T2 EX4 L7 (MEDCHEM OPIOIDS) (CHENG)

Nonopioid analgesics (two types)

NSAIDs

Tylenol

Natural molecule opioid analgesics (two)

Morphine

Codeine

Semi-synthetic opioid analgesics (one)

Oxymorphone

Synthetic opioid analgesics (one)

Methadone

What does it mean to be a semi-synthetic opioid analgesic

Based on morphine structure

What does it mean to be a synthetic opioid analgesic

Based on morphine pharmacophore

"Others" analgesics (four)

TCAs

Anticonvulsants

SNRIs

Anesthetics

MOA of non-opioid analgesics

Block production of prostaglandins via inhibition of COX1, COX2 or both

Describe peripheral sensitization pathway

Peripheral inflammation -> COX-2 upregulation in inflammatory cells -> prostaglandin production -> action on peripheral terminal PGE2 receptors -> Peripheral sensitization

Acetaminophen acts to prevent ____________

A. Central COX-2

B. Peripheral COX-2

C. Both

A. Central COX-2

Celecoxib acts to prevent ____________

A. Central COX-2

B. Peripheral COX-2

C. Both

C. Both

NSAIDs act to prevent __________

A. Central COX-2

B. Peripheral COX-2

C. Both

C. Both

T/F: NSAIDs block constitutive COX-1 mediated prostaglandin production.

True

Where is COX-1 located

Kidney, stomach, platelets

Why is COX-1 called a constitutive enzyme

Always present, as opposed to being induced by certain conditions

Where is COX-2 located

Macrophages, leukocytes, fibroblasts

Function of COX-1

Important housekeeping guy

Protect tummy, regulate gastric acid, maintain normal function of kidney

Function of COX-2

Triggers inflammation and pain

T/F: COX-1 enzymes are protective in nature

True

T/F: NSAIDs majorly excreted renally.

True

T/F: Most of the NSAIDs are weak organic acids.

True

Where was salicylic acid originally found

Bark of willow tree

WOTF is an irreversible COX inhibitor

A. Celecoxib

B. Aspirin

C. Acetaminophen

D. Ibuprofen

B. Aspirin

About how long does the antiplatelet effect of aspirin last?

8-10 days

T/F: In children under 12, aspirin has been linked to Reye's syndrome.

True

WOTF NSAIDs is a derivative of phenylpropionic acid

A. Aspirin

B. Ibuprofen

C. Acetaminophen

D. Naproxen

B. Ibuprofen

Selective COX-2 inhibitors (two)

Celecoxib

Meloxicam

MOA of acetaminophen

Inhibits prostaglandin synthesis via CNS inhibition of COX (not peripheral)

What are the targets of aspirin, ibuprofen, and acetaminophen?

Aspirin = cox1 and cox2 via irreversible inhibition

Ibuprofen = cox1 and cox2 via reversible inhibition

Acetaminophen = central cox2

Explain the action mechanism of aspirin

Irreversible inhibition of peripheral and central cox1 and cox2 to prevent prostaglandin synthesis

What is the difference between COX-1 and COX-2?

COX-1 in kidneys and tummy, protective in nature, housekeeping and constitutive enzyme

COX-2 only cares about pain and inflammation, present everywhere but peripheral sensitization is unique to it

Explain the mechanism of aspirin side effects on the stomach

Inhibition of Cox-1 (which protects the gastric mucosa) causes tummy vulnerability

List one COX-2 selective inhibitor

Celecoxib

What are the similarities and differences between the mechanisms of aspirin and acetaminophen

Aspirin is an irreversible inhibitor of cox 1 and 2 while acetaminophen is a reversible inhibitor

Aspirin inhibits peripheral prostaglandin synthesis as well as central prostaglandin synthesis, but acetaminophen only works centrally

Acetaminophen does inhibit central COX2

What is the action mechanism of acetaminophen liver toxicity

Acetaminophen has toxic metabolite NAPQI which is ordinarily broken down by glutathione; in excess (which will cause glutathione deficiency), tylenol will have too much NAPQI metabolite and can cause acute liver toxicity and failure

Describe opioid mechanism of action on mu receptor

Inhibit presynaptic Ca2+ conductance

Increase postsynaptic K+ conductance

Presynaptic action of opioids inhibits the neurotransmitter release, this is their major nervous system effect

The postsynaptic actions of opioids are usually inhibitory

What is the function of delta receptor

Analgesia, antidepressant effects

Convulsant effects, physical dependence

Perhaps of mu-opioid receptor mediated resp. depression

Selective agonist of delta receptor?

D-Ala-D-Leu enkephalin

Selective antagonist of delta receptor?

Naltrindole

What is the function of kappa receptor

Analgesia, anticonvulsant effects

Dissociative and deliriant effects

Diuresis, dysphoria, miosis, neuroprotection, sedation

Selective agonist of kappa opioid receptor?

Dynorphins

What is the function of mu 1 receptor

mu 1 = analgesia, physical dependence

What is the function of mu 2 receptor

mu 2 = respiratory depression

Selective agonists of mu 1, mu 2 receptors? (two)

Morphine, endorphins

Selective antagonists of mu 1, mu2 receptors? (one)

Naloxone

Similarity between all endogenous opioid peptides?

Share N-terminal sequence Tyr-Gly-Gly-Phe-Met/Leu

Endogenous opiates? (three)

Endorphin

Enkephalin

Dynorphins

Fentanyl is a ____________ opioid

Natural

Semi-synthetic

Synthetic

Synthetic

Dihydromorphine and diacetylmorphine are ___________ opioids

Natural

Semi-synthetic

Synthetic

Semi-synthetic

Codeine is a _________ opioid

Natural

Semi-synthetic

Synthetic

Natural

Levorphanol is a _________ opioid

Natural

Semi-synthetic

Synthetic

Synthetic

Meperidine is a _________ opioid

Natural

Semi-synthetic

Synthetic

Synthetic

Propoxyphene is a _________ opioid

Natural

Semi-synthetic

Synthetic

Synthetic

Hydromorphone is a _________ opioid

Natural

Semi-synthetic

Synthetic

Semi-synthetic

Oxycodone is a _________ opioid

Natural

Semi-synthetic

Synthetic

Semi-synthetic

Hydrocodone is a _________ opioid

Natural

Semi-synthetic

Synthetic

Semi-synthetic

Why codeine > morphine?

Favorable absorption and distribution

Dihydromorphine has _________ activity when compared to morphine

Increased

Decreased

increased activity

What are the targets of morphine?

Mu opioid receptor agonism

Explain the action mechanism of morphine

Morphine binds primarily to mu opioid receptors and agonizes them

Mu opioid receptors responsible for analgesia, respiratory depression, euphoria, sedation etc.

List the important function groups of morphine

Phenolic OH = required

Aromatic ring = required

N-methyl group = required

Substitutable functional groups include:

Ether bridge

6-alcohol

Double bond at 7-8

What is the difference between morphine and codeine in structure?

Codeine has a methyl group at position 3 instead of a hydroxyl group, promoting more favorable absorption, greater bioavailability (but weaker analgesic effect)

What kind of structural modifications can improve bioavailability of morphine?

Acetyl group -> facilitates crossing of BBB

Hydroxyl at 3 -> methyl -> decreased activity, better and quicker absorption, increased bioavailability

Make lipophilic = cross BBB, increase potency

What is the difference between morphine and heroin in structure?

Acetyl groups inc. lipophilicity facilitate crossing of BBB

What functional groups of morphine are kept in meperidine and fentanyl?

Only A and D ring in fent, meperidine

List two opioid antagonists and show their structure difference with morphine

Naltrexone, naloxone

Highly similar structure

Competitive inhibitors at binding site

What are the targets of tramadol?

Partial mu agonist but also acts on nonopioid receptors somewhere we don't altogether know