Cholinergic Drugs

Question 1

What are the two cholinergic receptors?

Answer 1

Nicotinic and Muscarinic

Question 2

ACh released from the ___ nerve terminal interacts with subunits of the ___ nicotinic receptor to open it, allowing ___ influx to produce local depolarization and contraction.

Answer 2

motor; pentameric; Na+

Question 3

The nicotinic receptor contains ___ subunits and binds ___ molecules of agonist.

Answer 3

five; two

Question 4

Nicotinic receptors can be homomeric or heteromeric. Describe adult and fetal skeletal muscle

Answer 4

Adult: two alpha-1, one each of beta, episilon, and delta
Fetal: two alpha-1, one of each beta, gamma, and delta

Question 5

Which subunit binds ACh?

Answer 5

alpha-1

Question 6

Why do nicotinic receptors have complex pharmacology?

Answer 6

there are many combinations of 5 subunits (a2-a7 subunits and B2-B5 subunits)

Question 7

In addition to acetylcholine, muscarinic receptors bind ___ and nicotinic receptors bind ___.

Answer 7

muscarine; nicotine

Question 8

How many different muscarinic receptors are there?

Answer 8

five, M1-M4 are better appreciated than M5

Question 9

___ receptors contain seven transmembrane domains whose ___ cytoplasmic loop is coupled to ___ proteins.

Answer 9

Muscarinic; third; G

Question 10

Which muscarinic receptors are linked to G-alpha-q and activate DAG and IP3 signaling and activate phospholipase C to promote Ca2+ release?

Answer 10

M1, M3 and M5 (odd)

Question 11

Which muscarinic receptors are linked to G-alpha-i and inhibit adenylate cyclase?

Answer 11

M2 and M4 (even)

Question 12

How are direct acting cholinergic agonists different from indirect acting?

Answer 12

direct: bind to muscarinic or nicotinic ACh receptors or both
indirect: cholinesterase inhibitor

Question 13

What is the purpose of the quarternary amine on acetylcholine?

Answer 13

binding to the receptor

Question 14

acetylcholine → ___ + ___ by what enzyme?

Answer 14

acetate; choline; acetylcholinesterase

Question 15

Which drug is similar to acetylcholine but is hydrolyzed much slower by esterase?

Answer 15

Carbachol (carbamylcholine)

Question 16

List 4 non-selective cholinergic agonists.

Answer 16

acetylcholine, muscarine, nicotine, carbamoylcholine

Question 17

List two nicotinic and muscarinic cholinergic agonists.

Answer 17

Nicotinic: dimethylphenylpiperazinium, succinylcholine
Muscarinic: pilocarpine, cevimeline

Question 18

What has a profound effect on the duration of cholinergic agonists?

Answer 18

hydrolysis by cholinesterase

Acetylcholine hydrolyzed rapidly (short duration of action)
Methacholine hydrolyzed slower (somewhat longer duration of action)
Carbachol, bethanechol, cevimeline, and alkaloids are not hydrolyzed (longer duration of action)

Question 19

___ muscarinic receptors on the sphincter muscles mediate pupil ___. ___ receptors on ___ muscle also mediate muscle contraction. This increases drainage by the ___ network and reduces ocular pressure.

Answer 19

M3; contraction; M3; ciliary; trabecular

Question 20

What type of muscarinic receptors are found on cardiac muscles? What happens when these receptors are activated?

Answer 20

M2

reduce cardiac output

Question 21

What type of receptors are expressed on vascular endothelial cells? What happens when these receptors are activated?

Answer 21

M3

vasodilation

Question 22

Activation of M3 receptors increase ___ in endothelial cells. The Ca2+/calmodulin complex activates ___ to produce ___, which travels to the smooth muscle cell, enhances ___ production leading to muscle relaxation (enhances myosin light chain phosphatase activity).

Answer 22

Ca2+; NOS; NO; cGMP

Question 23

What type of receptors are on the bronchial muscle and what happens when they are activated?

Answer 23

M3

contraction

Question 24

T/F. Most GI effects are contractile except for sphincter muscles which relax when M2 receptors are activated.

Answer 24

True.

Question 25

What type of receptor is found in secretory (salivary) glands? What happens when the receptor is activated?

Answer 25

M3 receptor Ca2+ stimulates release of glandular contents

Question 26

___ muscarinic receptors mediate ___ muscle contraction which aids in the voiding of the bladder.

Answer 26

M3; detrusor

Question 27

Why are tertiary amines better absorbed than quaternary amines?

Answer 27

Tertiary amines can be charged or uncharged but quarternary amines have a permanent charge. Therefore, they must be inside the cell to work and charged from works on Na+ channel

Question 28

___ and ___ are well absorbed after oral, subcutaneous or topical administration because they are not charged.

Answer 28

Pilocarpine; cevimeline

Question 29

What patients taking muscarinic agonists are at an increased risk of having adverse responses?

Answer 29

patients with asthma (bronchoconstriction), cardiovascular disease (vasodilation, reduced cardiac output), ulcer (lacrimation).

Question 30

What is the SLUD response to muscarinic agonists?

Answer 30

Salivation, Lacrimation, Urination, Defecation/Digestion

Question 31

What is the hypertensive response to parenteral injections of large doses of pilocarpine or cevimeline?

Answer 31

CNS effects, activation of sympathetic postganglionic neurons

Question 32

Why are intravenous and intramuscular routes generally avoided when administering muscarinic agonists?

Answer 32

because of cardiopulmonary effects topical routes favored, if possible

Question 33

Anticholinesterase which work by inhibiting the enzyme ___, which prevents hydrolysis of ___ thus increasing their concentration in the synapse and promoting more ___ action.

Answer 33

Acetylcholinesterase; ACh; ACh

Question 34

T/F. Since anticholinesterases promote ACh activity without binding to any receptor they are called indirectly acting cholinergic agonists.

Answer 34

True.

Question 35

How is the synapse organized to get rid of as much ACh as quickly as possible?

Answer 35

There is enough Acetylcholinesterase in the synapse to hydrolyze 3 X 10^8 molecules of ACh in 1 millisecond (10-3). Normally only 3 X 10^6 ACh are released into synapse.

Question 36

___ is a tertiary amine and ___ is a quarternary amine. Both are ___ reversible anticholinesterases.

Answer 36

Physostigmine; neostigmine; slowly

Question 37

T/F. Some reversible anticholinesterases are slowly hydrolyzed by cholinesterase.

Answer 37

True

Question 38

___ ___ is an example of an anticholinesterase that acts in a rapidly reversible manner and is not hydrolyzed at all.

Answer 38

Ambenonium chloride

Question 39

Sarin and Malathon are reversible acting organophosphates. Which one is an insectiside and which is a nerve gas?

Answer 39

``` Malathion = insectiside Sarin = nerve gas ```

Question 40

Organophosphate anticholinesterases act in completely ___ manner. They covalently react with the enzyme and are not ___ (unless treated with antidote). They are ___ to insects and to people and are only used to kill things.

Answer 40

irreversible; hydrolyze; poisonous

Question 41

T/F. In general, anticholinesterases produces effects that are similar to the direct acting cholinergic agonists.

Answer 41

True. In effect, increase the concentration of acetylcholine at effector site.

Question 42

T/F. The greater the cholinergic stimulation at the site, the greater the effect.

Answer 42

True. ACh must be supplied, if not present, then no effect. Smooth muscle of ocular system, GI tract, urinary bladder are major sites.

Question 43

T/F. Anticholinesterases produce muscarinic receptor mediated vasodilation.

Answer 43

False, anticholinesterases DO NOT produce muscarinic receptor mediated vasodilation because there is no parasympathetic innervation to vascular endothelium.

Question 44

Anticholinesterases can produce vasodilatory effects through autonomic ___.

Answer 44

ganglia

Question 45

___ (tertiary amine) can produce vasodilatory effects through action in the CNS. It is readily ___ after oral, subcutaneous, and topical administration. It is inactivated by plasma ___.

Answer 45

Physostigmine; absorbed; cholinesterases

Question 46

Which type of amine anticholinesterases pass through biological membranes with difficulty and are inactivated by plasma cholinesterases and/or through liver metabolism?

Answer 46

Quaternary

Question 47

What condition is atropy of the optic nerve and loss of vision due to elevation in intraocular pressure? What does therapy attempt to do?

Answer 47

Glaucoma Therapy aimed at stimulating musculature of the iris and ciliary body, increasing outflow or decreasing formation of vitreous humor.

Question 48

Muscarinic agonist decrease resistance to vitreous outflow through ciliary muscle contraction. What drugs are used? How are they applied? What is the adverse effect?

Answer 48

Pilocarpine, Physostigmine, and demecarium or echothiophate applied topically development of cataracts

Question 49

What drugs are frequently used to treat dry mouth (xerostomia)? What must be functional in these patients?

Answer 49

Pilocarpine and cevimeline (muscarinic agonists) functional salivary gland

Question 50

How is pilocarpine and cevimeline administered?

Answer 50

Pilocarpine: 5-10mg oral 3X day to increase parotid, submandibular and sublingual secretion. Max flow is produced within 30 mins, return to basal flow within 3 hrs. No significant affect on cardiac function or BP. SE: sweating, chills, nausea, and dizziness Cevimeline: 30mg, 3X day fewer side effects

Question 51

What type of drug is used to terminate the neuromuscular block of curare-like agents in general anesthesia?

Answer 51

Anticholinesterases

Question 52

Anticholinesterases are used to treat Myasthenia Gravis and can cross the blood brain barrier to improve cognitive function in Alzheimer's patients. What drugs treat each?

Answer 52

MG: autoimmune disease with antibodies directed against nicotinic ACh receptors A: donepezil, rivastigmine, galantamine

Question 53

___ and ___ are teritary anti-muscarinic natural products that will be absorbed and able to cross the ___ ___ ___

Answer 53

Atropine; Scopolamine; blood brain barrier

Question 54

___ is a quarternary amine derived from Scopolamine that is poorly absorbed and cannot cross the BBB.

Answer 54

Methscopolamine

Question 55

___ (tertiary amine) and ___ (quarternary amine) are synthetic anti-muscarinics.

Answer 55

Benztropine; Propanthaline

Question 56

In general, treatment with an anti-muscarinic drug places the target under control by the sympathetic nervous system. What is the exception?

Answer 56

Sweat gland, where signals from sympathetic and parasympathetic systems act upon muscarinic receptors at the target and are both blocked by the anti-muscarinic.

Question 57

Anti-muscarinics will cause pupil ___ and paralysis of ___. Intraocular pressure is not significantly affected except in the case of ___ ___ ___, in which they can cause a serious rise in pressure.

Answer 57

dilation; accomodation; narrow angle glaucoma

Question 58

How do anti-muscarinics treat COPD? Body temperature?

Answer 58

produce bronchodilation and diminish mucus production inhibit sweating and can elevate body temperature

Question 59

What is the pharmacologic effect of anti-muscarinics on the GI tract?

Answer 59

generally inhibit motility and only inhibit secretions at very high concentrations

Question 60

In the secretory glands (___ receptors), anti-muscarinics block ___ mediated secretion.

Answer 60

M3; parasympathetic

Question 61

___ anti-muscarinics cause mild bradycardia when given to limit salivation due to selective inhibition of prejunctional ___ receptors that limit ACh release. At ___ doses, the opposite effect is seen due to the direct action at the heart.

Answer 61

Oral; M2; higher

Question 62

How does atropine cause changes in urinary retention?

Answer 62

Detrusor muscles are relaxed by atropine and sphincter and trigone muscles are contracted.

Question 63

Give 5 therapeutic uses for anti-muscarinics.

Answer 63

1. dilate pupils for opthalmologic procedures 2. treatment of COPD (quarternary amines administered by inhalation) 3. Diminish salivary secretions before oral procedures 4. Anti-spasmodics, and anti-ulcer agents (not useful because of SE) 5. antidote to anti-cholinesterases

Question 64

Relate oral doses to the effects of antimuscarinics.

Answer 64

Lowest → highest 1. secretion (saliva, sweat, mucus) 2. mydriasis (pupil dilation) loss of accomodation and tachycardia 3. loss of parasympathetic control of bladder and GI smooth muscel 4. gastric secretion

Question 65

T/F. Unlike atropine, the quaternary amines anti-cholinergics are poorly absorbed, have a wide therapeutic margin, and are well tolerated.

Answer 65

True.

Question 66

What are the adverse effects of atropine?

Answer 66

Hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a wet hen. increased intraocular pressure, ventricular fibrillation, tachycardia, dizziness, nausea, dry mouth, blurred vision, extreme confusion, hallucinations

Question 67

What are the common symptoms known as anti-cholinergic toxidrome?

Answer 67

warm, dry skin from decreased sweating, blurry vision, decreased sweating/lacrimation, vasodilation, and effects on the CNS.

Question 68

When nicotine acts on the CNS it will penetrate the ___ and produce CNS effects, feelings of ___ being and ___ irritability.

Answer 68

BBB; well; decreased

Question 69

T/F. Ganglionic blockers are rarely used because they block sympathetic and parasympathetic ganglion and their lack of selectivity confers such a broad range of undesirable effects.

Answer 69

True

Question 70

Post-synaptic transmission of nerve impulses at skeletal muscle is mediated by ___ ACh receptors.

Answer 70

nicotinic

Question 71

Explain receptor desensitization.

Answer 71

Although cholinergic agonist biding to ACh receptor initially opens the ion gate (letting Na+ in), continued activity produces desensitization, a refractory state where the ion gate remains closed despite the continued presence of agonist.

Question 72

Drugs now used as ganglion blockers are classified as non-depolarizing competitive antagonists. List some examples of the drugs? What do they competitive antagonist against?

Answer 72

d-tubocurarine, pancuronium (bromide salt), atracurium acetylcholine

Question 73

___ is a depolarizing agent that has a more rapid ___ of action and a shorter ___ of action than non-depolarizing blocking agents.

Answer 73

Succinylcholine; onset; duration Because it is subject to hydrolysis by plasma and liver cholinesterases it has a shorter duration of action.

Question 74

Initially, succinylcholine activates ACh receptors but the chronic ___ at the muscle end-plate leads to ___ of voltage-gated Na+ channels and ___ ___. This is the ___ acting phase one block.

Answer 74

depolarization; inactivation; flaccid paralysis; shorter

Question 75

After a while, chronic exposure to succinylcholine leads to ___ of ACh receptors. This is the ___ acting phase II block.

Answer 75

desensitization; longer

Question 76

Neuromuscular blocking agents can be given ___ or ___ but it induces ___ ___. ___ infusion is the usual administration pre-surgery.

Answer 76

IV; IM; flaccid paralysis; Fast

Question 77

T/F. Neuromuscular blocking agents have side effects in CNS and on autonomics.

Answer 77

False, they do not get in CNS and have no particular effect on ganglia

Question 78

Neuromuscular blocking agents can promote ___ release from ___ cells.

Answer 78

histamine; mast

Question 79

What two drugs are used in endotracheal intubation?

Answer 79

1. succinylcholine (most rapid) - drug of choice | 2. rocuronium (non-depolarizing) - second place

Question 80

In adjunct to general anesthesia during surgery when a doc wants to block neuromuscular transmission what medium speed blocker is favored?

Answer 80

d-tubocurarine

Question 81

What is the most significant adverse effect when administering neuromuscular blockers?

Answer 81

respiratory failure but arrhythimas (ganglionic activities, pancurium worst) and bradycardia (succinylcholine worst) can also occur.

Question 82

T/F. Neuromuscular blocking agents can have drug interactions with anticholinesterases and general anesthetics.

Answer 82

True.

Question 83

T/F. Dentist may occasionally need to produce muscle relaxation when performing surgery (treating jaw fracture) and endotracheal intubation.

Answer 83

True