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Systems Pharmacology > Autonomic nervous system > Flashcards

Autonomic nervous system Flashcards

0
Q

Where does the sympathetic project to?

A

Projects to prevertebral and paravertebral ganglia.

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1
Q

Where does the sympathetic nervous system arise from?

A

Arises from the thoraco-lumbar spinal chord.

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2
Q

Composition of sympathetic nervous system?

A

Short preganglionic and long postganglionic.
At the ganglion, acetylcholine is the neurotransmitter and the receptor is nicotinic acetylcholine receptor.
At the postganglion, noradrenaline is the neurotransmitter and the receptors are alpha and beta receptors.

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3
Q

Where does the parasympathetic nervous system arise from?

A

Arises from the cranio-sacral spinal chord.

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4
Q

Where does the parasympathetic project to?

A

Projects to the ganglionic cells within innervated organs.

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5
Q

Composition of parasympathetic nervous system?

A

Long preganglionic and short postganglionic nerves.
The main neurotransmitter at the ganglion and postganglion is acetylcholine.
Ganglion receptor is nicotinic.
Postganglion receptors are muscarinic acetylcholine receptors.

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6
Q

Effects of sympathetic stimulation?

A 
Eyes - pupil dilation
Heart - increased rate and contraction 
Blood vessels - contriction
Lungs - bronchodilation
Sweat glands - activates sweat secretion
Salivary glands - reduced saliva production 
Intestines - reduced motility
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7
Q

Effects of parasympathetic stimulation?

A 
Eyes - pupil contriction
Heart - decreased rate and contraction 
Blood vessels - vasodilation in some 
Lung - bronchoconstriction
Exocrine glands - increased sweating, salivation, lacrimation
Intestines - increased motility
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8
Q

How is acetylcholine synthesised and metabolised?

A

Choline + acetyl coenzyme A
By the enzyme choline acetyltransferase in the cytoplasm of presnaptic axon.
Stored in vesicles and is released by exocytosis triggered by Ca2+ entry into the nerve terminal.
Some bind with receptors, some diffuse into cytoplasm, some are taken up by acetylcholinerase.
At fast cholinergic synapses ACh is released and hydrolysed rapidly so it acts for only a brief moment. Choline limits the duration of ACh by rapidly metabolising it.

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9
Q

What is acetylcholine?

A

Quarternary nitrogen compound.

Neurotransmitter in autonomic nervous system.

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10
Q

Main postjunctional receptor type at parasympathetic neuroeffector junction?

A

Muscarinic receptor.

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11
Q

Main postjunctional receptor type at striated muscle?

A

Nicotinic receptor.

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12
Q

Effect of uptake 1 and uptake 2 inhibitors on sympathetic neurotransmission?

A

Norepinephrine reuptake inhibitors for noradrenaline and adrenaline neurotransmitters inhibit by blocking the action of NET a transporter protein. As a result there are increased concentrations of norepinephrine and sympathetic nerve activity.
Uptake 1 inhibitor - cocaine
Uptake 2 inhibitor - corticosteroid

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13
Q

Parasympathomimetic agent - muscarine

A

Quaternary ammonium compound that is resistant to acetylcholinesterase. Does not stimulate nicotinic receptors. Selective for muscarinic receptors.

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14
Q

Parasympathomimetic agent - nicotine

A

No resemblance to ACh or muscarine structurally.
Does not stimulate muscarinic receptors.
Selective for nicotinic receptors.

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15
Q

Describe the catecolamine synthesis?

A

Tyrosine goes into neurones and converts to DOPA.
DOPA in the cytosol converts to dopamine.
Dopamine is taken up by vesicles and converted to noradrenaline.
Synthesised noradrenaline is stored in vesicles in sympathetic nerves.
It can be converted to adrenaline in the adrenal medulla.

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16
Q

Describe what happens at the cholinergic synapse?

A

The cholinergic synapse is a gap where a neurone produces acetylcholine and sends messages to other neurones or to skeletal muscle cells. Acetylcholine can take the following pathways:

  1. Diffuses
  2. Hydrolyses by acetlycholinesterase.
  3. Rapidly metabolised by choline and recycled .
  4. Binds to M2 receptors and decrease heart rate and contraction.
  5. Binds to M3 receptors in smooth muscles to cause secretion, contraction and vascular relaxation.
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17
Q

Potential fates of noradrenaline released from sympathetic nerves?

A
  1. Diffuses across the synapse.
  2. Binds and activates a2 receptors which reduce further release of noradrenaline by a negative feedback system.
  3. Diffuses across the synthase to bind and activate a1 and b receptors on target tissue.
  4. Taken back up to nerve terminal by NET (uptake 1). This requires energy.
  5. Taken back up by EMT and transports NA from synapse to nerve tissue. Limits duration of action of NA.
  6. Metabolised in the nerve tissue by the MAO and COMT enzymes which convert them into o-methylated metabolites.
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18
Q

Structures of catecholamines?

A

Structural modification of noradrenaline to produce synthetic catecolamines:
Increase bulkiness of substituents on the N-atom to create resistance to MAO.
Modification of catechol-OH groups creates resistance to COMT.

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19
Q

Pharmacology of physostigmine? (Or neostigmine)

A 
Reversible long acting inhibitor of acetylcholinesterase. 
Results in increased conc of ACh and indirectly stimulates nicotinic and muscarinic receptors. 
Physostigmine interacts with acetylcholinesterase at its anionic and estartic sites. Carbamylated product formed which hydrolyses in minutes to hours. ACh forms an acetylated intermediate while physostigmine is destroyed in the reaction.
Increases vasodepressor (increases blood pressure) effects of acetylcholine
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20
Q

Actions of a1 adrenoceptors?

A 
Found - postsynaptically
Blood vessels - vasoconstriction
Heart - increases rate and contraction
GI tract - decreases motility and tone
Lung - weak bronchoconstriction 
Smooth muscle cells - contraction
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21
Q

Actions of beta adrenoceptors?

A

Blood vessels - vasodilation
GI tract - motility and tone
Heart - increase rate and contraction
Lung - bronchodilation

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22
Q

Alpha receptor potency of stimulatory catecholamines?

A

Noradrenaline > adrenaline > isoprenaline

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23
Q

Beta receptor potency of stimulatory catecholamines?

A

Isoprenaline > adrenaline > noradrenaline

24
Q

Actions of a2 adrenoceptors?

A

Mostly found prejunctionally on sympathetic nerve endings.

Activation inhibits noradrenaline release. Negative feedback loop.

25
Q

Where are b1 adrenoceptors found and their effect?

A

Found in abundance in heart and intestinal tract.

Increases heart rate and contraction.

26
Q

Where are b2 adrenoceptors found and their effects?

A

Found in abundance in respiratory tract, blood vessels and liver.
Effects include: relaxation of airway and vascular smooth muscle, glycogenolysis/glyconeogenesis in the liver.

27
Q

Where are b3 adrenoceptors found?

A

Found relatively small numbers in fat cells and heart.

Potential targets for anti-obesity medication.

28
Q

Clinical uses of catecholamines (noradrenaline)?

A

It is a direct acting sympathomimetic that binds and stimulates adrenoceptors.
Treats:
Aanaphylactic reactions (B2) - adrenaline is first line treatment for acute anaphylactic rx induced by bee stings and penicillin.
Cardiac arrest (B1) - helps restore cardiac rhythm.
Local anaesthetic solutions (A1) - vasoconstrictor effect, increase duration, reduce risk of toxicity.

29
Q

Cardiovascular effects of catecholamines?

A

Noradrenaline - decrease heart rate, increase blood pressure, increase peripheral resistance.
Adrenaline - increase heart rate, increase blood pressure, decrease peripheral resistance.
Isoprenaline - increase heart rate, increase blood pressure, decrease significant peripheral resistance.

30
Q

What is an indirectly acting sympathomimetics?

A

Drugs that have no direct agonist activity at receptors. Instead taken up into noradrenergic nerves and displace noradrenaline which activates the receptors.
Example: Tyramine and amphetamine

31
Q

What is dexamphetamine?

A

An indirect acting sympathomimetic drug.
It is lipophilic so it exerts CNS effects.
Reduces appetite for food.
Postpones the need for sleep (analeptics)
No longer used due to abuse potential
Used to treat: narcolepsy (random sleeping) and children with ADHD.

32
Q

What is ephedrine?

A

It is a mixed acting sympathomimetic drug that is derived from a plant. Exerts action based on a combination of direct and indirect actions.
First orally active sympathomimetic.
Weak actions at a1 and b2 adrenoceptors.
Not a substrate for COMT or MAO.
Used clinically to relieve nasal congestion (vasoconstrictor)

33
Q

Clinical use of a1 adrenoceptor antagonists?

A

Treats hypertension.

a2 is usually not clinically useful.

34
Q

Clinical use of b1 adrenoceptor antagonists?

A

Treats angina, arrythmias, hypertension, myocardial infarction, migraine, heart failure, glaucoma, ventricular tachycardia and post-myocardial infarction.
b2 is not clinically useful.

35
Q

What are B1 adrenoceptor antagonists?

A

Prevents adrenoceptor agonists (noradrenaline, adrenaline etc) from binding to and activating B-adrenoceptors.

36
Q

What is propranolol?

A

Non-selective B adrenoceptor antagonist that is no longer clinically used. Used to treat hypertension and other forms of heart disease.

37
Q

What does oxymethylene do?

A

Improves antagonist potency. E.g. In propranolol

38
Q

Adverse effects of non-selective B-adrenoceptor antagonists?

A

Most reactions are due to excessive B-adrenoceptor blockade and the greatest danger occurs when the drug is first given.
B2 blockade - induce bronchoconstriction in asthmatics.
B2 blockade - potentiate hypoglycaemia in diabetics by inhibiting catecholamine induced mobilisation of glycogen stores and masking symptoms of hypoglycaemia such as tachycardia.
B1 blockade - congestive heart failure in untreated patients where maintenance of cardiac output depends on sympathetic drive.

39
Q

What is an adrenergic neurone blocker?

A

A drug that blocks the release of noradrenaline from sympathetic neurones by inhibiting excitation-release coupling.
Example: guanthidine.
Other actions also contribute to sympathetic neuronal blockade:
Taken up into sympathetic neurones via uptake 1. Stored in vesicles and then released as fake neurotransmitters. Initial sympathomimetic effect mediated via noradrenaline however noradrenaline is then displaced and stores depleted.

40
Q

Intravenous infusion of noradrenaline on heart rate and peripheral resistance?

A

Noradrenaline stimulates both a1 and a2 adrenoceptors to cause vasoconstriction. Consequently increases heart rate and force of contraction. There is an overall increase in peripheral resistance.
Can be used to treat hypotension.

41
Q

What is reserpine?

A

Different from adrenergic neurone blockers because it does not block excitation-release coupling. Very potent in its uptake into sympathetic nerves. It displaces noradrenaline and is stored. It then depletes noradrenaline and blocks nerve activity. It is much less active in the adrenal medulla.
Powerful CNS side effects: sedation and depression.

42
Q

What are cholinergic drugs?

A

Parasympathomimetics - muscarinic agonists - increase parasympathetic activity
Cholinesterase inhibitors - increase parasympathetic activity
Muscarinic antagonists - inhibits parasympathetic activity

43
Q

What is methacholine?

A

Binds to muscarinic receptors and is long acting.

44
Q

What is carbachol?

A

Binds to muscarinic or nicotinic receptors and is long acting.

45
Q

What is pilocarpine?

A

Binds to muscarinic receptors and is a miotic agent that increases glandular secretions.

46
Q

Clinical uses of muscarinic agonists?

A

Open angle glaucoma - drainage of aqueous humour impaired when pupil dilates. Iris tissue folding blocks the drainage angle. Muscarinic agonist constricts the pupil.
Urinary retention
Paralytic ileus
Assessment of pancreatic function

47
Q

Major contraindications of muscarinic agonists?

A

Asthma - bronchoconstriction, hyper secretion of mucus
Peptic ulcer - gastric acid secretion
Heart attack or coronary occlusion - bradycardia causing coronary insufficiency
Hyperthyroidism - hypersecretion of thyroid hormone

48
Q

What are cholinesterase inhibitors?

A

Cholinesterase inhibitors inhibit the catalytic activity of Cholinesterase enzymes that catalyse acetylcholine hydrolysis. Because of this, acetylcholine accumulates and cholinergic neurotransmission increases.

49
Q

What is edrophonium?

A

A short acting cholinesterase inhibitor. It combines reversible with acetlycholinesterasesterase anionic site and is effective for a few minutes.
Can be used to diagnose myasthenia gravis (skeletal muscle disease). In this autoimmune disease, nicotinic receptors are blocked by antibodies.

50
Q

What is orangophosphate?

A

Orangophosphate is a long acting irreversible Cholinesterase inhibitor. Interacts with acetylcholinesterase at the esteratic site. Phosphorylated ach-est is very stable. Oximes can reactivate phosphorylated ach-est if administered before bonding within the enzyme ages.

51
Q

Clinical uses of organophosphates?

A

Insecticides - parathion and marathion. Parathion has been responsible for more accidental deaths than any other insecticides.
Nerve gases - sarin, soman, tabun. Deadly at extremely low concentrations. Toxicity due to increase ACh at cholinergic synapses.
Eye - constriction of pupil. Decrease intraocular pressure for open angle glaucoma.
Skeletal neuromuscular junction - nicotinic receptor, reversal paralysis caused by curare like drugs.
Gastrointestinal system - lack of smooth muscle tone so contractions of lower oesophageal and gastric increases.
Treatment of atropine poisoning - acute toxicity caused by atropine, tricylic antidepressants, phenothiazines and antihistamines.

52
Q

Side effects of Cholinesterase inhibitors?

A

Death may result from respiratory failure following neuromuscular junction blockade in respiratory skeletal muscles. Acute poisoning effects such as: bronchoconstriction, accumulation of respiratory secretions, weakened respiratory muscles, bradycardia, sweating, salivation, constriction of pupils and increased GI tract activity.

53
Q

Treatment of poisoning with Cholinesterase inhibitor?

A

Stop exposure
Assist respiration
Administer cholinergic antagonist such as atropine
Administer oxime activator in the case of organophosphate
Administer anticonvulsant if needed
Monitor for potential cardiac irregularities

54
Q

What is atropine?

A

Competitive muscarinic antagonist.
It is a highly soluble belladonna alkaloid.
Inhibits ACh effects.

55
Q

Side effects of atropine?

A

Dry mouth and skin, urinary retention, cycloplegia, glaucoma, depression, hallucinations, increased body temp.

56
Q

Clinical uses of muscarinic antagonists?

A

Motion sickness, acute myocardial infarction, anticholinesterase poisoning, asthma, gastric ulceration, irritable bowel, Parkinsonism.

57
Q

Treatment of atropine poisoning?

A

Gastric lavage - prevent further absorption
Cholinesterase inhibitor - increase ACh at cholinergic synapse
Body temp is lowered - counter rise in temp
Anticonvulsant (diazepam) - counter CNS effects

Systems Pharmacology (11 decks)

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