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phar2005 term 1 > Cholinergic Pharmacology > Flashcards

Cholinergic Pharmacology Flashcards

1
Q

State the two classes of ACh receptors.

A

Muscarinic:
produced by muscarine and antagonised by atropine;
produced by low doses of ACh

Nicotinic:
produced by nicotine and antagonized by tubocurarine (or by repeated administration of nicotine);
produced only by high doses of ACh

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2
Q

Outline the four steps of Dale’s experiment on the effect of ACh on blood pressure.

A
  1. Small dose of ACh; vasodilation and bradycardia, due to muscarinic action - ends quickly, as ACh is degraded.
  2. Muscarinic actions blocked by atropine
  3. Large dose now stimulates ganglia (nicotinic action) causing vasoconstriction and tachycardia by activating the postganglionic neurones.
  4. Secondary effect due to adrenaline release from adrenal medulla (nicotinic effect - blocked by hexamethonium)
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3
Q

Distinguish between the physiological and pharmacological effects of muscarinic receptors.

A

Smooth muscle in the eye, bronchi, GI tract, bladder:
INNERVATED; CONTRACTION

Smooth muscle in most blood vessels:
NOT INNERVATED; RELAXATION (vasodilation)

Smooth muscle in arterioles in genitals:
INNERVATED; RELAXATION

Glands: salivary, lacrimal, GI tract, bronchial, sweat glands:
INNERVATED; SECRETION

Heart:
INNERVATED (conduction system, atria);
SLOW RATE AND CONDUCTION

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4
Q

Give some examples of muscarinic agonists, state whether they are muscarinic (M) or nicotinic (N), and their ???

A

ACh: both N and M;
quickly hydrolysed by cholinesterase (ChE)

metacholine: M;
slowly hydrolysed by ChE

carbachol (CCh): both N and M;
resistant to ChE

bethanechol: M;
resistant to ChE

pilocarpine: M;
resistant to ChE

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5
Q

List the main effects of muscarinic agonists.

A
  1. Bradycardia and reduced cardiac output –> decrease in blood pressure
  2. Vasodilation
  3. Salivation, lacrimation and sweating
  4. Bronchoconstriction and increased bronchial secretion
  5. Contraction of bladder
  6. Increased motility of GI tract
  7. Pupillary constriction (miosis) –> reduction of intraocular pressure
  8. Contraction of ciliary muscle, accommodation for near vision.
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6
Q

Discuss how the effects of atropine reveal parasympathetic tonic activity.

A

CNS: antiemetic (motion sickness; less tremor in Parkinson’s; excitation (toxic doses); cognitive impairment in elderly

Eye: pupil dilation (mydriasis); paralysis of accommodation, intraocular pressure may rise

Secretions reduced: saliva, tears, sweat, bronchi, GI

Smooth muscle relaxed (bronchi, GI tract)

Heart: may increase heart rate: no effect on blood vessels

Urinary retention

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7
Q

Give some examples of clinical uses of muscarinic agonists.

A
  1. Glaucoma (pilocarpine eye drops; not first choice)
  2. Relieve dry mouth (xerostomia; pilocarpine)
  3. Relieve paralytic ileus after abdominal surgery (oral bethanechol)
  4. Relieve urinary retention (bethanechol; catheterisation more common)
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8
Q

State what kind of antagonists act at muscarinic receptors, and give the three main drugs.

A

Competitive antagonists;

  1. Atropine (deadly nightshade berries)
  2. Hyoscine (a.k.a scopolamine, another plant product)
  3. Homatropine (synthetic analogue of atropine with a briefer action)
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9
Q

What kind of substance acts on muscarinic receptors, and what are the three main drugs?

A

Competitive antagonists;

  1. Atropine (found in deadly nightshade berries)
  2. Hyoscine (also called scopolamine, another plant product)
  3. Homatropine (a synthetic analogue of atropine with a briefer action.
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10
Q

Discuss the peripheral actions of muscarinic inhibitors.

A
  1. Block of secretions: saliva, tears, bronchial secretion, sweating
  2. Tachycardia; no change in blood pressure because most blood vessels have no parasympathetic innervation
  3. Pupil dilation (mydriasis) because of block of parasympathetic influence on sphincter pupillae;
  4. Inhibition of motility;
    secretions of GI tract (much larger doses, not complete)
  5. Other smooth muscle is also relaxed, e.g. bronchi, bladder (much larger doses, not complete)
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11
Q

What are the actions of atropine in the CNS?

A

No great effect in small doses;

At high doses (e.g. deadly nightshade poisoning), atropine causes marked stimulation resulting in restlessness, disorientation, and hallucination.

More subtle effects, such as attention and memory defecits, can appear at low doses in the elderly.

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12
Q

What are the actions of Hyoscine in the CNS?

A

Hyoscine is a powerful CNS depressant, causing sleep and amnesia.

Also has anti-emetic action (used in sea-sickness pills)

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13
Q

What is the likely mechanism by which Atropine-like drugs suppress tremor in Parkinson’s?

A

The likely mechanism is the blocking of cholinergic transmission in the basal ganglia.

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14
Q

Which drugs stimulate the ganglia?

A

Only nicotine is important.

Nicotine is a stable, volatile tertiary amine, readily absorbed through mucous membranes (e.g. mouth, lungs) and skin (nicotine patches).

In small doses, its main actions are central; larger doses stimulate ganglia and still larger doses block ganglia

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15
Q

What are the main effects of absorbing nicotine by smoking?

A
  1. CNS stimulant effect
  2. Increased parasympathetic and sympathetic activity;
    the vasoconstriction effect of nicotine may be the cause for the impairment in foetal growth caused by smoking in pregnancy (due to less placental blood flow), as well as the increased incidence of cardiovascular disease in smokers
  3. Release of antidiuretic hormone (ADH) from the posterior pituitary gland
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16
Q

What are the effects of ganglion-blocking drugs on the cardiovascular system?

A

The effects depend mainly on block of sympathetic system;

dilation of arterioles and veins –> decrease blood pressure, and loss of cardiovascular reflexes;

skin vasodilation

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17
Q

What are the effects of ganglion-blocking drugs on the GI tract?

A

The effects are due mainly to block of parasympathetic system;

inhibition of motility and secretion, leading to constipation, often severe

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18
Q

What are the effects of ganglion-blocking drugs on the genito-urinary system?

A

Block of parasympathetic leads to impairment of micturition, and to erection failure;

block of sympathetic inhibits ejaculation;
the net result is impotence

19
Q

What are the effects of ganglion-blocking drugs on the eye?

A

Loss of accommodation (hence blurred vision);

loss of pupillary reflex can cause photophobia

20
Q

Discuss the use of hexamethonium.

A

No longer used in man, but was the first effective antihypertensive when first introduced in 1949;

current antihypertensive drugs have far fewer side effects;

Trimetaphan is occasionally used to produce controlled hypotension during surgery

21
Q

What steps of synaptic function do NMJ blocking agents interfere with?

A
  1. Combination of transmitter with receptors

6. Production of postsynaptic response (inhibit/excite)

22
Q

Describe competitive NMJ blockers, and list some examples.

A

Also known as non-depolarizing curares;

have high affinity for nAChRs and has a long residence in its binding site; when ACh is released, it finds receptors already occupied by the blocker; the synaptic potential therefore becomes too small to elicit an action potential

tubocurarine, vecuronijum, pancuronium, aracurium

23
Q

Features of competitive NMJ blockers:

A
  1. Causes relaxation without preliminary excitation of muscles
  2. Relaxant effect antagonized by anticholinesterases
  3. Tetanic “fade” is more pronounced
  4. Myasthenia gravis patients (autoimmune loss of ACh receptors) are normally sensitive

These blockers have a relatively long duration of action; it is common in practice to reverse their action by administrating a cholinesterase blocker

24
Q

Describe suxamethonium as an example of depolarizing blockers.

A

Suxamethonium is an AGONIST of the nicotinic ACh receptor.

It is resistant to hydrolysis by the local cholinesterase, and therefore can bind and rebind to the receptor and cause a sustained depolarization of endplate region of muscle fibre.

After a first action potential, the muscle fibre membrane becomes inexcitable because the sodium channels around the endplate inactivate and cannot generate an AP

25
Q

Features of depolarizing NMJ blockers:

A
  1. Initial fasciculation (i.e. twitching) as endplate depolarization causes excitation of muscle fibres; if pronounced, this is associated with post-operative muscle pain
  2. Block not relieved (and may be enhanced) by anticholinesterases
  3. Myasthenia gravis patients are insensitive to blocking action
  4. Action at endplate causes release of K+ from muscle cells, causing hyperkalaemia; normally unimportant, but dangerous either if K+ is already high (e.g. in sever burns or crush injuries) or if K+ release is enhanced (e.g. diseases or injuries causing denervation).
26
Q

Outline the hydrolysation of suxamethonium by plasma cholinesterase.

A

Suxamethonium is hydrolysed rapidly by plasma cholinesterase so that action lasts only 5 minutes-ish

If plasma cholinesterase activity is low, action an be greatly prolonged to up to several hours. This can be due to a genetic abnormality, with low or absent ChE activity because of mutations (1:1400 - 1800 anaesthetic cases, depending on the population)

Other causes of low plasma ChE include liver disease, malnutrition, or use of anticholinesterase drugs

27
Q

State the main drug used to block cholinergic transmission.

A

BOTULINUM TOXIN (BOTOX):

blocks release of ACh at NMJ and ganglia, without affecting postsynaptic mechanisms; can be used for prolonged relief of muscle spasm in dystonia in severe localised excessive sudoration (and to reduce wrinkles by paralysing frown muscles)

28
Q

Discuss two other minor drugs that block cholinergic transmission.

A

HEMICHOLINIUM:
structurally similar to choline, competitive inhibitor of choline uptake by cholinergic nerve terminals, resulting in ACh synthesis falling behind ACh release

STREPTOMYCIN (and other AMINOGLYCOSIDE antibiotics):
also inhibit ACh release by blocking Ca2+ entry; this can cause weakness as a side effect and potentiates the action of NMJ blocking agents in anaesthesia

29
Q

List the two forms of cholinesterase that catalyse the hydrolysis of ACh to acetate and choline

A

Acetylcholinesterase

Butyrylcholinesterase

30
Q

Discuss the location and substrate specificity of acetylcholinesterase

A

LOCATION:
membrane-bound, at all cholinergic synapses;
also in RBC (function unknown)

SUBSTRATE SPECIFICITY:
specific for ACh and closely similar esters

31
Q

Discuss the location and substrate specificity of butyrylcholinesterase

A

LOCATION:
usually a soluble enzyme (sometimes membrane-bound); found in plasma, liver and many other tissues

SUBSTRATE SPECIFICITY:
fairly unspecific; hydrolysis faster for butyrylcholine than for ACh; can hydrolyse many other esters, including some drugs such as procaine, suxamethonium, cocaine

32
Q

Discuss the genetic aspect of butyrylcholinesterase (BuChE)

A

BuChE is controlled by an autosomal gene with several alleles; mutant alleles have low or absent activity.

33
Q

State the two main symptoms exhibited in individuals who are homozygous for mutant BuChE alleles.

A
  1. Greatly reduced rate of hydrolysis of some drugs (especially suxamethonium), which is clinically important in anaesthesia
  2. Reduced sensitivity of the enzyme to inhibition by dibucaine, forming the basis of blood screening by dibucaine number test
34
Q

Outline the average results of a dibucaine number blood screening test.

A

Numbers are % of enzyme inhibited by dibucaine.

Normal range: 70-90%

Heterozygotes: 50-70%, do not show abnormal suxamethonium sensitivity

Homozygotes: 10-20%, extremely sensitive to suxamethonium

35
Q

What are the two sites involved in the mechanism of action of cholinesterase?

A
  1. Catalytic (esteratic) site:
    contains a reactive serine OH group
  2. Anionic site:
    binds cationic quaternary ammounium group of ACh
36
Q

What are the three steps of enzymatic hydrolysis, as seen in the action of cholinesterase?

A
  1. Binding of ACh at the catalytic and anionic sites
  2. Transfer of acetyl group to serine OH group (on catalytic site)
  3. Dissociation of choline via spontanoeus hydrolysis of acetylated serine OH
37
Q

How many ACh molecules are hydrolysed at any one active site per second?

A

Roughly 10^4 (turnover)

38
Q

How are cholinesterase inhibitors classified?

A

Classified in terms of duration of action (i.e. stability of bond to active site):

  1. Short-acting anticholinesterases
  2. Medium or long acting reversible anticholinesterases
39
Q

Elaborate on the structure and function of short-acting anticholinesterases, providing an example.

A

STRUCTURE:
Possess a quaternary ammonium group, but no group complementary to the esteratic site.

FUNCTION:
Act competitively by binding to the anionic site through ionic bonding

EXAMPLE:
Edrophonium

40
Q

Elaborate on the function of medium- or long-acting anticholinesterases, providing an example.

A

FUNCTION:
Bind to both sites and form an ester bond with the serine hydroxyl group of the esteratic site (i.e. the drug being hydrolysed). Spontaneous hydrolysis is much slower when the serine OH is bound to neostigmine than when it is bound to an acetyl group and the enzyme is inactivated for several minutes.

EXAMPLE:
Neostigmine; Eserine

41
Q

Discuss the effects of anticholinesterases resulting from the inhibition of ACh hydrolysis at PERIPHERAL cholinergic synapses

A

PARASYMPATHETIC EFFECTS:
salivation, sweating, increased GI motility (–> vomitic, diarrhoea), bronchoconstriction, bradycardia, pupillary constriction, fall in intraocular pressure

NMJ:
facilitation of transmission at first; repetitive firing at normal junctions, restoration of transmission at junctions blocked by compete

42
Q

Discuss the effects of anticholinesterases resulting from the inhibition of ACh hydrolysis at CENTRAL cholinergic synapses

A

Mainly EXCITATORY

–> agitation and convulsions, followed by respiratory depression

43
Q

What are the five main uses of anticholinesterases?

A
  1. Treatment of glaucoma (as eye drops)
  2. Myasthenia gravis:
    quarternary compounds as they do not reach brain; atropine may be needed to control parasympathetic effects; edrophonoium is used to test for myasthenia gravis
  3. Reversal of competitive NMJ block following anaesthesia
  4. Organophosphates widely used as insecticides; poisoning is quite common among agricultural workers and gardeners, can be hard to diagnose
  5. Alleviate symptoms of Alzheimer’s (drugs selective for AChE and able to cross blood-brain barrier); effect is small, inconsistent and at best provides only temporary relief (months)
44
Q

Discuss the concept of cholinesterase reactivation by, for example, pralidoxime.

A

Following phosphorylation, CHe can be reactivated by oxime products such as pralidoxime.

Pralidoxime binds reversibly to the anionic site - this causes the oxime hydroxyl group to be at the right distance to react with the phosphate group and substitute for the serine hydroxyl.

This mechanism is used in treatment of organophosphate poisoning, but early treatment is essential.

phar2005 term 1 (10 decks)

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