NSAIDs, Opioids and Steroidal drugs

Question 1

What are NSAIDs and what are they used for

Answer 1

Synthetic non-steroidal anti-inflammatory drugs

Used for treatment of
inflammation
pain
fever

Mechanism of action not fully understood but is known to disruption prostanoid biosynthesis by inhibition of cyclo-oxygenase (COX) enzymes

Question 2

What are cyclooxygenase

Answer 2

Enzymes of prostanoid biosynthetic pathways
Consist of two identical protein monomers
Has hydrophobic entry
heme cofactor
Two key amino acids
- tyrosine and arginine

Question 3

What are the types of COX

Answer 3

COX 1
- constitutive isoform
Biosynthesis is constant within body
Inhibition of COX 1 = decreased gastric mucosa production

COX 2
- inducible form
Biosynthesis is stimulated by cytokines
Inhibition of COX 2 = anti-inflammatory, anti-pyretic and analgesic effects

Question 4

What are salicylates

Answer 4

Most are acidic due to COOH group
- ionic bonding to Arg 120
Weakly acidic phenol
All are reversible and competitive binding

Question 5

Answer 5

Salicylates

Reversible inhibition
Target mainly COX 1

Question 6

Answer 6

Anilides
Paracetamol

Activated of cannainoid receptors

Question 7

Answer 7

Profen

More potent due to high lipid solubility and COX binding
Target mainly COX 1
Reversible competitive inhibition of COX

Question 8

Answer 8

Fenamates

Anthranilic acid derivatives
Target mainly COX 1
Rarely used

Question 9

Answer 9

Aromatic acetic acids

Can contain aromatic or heteroaromatic structure
Target mainly COX 1
More lipophilic = more potent

Question 10

Answer 10

Etodolac

NSAIDs - COX 1
Aromatic acetic acid

Question 11

Answer 11

Diclofenac

NSAID
Selectivity 2:1

Question 12

Answer 12

Phenylpyrazolones

NSAID

contains acidic pyrazololone proton

Question 12

Answer 12

Oxicams

Acidic enol
quite active on COX 2

Question 13

Answer 13

Coxibs

Non-acidic
Act only on COX 2
Cardiotoxic side effects with increased potency

Question 14

What are the different types of opioid receptors

Answer 14

Mu
Endomorphin 1 and 2
Causes analgesia, respiratory depression, decreased GIT motility and emesis

Kappa
Dynorphins
Beta-endorphins
Causes analgesia, diuresis, sedation, constipation and dysphoria

Delta
Enkephalins
Beta-endorphins
Causes analgesia, diuresis, sedation, constipation, convulsions and dysphoria

Question 15

Answer 15

Morphine

Five fused rings with five chiral centres
Mainly protonated at physiological pH

Question 16

Explain the structure-activity relationship of morphines

Answer 16

N essential
Must be a tertiary amine - lipophilic = BBB penetration
N-methyl - agonist activity
3C = antagonist
4C = agonist

3-hydroxy subs
Phenolic characteristic
3-methoxy = codeine

6-hydroxyl subs
not required for activity
if lipophilic = better penetration of BBB

Question 17

Answer 17

Morphinans
Morphine analogue
No epoxy bridge = loss of ring D
-ve isomers = analgesics
+ve isomers = antitussives

Question 18

Answer 18

Benzomorphans
Morphine analogues
without rings C and D
Kappa agonist
Dysphoric effects

Question 19

Answer 19

4-phenylpiperidines
Morphine analoge
Without ring B, C and D

Question 20

Answer 20

Anikkidopiperidines
Morphine analogue
Structural modification of 4-phenylpiperidine
Analgesics at lower dose

Question 21

Answer 21

Buprenorphine
Morphine analogue
Contains tricylic structure
Agonist

Question 22

Answer 22

Naloxone and naltrexone
Mu antagonist
contains 3-OH, N-allyl, N-cyclopropylmethyl or N-cyclobutylmethyl sub

Question 23

Answer 23

Steran skeleton
19 carbons
4 ring structures
Makes up sex hormone structure

Question 24

Answer 24

Contains 4 cyclic structures, one is penta 3-C=O and 4-enone

Question 25

Answer 25

Testosterone analogue Addition of ester at C17 Increases lipophilicity

Question 26

Answer 26

Testosterone analogue Addition of methyl at C17 Blocks metabolism of C17 OH

Question 27

Answer 27

Testosterone analogue Addition of C11 hydroxyl group or C9a fluorine Improve anabolic/ androgenic ratio

Question 28

Answer 28

Testosterone analogue Removal of C19 methyl group Increase potency

Question 29

Answer 29

Testosterone analogue Addition of unsaturated group at C2/3 Prevent ring A metabolism

Question 30

Answer 30

Estradiol Based on estrogen Contains two hydroxyl groups 14.5 apart

Question 31

Answer 31

Estradiol analogue Increases oral bioavailability

Question 32

Answer 32

Estradiol analogue Increases orally availability

Question 33

Answer 33

Estradiol analogue Addition of ethynyl alkyne on C17 Increases oral activity

Question 34

Answer 34

As per testosterone skeleton Contains acetyl on C17

Question 35

Answer 35

Progesterone analogue Addition of C6 alkyl group Decreases metabolic reduction of ring A Preventing metabolic hydroxylation at C6 Increasing lipid solubility

Question 36

Answer 36

Progesterone analogue Addition of acetyl and ester on C17

Question 37

Answer 37

Adrenocortical drugs Cortisone C-O on C11 Hydrocortisone C-OH on C11 Aldosterone no OH on C17 C11 bridge

Question 38

Answer 38

Cortisone analogue Contains enone at C1/2

Question 39

Answer 39

Cortisone analogue Based on prednisolone Methyl at C6 Reduce metabolic hydrolysis = more potent

Question 40

Answer 40

Cortisone analogue Addition of F atom at C9 Prevent oxidation of C11-OH

Question 41

Answer 41

Cortisone analogue Addition of methyl at C16 Hinder metabolic attack at C17

Question 42

Answer 42

Cortisone analogue Addition of OH on C16 Increases metabolic activity of C17 side chain