Application of drug used to treatment of inflammation

Pharmacy

1. DRUGS USED TO TREAT PAIN,
INFLAMMATION & GOUT
By Lalisa.t
1 21-Feb-24 By lalisa, BpPharm, MPH

2. Pain , inflammation and gout (arthritis) are major health
problems
Drugs used in the management of pain, pyrexia and
inflammation can be categorized in to two major classes;
 Non-steroidal anti-inflammatory drugs( NSAIDs)
 have analgesic, antipyretic and anti-inflammatory
property.
Steroidal anti-inflammatory drugs
 mainly used to manage severe inflammation
Inhibit production of prostinoids & leukotrienes by
inhibiting phospholipase A2
Adjuvant analgesic /coanalgesic
TCAs, Antiepileptics, Steroids
21-Feb-24 2 By lalisa, BpPharm, MPH

3. Management of pain
•1. Mild pain
NSAID + adjuvant
•2. Moderate pain
Weak narcotic + NSAID + adjuvant
•3. Severe pain
Strong narcotic + NSAID + adjuvant

21-Feb-24 By lalisa, BpPharm, MPH 3

4. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
Have analgesic , antipyretic and at in higher doses, anti-
inflammatory effects.
Usually indicated for the treatment of acute or chronic
conditions where pain and inflammation are present
Their effects are related to inhibition of fatty acid COX
enzyme
COX is responsible for the formation of important
biological mediators called prostaglandins, prostacyclin
and thromboxane.
21-Feb-24 4 By lalisa, BpPharm, MPH

5. Two known isoforms COX; COX-1, COX-2.

 COX-1 is constitutive and has a 'housekeeping' role, involved in tissue
homeostasis, and is responsible for production of PGs involved in gastric
cytoprotection and platelet aggregation.

COX-2 is induced in inflammatory cells when they are activated and
inflammatory mediators are produced, so it is responsible for inflammation.

Most 'traditional' NSAIDs are inhibitors of both isoenzymes, although they
vary in the degree to which they inhibit each isoform.

anti-inflammatory and analgesic actions of NSAIDs is related to their
inhibition of COX-2
21-Feb-24 5 By lalisa, BpPharm, MPH

6.  NSAIDs have three major pharmacologically desirable actions, stemming from
suppression of prostanoid synthesis in inflammatory cells by inhibition of COX-2.

1. An anti-inflammatory action: the decrease in prostaglandin E
2 & prostacyclin
reduces vasodilatation and, indirectly, oedema.

2. An analgesic effect: decreased prostaglandin generation means less
sensitisation of nociceptive nerve endings to inflammatory mediators.

3. An antipyretic effect: interleukin-1 releases prostaglandins in the central
nervous system, where they elevate hypothalamic set point for temperature
control, thus causing fever. NSAIDs prevent this.
21-Feb-24 6 By lalisa, BpPharm, MPH

7. NSAIDs are generally indicated for the symptomatic relief of the
following conditions:
Rheumatoid arthritis
Osteoarthritis
Acute gout
Dysmenorrhoea (menstrual pain)
Metastatic bone pain
Headache and migraine
Postoperative pain
Mild-to-moderate pain due to inflammation and tissue injury
Pyrexia (fever)
Renal colic

21-Feb-24 7 By lalisa, BpPharm, MPH

8. Classification
NSAIDs can be classified based on their chemical structure as;
1. Salicylates
Aspirin (acetylsalicylic acid)
2. Propionic acid derivatives
Ibuprofen
Fenoprofen
Loxoprofen
3. Acetic acid derivatives
Indomethacin
Sulindac
Diclofenac
4. Selective COX-2 inhibitors (Coxibs)
Celecoxib
Rofecoxib
Parecoxib

21-Feb-24 8 By lalisa, BpPharm, MPH

9. Cont’d anti-inflammatory
Actions of NSAIDS
•Anti pyretic
•Anti inflammatory
•Analgesic
•Anti aggregatory [Reduce platelet plug and clot formation]
•Examples of NSAIDs

9 21-Feb-24 By lalisa, BpPharm, MPH

10. Cont’d anti-inflammatory
Uses of NSAIDs
•Mild analgesic
–PGI2 and PGE2 are hyperalgesic, which means that they
increase the sensitivity of pain receptors to painful stimuli
(mainly bradykinin)

•NSAIDs are useful to mild or moderate pain associated with
inflammation.

•Fever

•Anti inflammation
–Inflammation associated with arthritis in joints.
10 21-Feb-24 By lalisa, BpPharm, MPH

11. Cont’d anti-inflammatory
Adverse effects

•Gastrointestinal
–Local irritation because NSAIDs are acidic in nature

–Inhibit the mucosal synthesis of PGI2 and PGE2

–Prostanoids promote blood flow to GIT- production of mucous

–NSAIDs decrease the defense mechanisms of the GIT

•Bleeding time
–Decrease in TxA2 synthesis, will prevent platelet aggregation

–inhibit production of PGI2 produced by endothelial cells to
prevent platelet sticking.

–However, endothelial cells can regenerate COX (which platelets
cannot) so the inhibition of platelets is more prolonged.
11 21-Feb-24 By lalisa, BpPharm, MPH

12. Cont’d anti-inflammatory
Individual groups of NSAIDs

1. Salicylates
•Examples; Aspirin
•Uses:
–Analgesic
–Antipyretic

–Antithrombotic, 80 mg (at low dose inhibit thxA2 without
affecting prostacycline, PGI2, hence DOC for thrombosis)

–the only NSAID able to irreversibly inhibit COX-1, indicated for
inhibition of platelet aggregation.

–Rx of thrombosis and prevention of adverse CVS events.

12 21-Feb-24 By lalisa, BpPharm, MPH

13. Cont’d anti-inflammatory
•Adverse effects:
–The same as for all NSAIDs, but in addition to:
•Reyes syndrome

–encephalopathy leading to coma in children using aspirin to treat fever in
certain types of infection. [chicken pox, measles and mumps]

–Not recommended in children less than 14 years with these types of
infections and fever.
•Tinnitus
•Uric acid retention
–Aspirin at low dose competes for uric acid excretion in kidney tubules but
at high dose has minimal effect, so used for gout at higher dose.
13 21-Feb-24 By lalisa, BpPharm, MPH

14. Cont’d anti-inflammatory
•Pharmacokinetics of salicylates
–Aspirin (and all other NSAIDs) is acidic- well absorbed in the
stomach

–Distribution of aspirin is predominantly in plasma, 80-90% ppb.

–Slow to enter CNS

–To reduce the irritation on the stomach- buffered preparations can
be used (e.g. Asproclear)

–An alternative to a buffered solution is to have an enteric coating
14 21-Feb-24 By lalisa, BpPharm, MPH

15. Cont’d anti-inflammatory
2. Propionic acids
–More potent than aspirin and hence better at inhibiting
COX, but comes with more side effects.
–Naproxen (naprogesic)]
•Used to treat menstrual pain

•Ibuprofen
•Metabolised in liver & little excreted unchanged in urine
•GI iritation less frequently than aspirin
•Prutitis, rash, tinnitus, dizziness, fluid retention
•Rarely agranulocytosis, aplastic anemia.
15 21-Feb-24 By lalisa, BpPharm, MPH

16. Cont’d anti-inflammatory
3. Acetic acids
• Indomethacin
–Treatment of acute gouty arthritis, ankylosing spongylitis.
•Sulindac
–Prodrug of Diclofenac
–Longer halflife
•Diclifenac
–Potent cyclooxygenase inhibitor
–Accumulates in synovial fluid
–Used in RA, osteoarrthritis, acute muscloskeltal pain

•Both are highly potent drugs.
•Increase in adverse effects [GI problems]
•Predominantly used as anti-inflammatory, not as antipyretics or
analgesics.
•Can be given rectally to reduce gastric irritation.
16 21-Feb-24 By lalisa, BpPharm, MPH

17. Cont’d anti-inflammatory
Selective COX 2 inhibitors [COXIBS]
–Meloxicam
–Celecoxib
–Etoricoxib
– Rofecoxib
•Less adverse effects???
•Reduces the PGs produced in pathological situations

•Coxibs
–Have analgesic, antipyretic and anti-inflammatory effect
similar to nonselective NSAIDs but with fewer GI side effect
–No impact on platelet aggregation
17 21-Feb-24 By lalisa, BpPharm, MPH

18. Cont’d anti-inflammatory
Acetaminophen (paracetamol)
–Active metabolite of phenacetin
–Weak PG synthesis inhibitor in peripheral tissues and
possesses no significant anti-inflammatory effect
–Effective analgesic and antipyretic agent
–Useful in mild to moderate pain such as head ache, myalgia,
postpartum pain
–Adverse effect: hepatotoxic, hemolytic anemia and
methemoglobinemia
18 21-Feb-24 By lalisa, BpPharm, MPH

19. Cont’d anti-inflammatory
Drugs used in the treatment of gout
•Gout is due to an accumulation of uric acid (a
breakdown product of adenosine).
•High concentrations of uric acid lead to
crystallisation and deposition in the synovium of
joints, resulting in arthritic pain.
19 21-Feb-24 By lalisa, BpPharm, MPH

20. Cont’d anti-inflammatory
20 21-Feb-24 By lalisa, BpPharm, MPH

21. Cont’d anti-inflammatory
•Acute treatment of gout involves:
–NSAIDs
–Colchicine
–Glucocorticoids
•Chronic treatment involves:
–Allopurinol
–Colchicine
–Probenecid
21 21-Feb-24 By lalisa, BpPharm, MPH

22. Cont’d anti-inflammatory
•Colchicine
–Antimitotic agent; It interferes with tubulin- prevents leukocyte
migration

–Reduced leukocytes in the synovial joints affected by gout would
reduce the pain and discomfort

–Can be used as an acute treatment

–Also can be used as a chronic treatment as prevention
(prophylactically) in conjunction with allopurinol
22 21-Feb-24 By lalisa, BpPharm, MPH

23. Cont’d anti-inflammatory
•Allopurinol
–analogue of hypoxanthine

–inhibits xanthine oxidase, preventing hypoxanthine from
binding formed.

–product of allopurinol with xanthine oxidase is alloxanthine

–Alloxanthine is an irreversible inhibitor of xanthine oxidase.

–decreased synthesis of uric acid and the concentrations fall.
23 21-Feb-24 By lalisa, BpPharm, MPH

24. Cont’d anti-inflammatory
•Probenecid
–uricosuric agent (increases excretion of uric acid)

–inhibits tubular reabsorption of uric acid in kidneys

–limited use, not as effective as allopurinol

–It is used when a person has an inability to excrete uric acid (in
most patients, an increased uric acid is mainly due to an
increase in production and so allopurinol is better suited).
24 21-Feb-24 By lalisa, BpPharm, MPH

25. Histamine and its Antagonists

21-Feb-24 By lalisa, BpPharm, MPH 25

26. Histamine
•Synthesis and Storage
•Histidine  histidine decarboxylase  histamine
•Principal sites of storage
–Mast cells (in tissues)
–Basophils (in the blood)
–Neurons, where it acts as a neurotransmitter
•Termination of Histamine Action
•Three principal ways
–Cellular uptake
–Desensitization of cells
–Metabolism: most common pathway (histamine N-
methyltransferase, diamine oxidase, MAO)

21-Feb-24 By lalisa, BpPharm, MPH 26

27. Physiological Effects
•CVS
–Blood vessels
•Dilation of all vessels (H
1- and H
2-mediated, H
1 mainly through NO production while H
2 is through
 cAMP)
•Inhibits release of NE (H
3 on sympathetic neurons)
•es permeability of capillaries & post-capillary vessels (H
1)
–Heart +Ve inotropic and chronotropic (H
2- receptors)
•Extravascular Smooth Muscle
–Bronchial smooth muscle contraction (H
1-mediated)
–Uterine smooth muscle contraction (can cause abortion during anaphylactic reactions)
–Stimulate GI smooth muscle contraction
•Glandular Tissue
–Stimulates secretion of gastric acid and pepsin (H
2-Rs on parietal cells of the gastric
mucosa)
–Stimulates secretion by the salivary glands and glands in the small & large intestines.
–High concentrations of histamine promote the release of catecholamines from the adrenal
gland.
•Nervous System
–Postsynaptic H
1-Rs mediate maintenance of wakeful states, while H
1- & H
2-Rs participate
in regulation of blood pressure, body temperature, fluid homeostasis, and pain sensation
–H
1-Rs on sensory neurons in the epidermis and dermis mediate itch and pain, respectively.
–Presynaptic H
3-R serve as feedback inhibitors of the release of histamine, NE, & other
neurotransmitters.

21-Feb-24 By lalisa, BpPharm, MPH 27

28. Histamine Antagonists
•Effects of histamine can be diminished in four
ways:
–Inhibition of histamine synthesis
–Inhibition of histamine release from storage
granules
•Cromolyn , nedocromil, 
2-AR agonists
–Blockade of histamine receptors
–Physiological antagonism of histamine’s effects
•Epinephrine

21-Feb-24 By lalisa, BpPharm, MPH 28

29. H
1-Receptor Antagonists
•Divided into first-generation and second-generation agents
•Differ in their degree of distribution in to CNS and hence production of sedation
(Second generation agents are less sedating)
•The first-generation agents are also more likely to block autonomic receptors.
•MOA
–Are competitive inhibitors of H
1-Rs
–Blocks histamine mediated vasodilation, microvascular permeability, & sensory nerve terminal
stimulation.
–H
1-antagonists generally produce sedation through an effect on the CNS
–Non H
1-mediated effects
•Antimuscarinic activity of several first-generation
•The phenothiazines block AR, whereas cyproheptadine is an antagonist at serotonin receptors.
•Diphenhydramine, pyrilamine, and promethazine are effective local anaesthetics.
•Pharmacokinetics
–Rapidly absorbed following oral administration
–First-generation drugs enter the CNS readily.
–Many H
1 antagonists have active metabolites. The active metabolites of hydroxyzine, terfenadine,
and loratadine are available as drugs (cetirizine, fexofenadine, and desloratadine, respectively).
•Adverse Effects
–first-generation antihistamines
•Sedation, Antimuscarinic effects (dry mouth, urinary retention)
–Second-generation antihistamines

21-Feb-24 By lalisa, BpPharm, MPH 29

30. 21-Feb-24 By lalisa, BpPharm, MPH 30

31. Clinical Uses
•Allergic reactions
–Urticaria, allergic rhinitis, atopic dermatitis
–1
st
& 2
nd
generation drug have same efficacy but vary
in their tendency to cause sedation.
•Motion Sickness and Vestibular Disturbances
–Diphenhydramine, promethazine, Dimenhydrinate,
The piperazines (cyclizine and meclizine)
•Morning sickness: Nausea and Vomiting of
Pregnancy

21-Feb-24 By lalisa, BpPharm, MPH 31