Lecture 6: Analgesics Flashcards
What are drugs that treat inflammation and/or fever?
Aspirin and NSAIDs
What are drugs that block sensation?
Topical anesthetics
What are drugs that block pain?
- Acetaminophen
* Capsaicin cream
What are the two classes of pharmaceutical drugs?
- Those that are prescription only
* Those are directly available to the consumer
Why is there a huge diversity of products?
Because there is only a limited number of approved active ingredients, but they recombine the amounts
What is Analgesics?
Pain killing
What are some medications used for Analgesics?
- Tylenol
- Advil
- Motrin
- Robax
- Anacin
- Excedrin
What are some typical Decongestants?
- Sudafed
- Mucinex
- Coricidin
- Dristan
What are some common Cough, sleep, allergy medications?
- Buckley’s
- Benylin
- Dimetapp
- Robitussin
- NyQuil
- Claritin
What is Efficacy?
The ability to evoke a response or produce an effect
What are Primary Afferents?
Neurons that detect sensory information in the periphery
Where do Primary Afferents take sensory information?
From the periphery to the spinal cord
What do Primary Afferents synapse onto?
Secondary afferents in the spinal cord
What do Secondary Afferents do?
The carry sensory information from from the spinal cord to the brain
What do Efferent fibers do?
Take commands from the brain and send them to the periphery
Which part of the spinal cord do Primary Afferents enter?
They enter through the Dorsal horn
What helps to modulate the incoming primary afferents?
The descending signals sent by the pain system
What can activate the descending pathway?
Opioids and acetaminophen
What is the pathway of the modulating pain Efferents?
Parts of the brain synapse at PAG, then RVM, and then to the dorsal horn in the spinal cord
What is pain detected by?
Nociceptors
What are Nociceptors?
A specific class of primary afferents that detect pain
What are Polymodal Nociceptors?
Nociceptors that detect many types of painful stimuli
What are different types of painful stimuli detected by?
Specific receptors expressed on polymodal nociceptors
What are the receptors on nociceptors linked to?
Intracellular pathways that activate signalling that cause the generation of an action potential into the CNS
What cause the different types of pain sensations perceived?
The combination of what signalling gets activated
What are Transient Receptor Potential (TRP) channels?
Temperature sensitive ligand-gated ion channels
What are different types of TRP channels tuned to respond to?
Very specific temperatures
What is TRPM8 activated by?
Temperature below 10ºC
What is TRPV1 activated by?
Hot temperatures above 43ºC
Aside from temperature what can TRPV1 and TRPM8 be activated by?
Ligands
Which TRP does menthod activate?
TRPM8
Which TRP does Capsaicin activate?
TRPV1
What do other receptors respond to?
Inflammatory molecules
What are inflammatory molecules released from?
Surrounding immune cells following tissue injury or infection
What are examples of inflammatory molecules?
- Bradykinin
- Cytokines
- Prostaglandins
What is the Axon Reflex?
Increased pain sensitivity due to inflammation
What is Hyperalgesia?
Increased pain sensitivity in a region
What would aim to such down the increased sensitivity of pain signals?
- Opioids
- Cannabinoids
- Noradrenaline
How does Bradykinin work?
It bind to the B2 receptor which activates PKC and phosphorylates the TRPV1 channel which enhances the ability of TRPV1 to open and cause depolarization
What is Arachidonic acid?
A fatty acid present in phospholipids of cell membranes
How is Arachidonic acid freed from the phospholipase molecule?
By the enzyme Phospholipase A2
What does Phospholipase A2 do?
Frees arachidonic acid from the phospholipase molecule
What is Arachidonic acid key in?
Inflammatory mediation
What is Arachidonic acid converted into by COX1 and COX2?
Prostandoids
What do COX1 and COX2 do to Arachidonic acid?
They convert it to Prostanoids
What are Prostanoids?
A family of signalling molecules
What are some Prostanoids?
- Prostaglandins
- Prostacyclin (PGI2)
- Thromboxane (TXA2)
What are Prostaglandins associated with?
Inflammation
What is different about COX2?
It is the inducible form of the COX enzyme
Where does COX2 occur?
Only in areas of inflammation
When is COX1 expressed?
It is constitutively expressed (expressed all the time)
Since COX1 is constitutively expressed, what does it do?
It facilitates baseline production of certain prostaglandins like PGI2 which protects certain organs and facilitates mucus secretion
What is COX2 induced by?
Inflammation
What is the site of Aspirin and NSAIDs?
COX1 and COX2 enzymes
What does the Prostanoid pathway do generally?
It is either inflammatory (COX2) or it is protective
What does the enzyme 5-lipoxygenase (LOX) do to arachidonic acid?
It metabolizes arachidonic acid into various leukotrienes
How do Prostaglandins and Leukotrienes drive inflammation?
They are vasodilators, pyrogenic (fever inducing) and attract immune cells
Where are Prostaglandins and leukotrienes especially pyrogenic?
When they reach the thalamus
What happens with immune cells once they are attracted by prostaglandins?
They can be induced to attract COX2
Where is COX1 primarily expressed?
In non-inflammatory cells (blood vessels, platelets, gastric mucosa)
Where is COX2 mainly expressed?
In inflammatory cells
What do non-selective NSAIDs target?
Both COX pathways
What do COX2 specific NSAIDs target?
The COX2 pathway
Where are the cells that express the inducible COX2 pathway found?
Cells that respond to inflammatory stress like macrophages, synoviocytes, endothelial cells, kidneys
What do Aspirin and other non-selective NSAIDs do?
Inhibit both COX isoforms
What happens when aspirin and nsaids inhibits both COX isoforms?
Prostaglandin production decreases, inhibiting inflammation and reducing pain and fever
How do Aspirin and other NSAIDs reduce fever?
By inhibiting the COX pathway they suppress prostaglandin synthesis in the brain that is stimulated by pyrogens
Which COX pathway would it be bad to inhibit?
COX1 because it is supposed to be constitutively active
Why are Non-selective NSAIDs associated with gastric toxicity?
Because they inhibit COX1 which is supposed to constitutively active and produce mucus in the stomach, bicarbonate, and blood flow
What can chronic use of non-specific NSAIDs do?
Cause gastric toxicity like gastric ulceration, upper GI bleeding and renal failure
What can chronic use of non-specific NSAIDs do?
Cause gastric toxicity like gastric ulceration, upper GI bleeding and renal failure
What can chronic use of non-specific NSAIDs do?
Cause gastric toxicity like gastric ulceration, upper GI bleeding and renal failure
How can the gastric toxicity due to non-specific NSAIDs be bypassed?
Specific COX2 inhibitors have been developed
What do COX2 inhibitors do?
They reduce inflammation in chronic inflammatory diseases, but are less effective at treating acute pain
What are specific COX2 inhibitors also associated with?
Higher risk of Cardiovascular toxicity
What does Acetaminophen inhibit?
COX3
Where is COX3 found most abundantly?
In the cerebral cortex
What is the difference between the effects of acetaminophen and NSAIDs?
Acetaminophen lacks the anti-inflammatory effects
What are the effects of Acetaminophen?
It is an analgesic and antipyretic agent
Which enzymes does Acetaminophen block?
COX1 and COX3
How can Acetaminophen be toxic?
When taking by overdose in patients it can lead to liver damage and death
What are the most widely used topical anesthetics?
- Procaine
- Lidocaine
- Bupivacaine
What do most local anesthetics contain?
- Hydrophobic (aromatic) moiety
- A linker region
- Substituted amine (hydrophilic region)
What is the hydrophilic region of a topical anesthetic?
The substituted amine
What does the nature of the linker region of a topical anesthetic do?
Determine pharmacological properties
What does an ester linker region mean?
Because they are hydrolyzed easily they are able to get rid of in the body so they have a shorter affect
What is the effector mechanism of local anesthetics?
They bind reversibly to an intracellular site within the pore of sodium channels and block ion movement through the pore
What must anesthetics do in order to block a pore?
They must cross the cell membrane
Why does hydrophobicity increase the potency and duration of action of an anesthetic?
Because the Na+ channel binding pocket it hydrophobic and anesthetic must cross the hydrophobic cell membrane
What do all local anesthetics do?
Block all sensation and can cause motor paralysis
What do local anesthetics have higher affinity for?
The open conformation of the sodium channel, so they preferentially block neurons that are active (nociceptors when there is pain)
What are different types of painful stimuli detected by?
Specific receptors on polymodal nociceptors
What is the active ingredient in chilli pepper?
Capsaicin
What is Capsaicin an agonist for?
The TRPV1 receptor
What does capsaicin do to TRPV1 receptors?
It activates normal signalling TRPV1
What does initial application of Capsaicin do?
Gives a sense of burning
What does chronic activation of TRPV1 induced by capsaicin do?
Cause desensitization of TRPV1 which blocks its ability to transmit afferent information. Basically blocks its function to signal for pain leading to analgesia
What does chronic activation of TRPV1 induced by capsaicin do?
Cause desensitization of TRPV1 which blocks its ability to transmit afferent information. Basically blocks its function to signal for pain leading to analgesia
