MSKS Pharmacology Lecture 2_Antispasmodic and Spasmolytic Agents

Question 1

What are antispasmodic agents used to treat?

Answer 1

Acute local spasm due to injury or muscle strain

Question 2

What are spasmolytic agents used to treat?

Answer 2

Neurodegenerative disorders (Multiple Sclerosis, ALS), cerebral palsy, spinal injury

Question 3

What causes Spasticity?

Answer 3

deficit in upper motor neuron signaling leaves lower motor neurons hyperexcitable (because they upregulate their receptors)

Question 4

What are the three targets of Pharmacological treatments of spasticity

Answer 4

• Lower motor neurons • Interneurons in the reflex arc • Skeletal muscle directly

Question 5

How do CNS-active spasmolytics decrease alpha motor neuron activity

Answer 5

• (1) reducing activity of the excitatory interneurons • (2) enhancing activity of the inhibitory interneurons

Question 6

What two inhibitory receptors are on the inter motor neuron?

Answer 6

alpha 2 and GABAb (both of which are Gi coupled receptors)

Question 7

What inhibitory receptors are on the lower motor neuron?

Answer 7

alpha 2 and GABAb (both of which are Gi coupled receptors) and GABAa (which is a Cl- ion channel)

Question 8

What receptor does Baclofen act on?

Answer 8

GABAb

Question 9

What receptor does Diazepam act on?

Answer 9

GABAa

Question 10

What receptor does Tizanidine

Answer 10

𝛼2-adrenergic receptor agonists

Question 11

Baclofen, Diazepam, and Tizanidine are all examples of what?

Answer 11

Centrally acting spasmolytic agents

Question 12

What are Benzodiazepines (BZDs) used to treat and what is their mechanisium of action?

Answer 12

They are used as CNS-active sedatives and anxiolytics. Their mechanisium of action is Positive allosteric modulation (this means that they are not direct agonists but they will alter the structure of the GABAa receptor such that when GABA does bind, the Cl channel is open longer) of GABAa receptors.

Question 13

How are BZDs metabolized?

Answer 13

Hepatically by CYP3A4

Question 14

What are the Adverse drug responses to Diazepam

Answer 14

• Daytime drowsiness and sedation (especially for long-acting) • Rebound insomnia/anxiety • Anterograde amnesia • Coma and respiratory depression when used with other CNS depressants (esp. alcohol) • Alcohol improves rate of absorption and acts at GABAA receptor

Question 15

What is Flumazenil used for? What is a key consideration with its use?

Answer 15

Flumazenil is used to treat BZD overdoses. Flumazenil has a very short half life (less than 1.5 hours) which means it can be matabolized from the system while there are still overdose levels of the BZD

Question 16

How does Baclofen work?

Answer 16

It is a direct agonist of the GABAb receptors. Agonizing GABAb receptors opens K+ channels, leading to hyper polarization of a cell.

Question 17

What is the mechanisium of action of Gabapentin?

Answer 17

It reduces the exitation of lower motor neurons by inhibiting the releasae of glutamate from the interneuron. It does this by preventing the opening of the presynaptic Ca channels. It is typically well tolorated with few adverse side effects

Question 18

What is the ADR of Tizanidine?

Answer 18

Because it acts on Alpha 2 receptors, it will also agonize these receptors in the ANS. This can lead to hypotention. It also causes hepatotoxicity and is metabolized by CYP1A2 (smoking is an inducer of this enzyme)

Question 19

What is the mechanisium of action of Botulinum Toxin Type A?

Answer 19

It cleaves the SNARE proteins that Meadiate the release of ACh from the neuron.

Question 20

Three facts about Antispasmodics

Answer 20

• Centrally active agents that treat peripheral muscle spasms by targeting the brain stem • Largely unknown MOA • Major interactions with other CNS-depressant drugs

Question 21

Cyclobenzaprine has what side effects?

Answer 21

Strong antimuscarinic side effects, significant sedation, confusion and transient visual hallucinations, seizures, tachycardia, hypotension • Rare, but life threatening: Neuroleptic malignant syndrome (can be reversed with dantrolene)

Question 22

Why is carisoprodol at risk of abuse?

Answer 22

Carisoprodol is metabolized to meprobamate (CYP2C19), a Schedule IV drug with sedative action and abuse liability

Question 23

Cyclobenzaprine and carisoprodol are examples of what?

Answer 23

Antispasmodics

Question 24

Summary sheet

Answer 24