyltransferase (ChAT)
This occurs in the nerve cytoplasm
ChAT inhibitors are not used clinically.

61
Q

How is acetylcholine stored?

A

Store is maintained by energy dependent pumps into synaptic vesicles.

62
Q

What happens when there is inhibition of pumps storing ACh?

A

Drugs such as Vesamicol leads to the depletion of stores by inhibiting the pumps

63
Q

What is Acetyltriethylcholine?

A

Formed from triethylcholine by ChAT, which can also be taken up and stored.
Then it can be released as a false neurotransmitter.
(has weak effect on the postsynaptic receptors)

64
Q

How is acetylcholine released?

A

Always requires Ca entry into nerve endings.

Occurs by exocytosis where the vesicle membrane fuses with the cell membrane

65
Q

What drugs affect the release of acetylcholine?

A

Massive release and depletion of vesicle evoked by alpha-latrotoxin (black widow spider venom)

Release can be blocked by the botulinum toxin.

66
Q

How is ACh removed from the synaptic cleft and inactivated?

A

Diffusion is not important unless cholinesterase is inhibited.

Hydrolysis of ACh by AChE in a non-reversible reaction

67
Q

what is Sarin?

A

A neurotoxin developed as a chemical weapon in the 1950s

An acetylcholinesterase inhibitor which hence blocks skeletal neuromuscular transmission and augments parasympathetic effects

68
Q

How is acetylcholine feedback?

A

Cholinergic nerves have presynaptic or prejunctional receptors:

• ACh(muscarinic) inhibits release of ACh (enteric) • ACh (nicotinic) increases the release of ACh probably less functionally important) • ATP is converted to adenosinewhich inhibits release (A1 receptors) • Morphine (opioids)inhibit release (µ-receptors), leading to constipation • Noradrenalineinhibits release (a2-adrenoceptors); ‘sympathetic cross-inhibition’ in tissues

69
Q

What are the main receptors for ACh?

A

Nicotinic receptors

Muscarinic receptors

70
Q

How are receptors classified?

A

Anatomical
Chemical/pharmacological
Molecular

71
Q

How can we determine between pharmacological or molecular receptors?

A

Pharmaxological - Potency series of agonists or specific antagonists

Molecular - Well suited to knockout and expression systems

72
Q

Where are nicotinic receptors found?

A

Skeletal muscle

```
Autonomic ganglia
Not the same type of nicotinic receptor though
~~~

73
Q

What are nicotinic receptor agonists?

A

Nicotine

Transiently stimulate ganglia and motor end-plate if given briefly at very high concentrations.

74
Q

What are some nicotinic receptor antagonists?

A

Selectively antagonised by autonomic ganglia (and CNS)
Hexamethonium

Non-specific antagonist - d-tubicurarine

75
Q

What is Hexamethonium?

A

Nicotinic antagonist which blocks the autonomic ganglia.

Used to treat high blood pressure.

76
Q

What is the mechanism of action of hexamethonium?

A

Blocks the ion channel

77
Q

What is the unusual mechanism of action of galantamine?

A

• Found in the Snowdrop (Galanthus sp.) • Act on nicotinic receptors to increase their activity (allosteric potentiating ligand or ‘positive allosteric modulator) • Also has anticholinesterase activity • Used for the treatment of Alzheimer’s disease (central action) • Peripheral side effects include an changes in gut motility.

78
Q

What are muscarinic cholinoceptors?

A

a relative potency seriesfor agonists (when cholinesterase is inhibited): methacholine, muscarine > carbachol&raquo_space;> nicotine

79
Q

What are some muscarinic antagonists?

A

M1 (Pirenzepine) - stomach, salivary glands
M2 (Gallamine) - cardiac muscle
M3 - smooth muscle

Less specific antagonists - atropine, hyoscine, cyclopentolate

80
Q

What are some clinical uses of antimuscarinic drugs?

A
  • Asthma (ipratropium)
  • To treat bradycardia (atropine)
  • To decrease gut motility; decrease secretions (pirenzapine)
  • During operations: decrease secretions, decrease AChEI side-effects (atropine)
  • To dilate pupils (tropicamide)
  • Urinary incontinence (oxybutynin)
  • Motion sickness (hyoscine)
81
Q

What are some muscarinic agonists?

A

Parasympathomimetics

ACh
Carbachol
Muscarine
Pilocarpine

82
Q

What are the effects of parasympathomimetics?

A

Cardiovascular - decreased heart rate, cardiac output

Smooth muscle -contracts, vascular dilates via endothelium (EDRF = NO)

Exocrine glands -secrete -sweating, lacrimation, salivation, bronchial secretion

83
Q

What are some uses of parasympathomimetics?

A

Rarely used to widespread side effects

May be used for the treatment of glaucoma

Fundamentals of Pharmacology (19 decks)

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