CLASS REVIEW NOTES

UNIT - 6 Inflammation &

Pain Management

- Autocoids
- Pain Management
- Gout
- Osteoarthritis
- Rheumatoid Arthritis

FOR PREPARATION
I N T E R N A T I O NAL PHARM ACIST COMP E T E N C Y D E V E L OP ME N T P R OGR A M (I PC D )

FPGEE | NAPLEX| PEBC | KAPS | CAOP

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AUTOCOIDS

1. HISTAMINES

2. SEROTONIN (5HT)

3. PROSTAGLANDINS

4 LEUKOTRIENES
4.

Autociods
 Autacoids are substances with diverse physiological & pharmacological activities which
are grouped together mainly as they participate in physiological & pathophysiological
responses to injury.

 They cannot be classed as hormones or neurotransmitters & as they usually have a brief
lifetime & act near their sites of synthesis, they are often described as local hormones,
but true hormones reach their site of action via the bloodstream hence the term used is
autacoid (greek derivation for “self-remedy”).

 cytokines are not included as autacoids

 Generally, autocoids can be characterized as amine type and endogenous type.
 Amines type: Examples: Histamine, and serotonins.
 Endogenous peptides (ecosanoid): Prostaglandins, prostacyclin, thromboxane,
leukotriene, and bradykinin.
 Site of production for endogenous peptides are GIT, kidneys, lungs, pancreas and
uterus.

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Autociods
Examples: Serotonin, Histamine, Bradykinin, Adenosine,
Prostaglandin, Leucotiences
Role of Autocoids
 Prostaglandins – pain sensation, development of inflammation,
edema
 Thromboxane – aggregation of platelets
 Prostacyclin – inhibition of platelet aggregation
 Leukotrienes – inflammation,, chemo tactic properties
p p (p
(pull substances
to them), bronchoconstriction.

CYTOKINES:
CYTOKINES:
• Cytokines are small proteins released by cells which act through binding
to cell wall receptors and affect the behaviour of other cells and perhaps
the same cell which are particularly important in the immune response.
response
Cytokines Examples:
 Chemokines - Mediate Chemotaxis
 Interferon
 Interleukins - Mainly Produced By T-Helper Cells
 Lymphokines
L mphokines - Produced
Prod ced ByB Lymphocytes
L mphoc tes
 Monokines - Produced By Monocytes
 Colony Stimulating Factors
 TNF

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HISTAMINES:

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Histamine
• Histamine is a biogenic amine present in many animal and plant tissues. It is
also present in venoms and stinging secretions. It is synthesized by
decarboxylation of the amino acid, histidine. Histamine is mainly present in
storage granules of mast cells in tissues like skin,
skin lungs,
lungs liver,
liver gastric
mucosa, placenta, etc. It is one of the mediators involved in inflammatory and
hypersensitivity reactions.
Mechanism of action and effects of histamine
• Histamine exerts its effects by binding to histamine (H) receptors H1 and H2.
Uses: Histamine has no valid clinical use.
Betahistine
• It is a histamine analogue that is used orally to treat vertigo in Meniere’s
disease. It probably acts by improving blood flow in the inner ear. The side
effects are nausea, vomiting, headache and pruritus.
• It should be avoided in patients with asthma and peptic ulcer.

Histamine liberators and its effects.

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Histamines: Physiology
Histamines : The autocoids
• Act on three receptors H1, H2 and H3.
• Present: Skin, lymph, and GI tract
• Release: mast cells,
cells basophiles
• Stimuli: Drugs such as opioids (except fentanyl), venoms, trauma, and vancomycin
(red man syndrome).

H1 receptor activation : H1‐ typical allergic and Anaphylactic Response to

histamines.
• ↑ Bronchoconstriction
• ↑ Vasodilation (via NO): ↓ B.P
• ↑ Increase capillary permeability
• ↑ Spasmodic contrac ons of gastrointes nal smooth muscle (GI)
• ↑ Ac va on of peripheral nocieptive receptors = ↑ pain and pruritus

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Use of Histamine Blockers

H1 Blockers Use for following Conditions Management:
 Allergic reactions
 Allergic Rhinitis (hay fever), and runny nose
 Conjunctivitis
C j ti iti
 Rhinoviral infections (common cold)
 Urticaria
 Motion sickness
 Nausea and vomiting (in pregnancy)
 Preoperative
P ti sedation
d ti
 Sleep aid
Antihistamine are classified in two category
 Sedative Antihistamine
 Non Sedative Antihistamine

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First-generation H1-blockers
They are the conventional antihistamines.
Pharmacological actions
 H1-blockers
H1 blockers cause central nervous system (CNS) depression
depression—
sedation and drowsiness. Certain antihistamines have antiemetic
and antiparkinsonian effects.
 They have antiallergic action, hence most of the manifestations of
Type-I reactions are suppressed.
 They have anticholinergic actions—dryness of mouth
mouth, blurring of
vision, constipation, urinary retention, etc.

First-generation H1-blockers- Uses

1. Allergic diseases: H1-antihistamines are used to prevent and treat
symptoms of allergic reactions.For example, pruritus, urticaria, dermatitis,
rhinitis, conjunctivitis and angioneurotic oedema respond to these drugs.
2 Common
2. C ld They
cold: Th produced symptomatic
t ti relief
li f b
by sedative
d ti and
d
anticholinergic actions.
3. Preanaesthetic medication: Promethazine is used for its sedative and
anticholinergic effects.
4. As antiemetic: Promethazine, diphenhydramine, dimenhydrinate, etc. are
useful for pprophylaxis
p y of motion sickness because of their anticholinergicg
action. They act probably on the vestibular apparatus or cortex. Sedative
effect also contributes to their beneficial effect. These drugs are useful in
morning sickness, drug-induced and postoperative vomiting. Promethazine is
used to control vomiting due to cancer chemotherapy and radiation therapy.

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First-generation H1-blockers- Uses

 Parkinsonism: Imbalance between dopamine and acetylcholine (DA and
ACh) in the basal ganglia produces parkinsonism. Promethazine,
diphenhydramine or orphenadrine are used to control tremors, rigidity and
parkinsonism due to their anticholinergic
sialorrhoea of p g and sedative
properties. Promethazine and diphenhydramine are also useful for the
treatment of extrapyramidal side effects caused by phenothiazines or
metoclopramide.
 H1-blockers are used to control mild blood transfusion and saline infusion
reactions (chills and rigors) and as adjunct in anaphylaxis.
 Cinnarizine, dimenhydrinate and meclizine are effective for controlling
vertigo in Meniere’s disease and in other types of vertigo.
 Sedative and hypnotic: H1-antihistamines (e.g. promethazine and
diphenhydramine) are used to induce sleep, especially in children during minor
surgical procedures.

Second-generation H1-blockers
Second-generation H1-blockers:
Cetirizine, loratadine, azelastine and fexofenadine are highly selective for
H1-receptors and have the following properties. They:
 Have no anticholinergic effects.
 Lack antiemetic effect.
 Do not cross blood–brain barrier (BBB), hence cause minimal/no
drowsiness.
 Do not impair psychomotor performance.
 Are relatively expensive.
Uses
• Second-generation H1-blockers are used in various allergic disorders—
rhinitis, dermatitis, conjunctivitis, urticaria, eczema, drug and food
allergies.

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Comparison
Sedating antihistamines
• Uses, allergies, motion sickness, vertigo, itch due to skin disorders, nausea
and sedation including premedication.
• Adverse effects,
effects often have anticholinergic and CNS adverse effects
(drowsiness).
• Length of action, many are short acting but some, eg promethazine, act for
up to 12 hours.
• Structural resemblance to histamine
Less sedating antihistamines
• Uses, allergies.
• Adverse effects, often better tolerated then sedating antihistamines (less
sedating as they cross the blood–brain barrier poorly; reduced anticholinergic
adverse effects due to poor affinity for muscarinic receptors).
• Length of action, most are long acting and can be taken once daily.

H2-Receptors Activation : Physiology

H2-Receptors Activation : Physiology
• ↑ Gastric acid secretion and ↑ GI ulcer.
• H2-receptors responses to histamine such as: Increased secretion of
gastric acid, Increase pepsin and Intrinsic factor (Castle’s factor).
• H2 receptor antagonist competitively block H2 receptors thus blocking the
effect of histamines on gastric secretions.
• H2 antagonist Example: Ranitidine,
Ranitidine Cimetidine,
Cimetidine Famotidine,
Famotidine and
Nizatidine

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SEROTONIN (5‐HYDROXY TRYPTAMINE – 5HT)

Serotonin
• Tryptophan (amino acid) → 5-hydroxy tryptophan → Serotonin
(Neurotransmitter) → 5-Hydroxyinolacetic acid.
• Conversion of tryptophan to serotonin takes place in two reactions :
hydroxylation and decarboxylation catalyzed by tryptophan hydroxylase
and L-amino acid decarboxylase, respectively.
• Serotonin contains an indole ring.

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Physiological functions of serotonin receptors

• Physiological functions of serotonin receptors: Serotonin group has several
subtypes of receptors:
 5HT1(A‐G)
 5HT1, 5HT2, and 5HT3→ →Anxiety,y, depression,
p , aggression,
gg , impulsive
p and
appetite
 5HT1D→Auto receptors inhibit presynap c ac vity in both serotoninergic
and adrenergic neurons in the CNS.
 5HT2→Vasoconstric on, platelet aggrega on
 5HT3→Nausea / vomi ng
 5HT4→ R Release
l off acetylcholine
t l h li iin th
the enteric
t i region.
i
5HT1(A‐G)
 Found in the CNS (inhibitory) and smooth muscles (excitatory or inhibitory).
 5HT1A partial agonist = Buspirone
 Used as anxiolytics (specially general anxiety disorders)

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Receptor agonist and antagonist

5HT1D/1B receptor agonist:
• TRIPTANS (all are indole derivatives); Sumatriptan, Rizatriptan and so on
• 5HT1D receptor
p agonist
g side effects: Feeling
g of warmth, dizziness, tightness
g or
heaviness in the chest, rarely patient may experience chest pain.
5HT2:
• 5HT2: Found in the CNS (excitatory), in periphery stimulation causes
vasoconstriction, GI constriction, branchial and smooth muscle constriction
and stimulation of platelet aggregation.
• 5HT2A: RESPIRIDONE, OLANZAPINE AND CLOZAPINE = 5HT2A
ANTAGONIST
• 5HT3 : Linked directly to ion channels, activation opens ion channels.
• 5HT3 antagonist = setrons (Ondansetron, granisetron)

Serotonin antagonist
Serotonin antagonist
5HT3 receptor antagonist
 Ondansetron (indole derivatives)
 Granisetron (benzimidazole derivative)
Ondansetron side effects: Constipation, headache, dizziness and granisetron;
diarrhea
Ergot alkaloids and derivatives with antagonist/partial agonist activity
include:
 Ergonovine
 Dihydroergotamine (DHE)
 Methysergide, Bromocriptine
 5HT4 agonist: Found in periphery and GI smooth muscles. Thereby these
drugs are used in chronic constipation. Cisapride (a benzamide) and
Tegaserod (indole derivative) : (use in IBS)

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PHYSIOLOGY OF INFLAMMATION

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Products of Arachidonic acid

• Prostaglandins (PGs) are products of long-chain fatty
acids. Arachidonic acid is the precursor for the
biosynthesis of all PGs. The enzyme involved in the
formation of PGs from arachidonic acid is
cyclooxygenase (COX).

• Another class of substances obtained from arachidonic

acid by the action of lipoxygenase is leukotrienes.

PROSTAGLANDINS

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Prostaglandins

 The main PGs in humans are prostaglandin E2 (PGE2),

prostaglandin
p g F2 ((PGF2)) and p
prostacyclin
y ((PGI2).
)
 There are two forms of COX: COX-1 and COX-2.
 COX-1 is constitutive (it is always present) and is widely
distributed. It participates in various physiological functions such
as protection of gastric mucosa, homeostasis, regulation of
cell division, etc.
 COX-2 is induced during inflammation by cytokines and
endotoxins.

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Effects and uses of prostaglandins.

Pharmacological actions and uses

 Gastrointestinal (GI) tract: PGE2 and PGI2 reduce acid secretion and increase the
secretion of mucus in the stomach (cytoprotective action). Misoprostol (PGE1
analogue) is used for the prevention of nonsteroidal antiinfl ammatory drug (NSAID)-
induced ulcers.
 Cardiovascular system: PGD2, PGE2 and PGI2 causes vasodilatation. PGF2
constricts pulmonary veins and arteries. Thromboxane A2 (TXA2) is a vasoconstrictor.
 PGE1 (alprostadil) is used to maintain the patency of ductus arteriosus before
surgery.
 Prostacyclin (PGI2) decreases peripheral, pulmonary and coronary resistance. PGI2
(
(epoprostenol)
t l) iis used
d tto ttreatt pulmonary
l h
hypertension.
t i
 Platelets: PGI2 inhibits platelet aggregation. Hence, it is used during haemodialysis to
prevent platelet aggregation.
 Eye: PGF2 has been found to decrease intraocular tension. Its analogue, e.g.
latanoprost, bimatoprost, travoprost and unoprostone are used in glaucoma.

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patency of ductus arteriosus

Pharmacological actions and uses

Pharmacological actions and uses
 Uterus: PGE2 (low concentration) and PGF2 contract the pregnant
uterus PGs are mainly used in mid-trimester abortion and missed
uterus.
abortion. Other uses include induction of labour, cervical priming
and postpartum haemorrhage.
 Male reproductive system: PGE1 (alprostadil) is useful for the
treatment of erectile dysfunction.
Adverse effects
• They are nausea, vomiting, diarrhea, fever, flushing, hypotension and
backache (due to uterine contractions). Injections are painful due to
sensitization of nerve endings.

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Clinical uses of prostanoids

Gynaecological and obstetric:
 termination of pregnancy: gemeprost or misoprostol (a metabolically stable
prostaglandin (PG)E analogue
 induction of labour: dinoprostone or misoprostol
 postpartum haemorrhage: carboprost.
Gastrointestinal: To prevent ulcers associated with non-steroidal anti-inflammatory
drug use: misoprostol.
Cardiovascular:
 to maintain the patency of the ductus arteriosus until surgical correction of the
defect in babies with certain congenital heart malformations: alprostadil (PGE1)
 to inhibit platelet aggregation (e.g. during haemodialysis): epoprostenol (PGI2),
especially if heparin is contraindicated
 primary pulmonary hypertension: epoprostenol
Ophthalmic: open-angle glaucoma: latanoprost eye drops.

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LEUKOTRIENES

Leukotriene
• These are obtained from arachidonic acid by the action of lipoxygenase.
• Leukotriene Antagonists
• These drugs competitively block the effects of cysteinyl leukotrienes (LTC4
(LTC4,
LTD4 and LTE4) on bronchial smooth muscle. Thus, they produce
bronchodilatation, suppress bronchial inflammation and decrease
hyperreactivity.
• They are well absorbed after oral administration, highly bound to plasma
proteins and metabolized extensively in the liver.
• They are effective for prophylactic treatment of mild asthma. They are well
tolerated and produce fewer adverse effects—headache, skin rashes and
rarely eosinophilia.

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Leukotriene Antagonists

BEST WISHES

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Pain Management

Analgesic
 What is an analgesic?
 What is the pain scale?
 What is Analgesic Ladder?
 What is neuropathic pain?
 Type of Analgesic?
 Analgesics are drugs that relieve pain without significantly altering consciousness.
They relieve pain without affecting its cause.
 Analgesics
A l i are two
t types
t Opioids
O i id (N
(Narcotic)
ti ) and
dNNon O
Opioids
i id (NSAIDS)
Common Terms
Antipyretic: a drug to reduce fever
An analgesic: a drug used to relieve pain
Anti-inflammatory: Drugs that reduce redness and swelling
Antiplatelet: Prevent platelet aggregation.

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Physiology of pain sensation

• Unmyelinated (C-fiber) nociceptors mediate the burning pain from noxious heat
stimuli and pain from prolonged mechanical stimuli.
• Myelinated (A-fiber) nociceptors mediate the sharp, pricking pain associated with
application of intense heat or sharp objects
objects.
• Nociceptors are sensory receptors that detect signals from damaged tissue or
the threat of damage and indirectly also respond to chemicals released from the
damaged tissue. Nociceptors are free (bare) nerve endings found in the skin,
muscle, joints, bone and viscera.
• The periaqueductal gray (PAG, also known as the central gray) is a brain region that
plays a critical role in autonomic function, motivated behavior and behavioural
responses to threatening stimuliPAG is also the primary control center for
descending pain modulation.
• When activated, these interneurons release either enkephalin or dynorphin
(endogenous opioid neurotransmitters), which bind to mu and kappa opioid
receptors, respectively, on the axons of incoming C and A-delta fibers carrying pain
signals from nociceptors activated in the periphery.

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NSAIDS

NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Classification
Nonselective cyclooxygenase (COX) inhibitors
 Salicylates: Aspirin
 Propionic acid derivatives: Ibuprofen, ketoprofen, naproxen, flurbiprofen.
 Acetic acid derivatives: Diclofenac, aceclofenac.
 Fenamic acid derivatives: Mefenamic acid.
 Pyrrolo–pyrrole derivatives: Ketorolac, etodolac.
 Oxicam derivatives: Piroxicam, tenoxicam.
 Indole derivatives: Indomethacin.
Indomethacin
Preferential COX-2 inhibitors: Nimesulide, meloxicam, nabumetone.
Highly selective COX-2 inhibitors: Etoricoxib, parecoxib, lumiracoxib.
Analgesic—antipyretics with poor anti-inflammatory effect: Paracetamol, nefopam.

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Mode of action
COX is the enzyme responsible for the biosynthesis of various prostaglandins. There
are two well recognized isoforms of COX: COX-1 and COX-2. Nonsteroidal anti-
inflammatory drugs (NSAIDs) have analgesic, antipyretic and anti-inflammatory
actions. They inhibit the synthesis of prostaglandins by inhibiting cyclo-oxygenase.
Cyclo-oxygenase (COX).
Aspirin
A d mostt off nonsteroidal
i i and t id l anti-inflammatory
ti i fl t drugs
d (NSAIDs)
(NSAID ) inhibit
i hibit b
both
th
COX-1 and COX-2 isoforms, thereby decreasing prostaglandin and thromboxane
synthesis.
Inhibition of COX-1 is associated with impaired gastric cytoprotection and
antiplatelet effects.
Inhibition of COX-2 is associated with anti-inflammatory and analgesic action.
 Reduction in glomerular filtration rate and renal blood flow is associated with
both COX-1 and COX-2 inhibition.
Most NSAIDs are nonselective, inhibiting both COX-1 and COX-2. Although selective
COX-2 inhibitors have little or no effect on COX-1 at therapeutic doses, they are still
associated with GI adverse effects.
Aspirin causes irreversible inhibition of COX. The rest of the NSAIDs cause
reversible inhibition of the enzyme.

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Indications & Contraindication

Indication:
• Rheumatoid arthritis, including juvenile rheumatoid arthritis,
• Osteoarthritis
• Other inflammatory arthropathies
arthropathies, eg ankylosing spondylitis
spondylitis, psoriatic arthritis and
Reiter's syndrome and Acute gout
• Pain, especially due to inflammation and tissue injury (eg dysmenorrhoea, metastatic
bone pain, renal colic, headache, migraine, postoperative pain)
• Fever
Contraindications
• Active
A ti peptic
ti ulcer
l di
disease or GI bleeding
bl di
• Allergic reactions to NSAIDs, including aspirin
Important Point:
• Reye’s syndrome in children with chickenpox and flu (primarily ASA)
• Salicylate allergies: If allergy with one NSAID’s avoid all other NSAID’s use

Adverse effects
GIT: Nausea, vomiting, dyspepsia, epigastric pain, acute gastritis, ulceration and
GI bleeding.
Bronchospasm (aspirin-induced asthma) is due to increased production of
leukotrienes. Incidence of hypersensitivity is high in patients with asthma, nasal
polyps, recurrent rhinitis or urticaria. Therefore, aspirin should be avoided in such
patients.
In people with G6PD deficiency, administration of salicylates may cause
haemolytic anaemia.
Prolonged use of salicylates interferes with action of vitamin K in the liver
decreased synthesis
y of clotting yp p
g factors ((hypoprothrombinaemia) ) predisposes
p p to
bleeding (can be treated by administration of vitamin K).

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Adverse effects

Reye’s syndrome: Use of salicylates in children with viral infection may cause
hepatic damage with fatty infiltration and encephalopathy—Reye’s syndrome.
Hence salicylates are contraindicated in children with viral infection
Hence, infection.
Pregnancy: These drugs inhibit PG synthesis, thereby delay onset of labour and
increase chances of postpartum haemorrhage. In the newborn, inhibition of PG
synthesis results in premature closure of the ductus arteriosus.
Analgesic nephropathy: Slowly progressive renal failure may occur on chronic
g doses of NSAIDs. Renal failure is usually
use of high y reversible on stoppage
pp g of
therapy but rarely, NSAIDs may cause irreversible renal damage.
Counselling
• If you develop swollen ankles, difficulty in breathing, black stools or dark coffee-
colored vomit, stop taking the medicine and tell your doctor immediately.

Counseling and practice points

Practice points
• about 60% of patients will respond to any NSAID; those who do not respond to one
may respond to another
g
• in osteoarthritis, maximal analgesic and anti-inflammatoryy effects are usuallyy seen
within 2 weeks; if appropriate responses are not observed within 3 weeks, try a
different NSAID
• there is no rationale for using >1 NSAID at a time (excluding low dose aspirin)
• for extra pain relief NSAIDs may be used with paracetamol and, if pain is severe,
an opioid,
• seek specialist advice if a patient has aspirin
aspirin-induced
induced asthma and great need for
an NSAID (may be able to tolerate a selective COX-2 inhibitor, with first dose
given under medical supervision)
• do not stop low dose aspirin treatment when using an NSAID (NSAID
antiplatelet effect is unreliable)
• Use PPI or Misoprostol with NSAID for protection of GI Side effects

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cers
NSAID’s induced ulc

Treatment of NSAID’s induced ulcers

NSAID’s induced ulcers Misoprostol
 PGE1 analog
Risk factors for Development  Increases bicarbonate secretions
of upper GI side effects with  Increase mucus secretions
NSAID
Proton ppump p inhibitor (omeprazole,
( p , lansoprazole)
p )
Age >65,  Proton pump inhibitors elevate pH 4
 Acts as an antacids
Anticoagulants or oral  Prevents and treat NSAID induced ulcers
Sucralfate
glucocorticoids  Mucus protective agent, it is mixture of aluminum
hydroxide and sulphate sucrose (disaccharide).
History of peptic ulcer disease
 Should be avoided with antacids
History of upper GI conditions  Taken empty stomach
For Prevention: Along with NSAIDS – misoprostol
Comorbid medical conditions (cytoprotective) anitidine and proton pump inhibitors are
often administered at the same time as NSAIDS to
prevent ulcers.

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Acetyl Salicylic Acid

Mechanism:
In low doses inhibits platelet COX production of thromboxane A2 preventing platelet
aggregation.
Cox permanently inhibited for life of the platelet & Platelet life 7-10 days
Dosage regimen for aspirin
• Analgesic dose: 2–3 g/day in divided doses.
• Anti-infl ammatory dose: 4–6 g/day in divided doses.
• Antiplatelet dose: 50–325 mg/day (low-dose aspirin).
Key points:
Antiplatelet low dose (60 to 80 mg). Due to permanent action on TxA2 thus prevent
platelet aggregation
Analgesia: Moderate dose, may be two tablets (325 mg bid). Due to inhibition of Cox1 and
Cox2 (prevent prostaglandin formation).
Antipyretics. Moderate dose, may be 4 to 8 tablets. Pyrogen increase PGE2 formation,
which is inhibited by ASA
Anti-inflammatory. Moderate to high dose. Inhibit Cox2 which is induced during
inflammation.

SALICYLISM
Salicylism
• Salicylate intoxication may be mild or severe. The mild form is called salicylism.
• The symptoms include headache, tinnitus, vertigo, confusion, nausea,
g diarrhoea, sweating,
vomiting, g hyperpnoea,
yp p electrolyte
y imbalance, etc. These
symptoms are reversible on stoppage of therapy.
Acute Salicylate Poisoning
• Manifestations are vomiting, dehydration, acid–base and electrolyte imbalance,
hyperpnoea, restlessness, confusion, coma, convulsions, cardiovascular
collapse, pulmonary oedema, hyperpyrexia and death.

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SALICYLISM
• Treatment
• There is no specific antidote for salicylate poisoning. Treatment is symptomatic.
Hospitalization.
 Gastric lavage followed by administration of activated charcoal (activated
charcoal adsorbs the toxic material—physical antagonism).
 Maintain fluid and electrolyte balance. Correct acid-base disturbances.
 Intravenous sodium bicarbonate to treat metabolic acidosis.
 It also alkalinizes the urine and enhances renal excretion of salicylates
(since salicylates exist in ionized form in alkaline pH).
 External cooling.
 Haemodialysis in severe cases.
 Vitamin K1 and blood transfusion, if there is bleeding.

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Differences Between Nonselective COX and Selective COX-2 Inhibitors

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Paracetamol
Paracetamol is effective by oral and parenteral routes. It is well absorbed, widely
distributed all over the body, metabolized in liver by sulphate and glucuronide conjugation.
The metabolites are excreted in urine
Acute paracetamol poisoning: Acute overdosage mainly causes hepatotoxicity—
symptoms are nausea,
nausea vomiting,
vomiting diarrhoea,
diarrhoea abdominal pain
pain, hypoglycaemia
hypoglycaemia, hypotension
hypotension,
hypoprothrombinaemia, coma, etc. Death is usually due to hepatic necrosis.
Mechanism of toxicity and treatment
The toxic metabolite of paracetamol is detoxified by conjugation with glutathione and
gets eliminated. High doses of paracetamol cause depletion of glutathione levels. In the
absence of glutathione, toxic metabolite binds covalently with proteins in the liver and
kidney
d ey aand
d causes necrosis. acety cyste e o
ec os s N-acetylcysteine or o
oral
a methionine
et o e replenishes
ep e s es tthe e
glutathione stores of liver and protects the liver cells.
Alcoholics and premature infants are more prone to hepatotoxicity.
Activated charcoal is administered to decrease the absorption of paracetamol from the
gut. Charcoal haemoperfusion is effective in severe liver failure. Haemodialysis may be
required in cases with acute renal failure.

NAPQI, N-acetyl-p-benzo-quinoneimine.
oxicity
m of paracetamol to
Mechanism

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 7/18/2022

Differences Between Aspirin and Paracetamol

OPIOID ANALGESIC

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 7/18/2022

Opiods: Mode of action

Opioid analgesics mimic endogenous opioids by activating opioid receptors in the central
and peripheral nervous systems to produce analgesia, respiratory depression,
sedation and constipation.
They prevent transmission of the pain impulse by acting pre- and post-synaptically
in the spinal cord,
cord and by modulating the descending inhibitory pathways from the
brain.
Cough suppression occurs in the medullary centre of the brain.
Opioid analgesics bind with stereospecific receptors in the CNS. The most studied
subtypes of opioid receptors are mu (μ), delta (δ) and kappa (κ).
 There are three known ppeptide
p neurotransmitters that act on mu,, delta and kappa
pp
receptors. Enkephalin (mu
( ) Endorphine (mu),
& delta), ( ) Dynorphine (kappa)
( )
Pure opioid agonists such as morphine act primarily at the mu receptor.
Mixed agonist-antagonists such as butorphanol, nalbuphine and pentazocine are
most active at the kappa receptor.
Buprenorphine is a partial agonist at the mu receptor and an antagonist at the
kappa receptor.

Mu receptor simulation (supraspinal, Side effects (Is these side effects look like
spinal) cause Anticholinergic side effects? )
 Analgesia  Constipation (increase GI tone)
 Respiratory depression  Sedation, drowsiness
 Euphoria  Miosis
 Physical dependency  Respiratory depression
 Pupil constriction  Urinary retention
Therapeutic use:
 Hypotension
 Analgesics (moderate to severe
pain) Opioid Withdrawal:
 Antitussive (dextromethorphan,
(dextromethorphan  Diarrhea
codeine)  Nausea, vomiting, Muscle ache
 Antidiarrheal (Loperamide)
 Lacrimation or rhinorrhea
Opioid overdose gives three characteristic
symptoms such as pinpoint pupil, Decrease  Fever and dilated pupil (mydriasis)
respiration (hypoxia), constipation, coma and  Autonomic hyperactivity
somnolence.

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 7/18/2022

Key management points:

Respiratory depression: The most serious adverse effect of opioids; this is best judged by the
degree of sedation; respiratory rate reduction is a late and unreliable indicator. Sedation is
best monitored by using a sedation score, an example of which is given below:
Sedation score:
• 0 – wide awake
• 1 – easy to rouse
• 2 – easy to rouse, but cannot stay awake
• 3 – difficult to rouse.
Aim to keep the sedation score <2; a score of 2 represents early respiratory depression.
p
Constipation: Tolerance develops
p slowly,y, if at all. Attention to fluid intake,, diet and mobilityy plus
p
regular laxative use (eg senna, sorbitol) is essential as soon as chronic opioid treatment is
started.
Equianalgesic dosing: Changing Opioid: If the adverse effects of morphine, eg delirium,
become intolerable, opioid substitution may reduce refractory adverse effects. When changing
drugs, consider equianalgesic doses.

Counseling & Practice points

Counselling
• This medication may make you feel drowsy and may increase the effects of alcohol. If
you are affected, do not drive or operate machinery.
• B
Be careful
f l when
h you stand
d up as this
hi medicine
di i might
i h make
k you ffeell di
dizzy if you stand
d up
too quickly.
Practice points
• a key advantage of opioids in the management of pain is that they can be given by a
variety of routes (oral, transmucosal, rectal, IV, SC, IM, transdermal, epidural and
intrathecal); they can also be easily titrated, are highly effective and have a favourable
risk/benefit ratio
• always use a laxative (eg docusate with senna, sorbitol) for people requiring regular
opioids,
• Naloxone is used to reverse opioid sedation and respiratory depression

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7/18/2022

16
 7/18/2022

Drug and Therapeutics effects

Meperidine
 Mu receptor agonist
 Used during labor. Anticholinergic effect. No miosis, Tachycardia (IV), Toxic doses
may cause CNS stimulation.
stimulation
 The least respiratory depression and less constipation
 Normeperidine (metabolite) - hallucinations and convulsions
 Constipation and urinary retention less than for morphine.

Fentanyl
 mu agonist
agonist. Produce short duration of action 1-2hr
1 2hr. It does not cause histamine
release up on iv injection. Fentanyl patch produce analgesia for 72 hrs.

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 7/18/2022

Best wishes

18
 7/18/2022

GOUT

Gout
• Disorder of Purine metabolism characterized by recurrent attacks of acute
inflammatory arthritis ‐ a red, tender, hot, swollen joint.
• it may also present as tophi, kidney stones, or urate nephropathy
• caused by elevated levels of uric acid in the blood which crystallize and are
deposited in joints, tendons, and surrounding tissues.
• The MTP (metatarsophalangeal) joint at the base of the big toe is the most commonly
affected (~50% of cases).
Causes
• Hyperuricemia is the underlying cause of gout
• This can occur for a number of reasons, including diet, genetic predisposition, or under
excretion of urate
• Renal under excretion of uric acid is the primary cause of hyperuricemia in about 90% of
cases, while overproduction is the cause in less than 10%
• About 10% of people with hyperuricemia develop gout at some point in their lifetimes

1
 7/18/2022

Etiology
 Lifestyle
Genetics
• Dietary causes account for about
12% of gout.  Familial juvenile
• Alcohol,, fructose‐sweetened drinks,, hyperuricemic nephropathy
meat, and seafood (+),  Medullary cystic kidney
• Coffee, vitamin C and dairy products disease
as well as physical fitness (‐)
• Hypoxanthine‐guanine
 Medical conditions
• Metabolic syndrome
phosphoribosyltransferase d
• Renal failure eficiency (HPRT) deficiency
• BMI >35 in male – risk increase is a hereditary disorder of
threefold purine metabolism
 Medication associated with uric acid
• Diuretics, niacin, aspirin and overproduction
Cyclosporine

Gout
Characteristics
• Resembles arthritis
• Sudden pain in the big toe, with the pain continuing to the leg
• Usually occurs after the age of 35 and is characterized by specific heritable
metabolic defects
• Obesity is usually associated with a gouty condition
Diagnosis: with clinical symptoms, Synovial fluid, Blood tests, and X‐ray
Management
• Acute Pain Management
• Long term Management
• Prophylaxis
• Lifestyle modification and non Pharmacological management

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 7/18/2022

 Acute stage
• Rigid restriction of food containing purine
• Diet high in carbohydrates, moderate in protein and low in fat
• Fluids (up to 3 liters per day) should be forced to assist the excretion of
uric acid and to minimize the possibility of calculi formation
• Sodium bicarbonate or trisodium citrate
• Potassium salt of carbonate and citrate
 Interval stage
• Dietary management + Uricosuric drugs
• Normal
N l adequate
d t di
diett adjusted
dj t d tto achieve
hi ideal
id l weight
i ht
• Moderate in protein (60 to 70 gms)
• Increase in carbohydrates and relatively low in fat
• Should avoid food high in purine

Special consideration
 Alcohol
• Mild to moderate
• Lactic acid during the metabolism of ethanol
 Obesity
• Reduced and maintain a body weight that is 10 to 15 % below the
calculated normal weight
• Weight reduction should be deferred until the serum uric acid conc. Has
been bought under control
 Low
Lo purine
p rine diet
• Normal diet – 600 to 1000 mg of purine daily
• In cases of severe or advanced gout the purine content of the daily diet
is restricted to approximately 100 to 150 mg
• Fat is kept to 40% of the caloric intake

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 7/18/2022

Pathophysiology: Gout

4
7/18/2022

5
 7/18/2022

Dietary Management
 Restriction of Purine rich diet
 Drugs have largely replaced the need for rigid restriction of purine
 All food have some traces of nucleoprotein from which purines are derived
 Purines are synthesized in the body from simple metabolites, which are constantly
available from dietary CHO, COOH, Fat and endogenous purine breakdown
 Restriction of food containing nucleoproteins is indicated in patient with high uric
acid level
 Excessive use of fats should be avoided, since fats are believed to prevent the normal
excretion of urate
 Protein intake should be adequate but not excessive
 The calories should be maintained with carbohydrates
 Carbohydrates have a tendency to increase uric acid excretion

Substances Affecting Urate Levels

URATE – INCREASING AGENTS URATE – DECREASING AGENTS
 Pyrazinamide  Probenecid
 Nicotinate  Sulfinpyrazone
 Lactate, β‐  Losartan
hydrokybutyrate,acetoacetate
 Salicylate (high‐dose)
 Salicylate (low dose)
 Fenofibrate
 Diuretics
 Amlodipine
 Cyclosporine
 Xanthine oxidase inhibitors
 Tacrolimus
 Ethambutol
 Allopurinol

 β ‐Blockers  Febuxostat
 Urate – decresing agent  Uricase

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 7/18/2022

Non‐Pharmacological Management

Non‐Pharmacological Management
• Avoid vigorous exercise
• Limit
Li i alcohol
l h l consumption.
i
• Drink at least two litres (eight glasses) of water every day (unless your
fluid intake has been restricted by your doctor).
• Eat regular, healthy meals, including plenty of fruit, vegetables and
grains. Limit foods high in fat, sugar or salt.
• Limit or avoid foods that can increase blood uric acid levels (Eg: Legumes
and Protein diet).
• Keep to a healthy weight.

Pharmacological management
Acute Management :
 Non‐steroidal anti‐inflammatory drugs (NSAIDs) are first‐line therapy
(Aspirin should be avoided as it may exacerbate the condition)
• If NSAIDs are contraindicated, corticosteroids may be used:
(methylprednisolone 40‐80mg); Oral prednisolone or prednisone (25mg
daily,reducing to zero over seven to 10 days).
• If NSAIDs and corticosteroids are contraindicated or inappropriate,
inappropriate
colchicine can be used at a dose of 1mg initially, followed by 500mcg
every two to three hours. until pain resolves or signs of toxicity (e.g.
nausea, vomiting, diarrhoea) are experienced. Max. dose= 8mg.

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 7/18/2022

Chronic :Management

Chronic :Management
 Allopurinol : reduces uric acid synthesis by inhibiting xanthine oxidase.
The recommended dose is 50‐100mgg orallyy daily, y, increasingg over one to
two weeks to maintain plasma urate levels in the normal range, up to 200‐
300mg daily.
 Probenecid: is the only uricosuric agent currently available. It is actively
secreted in the proximal tubule and prevents the reabsorption of urate,
increasing renal clearance. The recommended dose is 250mg orally twice‐
daily for one week
week, increasing over several weeks to 1g twice‐daily
twice daily.
 Sulfapyrazine
 For Patient of low Excretion: Probenacid
 For Patient of High Production: Allopurinol

ALLOPURINOL
Mode of action
Reduces uric acid production by inhibiting xanthine oxidase, and lowers
plasma and urinary urate concentrations. Allopurinol is metabolised to
oxypurinol, which also inhibits xanthine oxidase.
C
Counselling
lli
Take this medicine shortly after food to reduce the possibility of stomach
upset.
If you develop a rash, swollen lips or mouth, persistent fever or sore throat,
stop taking allopurinol and tell your doctor immediately.
Make sure that you drink lots of fluids during treatment to prevent kidney
stones.
stones
This medicine may make you feel dizzy or drowsy; do not drive or operate
machinery if you are affected.

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 7/18/2022

ALLOPURINOL
Practice points
Allopurinol is not indicated for the treatment of asymptomatic
hyperuricaemia
Wait until attack has settled before starting treatment with allopurinol
(changes in uric acid concentration may worsen and prolong acute attack)
Once treatment is established, continue allopurinol at the current dose,
even during acute attacks of gout
Prophylaxis with colchicine or a low dose NSAID may be needed during
induction phase with allopurinol (1–3 months)
Check uric acid concentration after 4 weeks and adjust dose; aim for uric
acid concentration <0.38 mmol/L (failure to achieve normal uric acid
concentrations may indicate poor compliance)
Stop allopurinol if rash develops, there are other signs of allergy, liver
function is abnormal, or blood dyscrasias occur

PROBENECID
Mode of action
• Increases renal excretion of uric acid by blocking its renal tubular reabsorption.
Reduces the renal tubular excretion of some acidic drugs (eg penicillins), increasing
their plasma concentration and prolonging their duration of action. Probenecid has
no analgesic
g or anti‐inflammatory action.
Indications
• Gout prophylaxis, where urate‐lowering treatment is required
adjunct to beta‐lactam antibacterial treatment (penicillins and certain
cephalosporins)
adjunct to cidofovir treatment for CMV retinitis in HIV
Counselling
• This medicine may be taken with food to reduce stomach upset. upset
• Do not take aspirin for pain relief as it will reduce the effect of probenecid.
• Make sure that you drink lots of fluids during treatment to prevent kidney stones.

9
 7/18/2022

PROBENECID
Practice points
• Ensure adequate fluid intake during the first few months of treatment to
reduce the risk of uric acid kidney stones; if necessary, use urinary
alkalinisers
lk li i
• Check renal function and complete blood count regularly
• Wait until attack has settled before starting treatment with probenecid;
changes in uric acid concentration may exacerbate and prolong acute
attacks
• Continue probenecid if an acute attack of gout occurs
• Probenecid is not indicated for the treatment of asymptomatic
hyperuricaemia
• Prohibited in elite sports as it may be used to mask detection of banned
substances

COLCHICINE
Mode of action
• Inhibits neutrophil migration, chemotaxis, adhesion and phagocytosis in the
inflamed area; reduces the inflammatory reaction to urate crystals but has no
effect on uric acid production or excretion.
Dosage
• Prophylaxis of gout: 500 micrograms once or twice daily.
• Acute gout: 1 mg initially, then 500 micrograms every 6 hours until pain relief or
toxicity (eg nausea, vomiting, diarrhoea) occurs. Maximum dose 6 mg per course.
p
Do not repeat the course within 3 days.
y
Counseling
• Nausea, vomiting and diarrhoea often occur within 24 hours of starting colchicine
for acute gout; stop treatment immediately when they occur. Do not take more
than 12 tablets (6 mg) in a course to treat acute gout or repeat the course within
3 days.

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 7/18/2022

COLCHICINE
Practice points
• Consider for acute gout only when nsaids and corticosteroids (systemic or intra‐
articular) are contraindicated or inappropriate
• Although it has been used for decades,
decades published doses for acute gout are based
on little evidence
• Toxicity (eg nausea, vomiting, diarrhoea) can easily occur; be careful to use
suitable doses, especially in renal impairment
• Joint inflammation subsides within 48 hours in 75–80% of patients; colchicine
toxicity often occurs before pain is relieved
• Risk of toxicity due to colchicine accumulation if acute course repeated too quickly
or if it is continued when GI effects occur (elimination can take >10 days)
• Colchicine may be used instead of nsaids in heart failure as it does not cause fluid
retention
• Measure complete blood count before using colchicine for prophylaxis; repeat
after 1 and 6 months, then annually

RASBURICASE
Mode of action:
Recombinant urate oxidase enzyme which catalyses the
enzymatic
y oxidation of uric acid into allantoin which is more
water soluble than uric acid and less likely to precipitate in
the renal tubules.
Indications
• Treatment and prophylaxis of acute hyperuricaemia
associated with tumour lysis in haematological malignancy
Contraindications
• G6PD deficiency
Haemolytic anaemia

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 7/18/2022

RASBURICASE
Practice points
• Give initial dose up to 48 hours before chemotherapy if patient has
baseline hyperuricaemia and 24 hours before if not
• Does not affect hyperkalaemia, hyperphosphataemia and hypocalcaemia
of tumour lysis syndrome
• Hydrogen peroxide is a by-product of uric acid oxidation and may
induce haemolytic anaemia
• Uric acid degradation may continue ex vivo in blood taken for assay;
slow oxidation by using chilled heparin-containing tubes, immerse in an
ice/water bath and transport immediately to laboratory
• Antibodies to rasburicase form in about 50% of patients; significance is
unknown

Specific Advice
 In renal failure patient = Probenecid & Thiazide diuratic shouldn’t be
given.
 Allopurinol
All i l start with
i h 100
100mg ddaily
il upto 900mg
900 gradually
d ll
 Don’t give allopurinol in acute condition.
 Interaction : probenacid + Penicillin
 Allopurinol + Azathyoprin or Mercaptopurin: Reduce the Azathyoprin
dose one third to one quarter
q
 Plenty of water with allopurinol
 Allopurinol side effect

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 7/18/2022

BEST WISHES

13
 7/18/2022

Osteoarthritis and Strain and Sprain

Common Terms
• Synovial fluid: is a viscous, non‐ Normal joints:
Newtonian fluid found in the cavities • Joints, where two moving bones come together,
of synovial joints are designed to protect bone ends from wearing
• Tendons : fibrous connective tissue away and to act as shock absorbers.
that usually connects muscle to A joint is made up of:
bone and is capable of withstanding • Cartilage – a hard, slippery, protective coating on
tension. the end of each bone. Made up of water +
• Ligaments: fibrous connective tissue Chondrocytes + Extra cellular matrix
that connects bones to other bones • Joint capsule – a tough covering that holds all the
• Strain : Muscle fiber breaks and bones and other joint parts together
Inflame • Synovium
S i – a thin
thi membrane
b lining
li i inside
i id the
th
• Sprain : Ligament Muscle breaks joint capsule
• Tendonitis : Breakage of Tendons • Synovial fluid – a fluid that lubricates the joint
• Muscles, ligaments, and tendons – • Muscles, ligaments, and tendons – that keep the
That keep the bones stable and bones stable and allow the joint to bend and
allow the joint to bend and move. move.

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 7/18/2022

Pathophysiology

Osteoarthritis is a degenerative joint

disease, generally believed to result
from an imbalance in erosive and
reparative processes.

There is debate as to whether the

initial pathological changes occur in
articular cartilage or subchondral
bone.

Healthy cartilage allows smooth

movement of one bone against
another. Cartilage contains
chondrocytes and an extracellular
matrix composed of proteoglycans
and a network of collagen fibres

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 7/18/2022

Physiology
• Chondrocytes: maintain the integrity of the extracellular matrix in
healthy cartilage through both anabolic (production of the components of
the extracellular matrix) and catabolic (production of metalloproteinases,
protein degradation enzymes) activity.
• Proteoglycans: provide resiliency by forming aggregates with hyaluronic
acid that are hydrophilic and retain water. When the joint is under
mechanical stress, they release water, absorbing it again when the stress
diminishes.
• Collagen fibers: provide strength and anchor the cartilage to the bone.

Pathophysiology: Role of Interleukin

Role of Interleukin in Pathophysiology

IL‐1 (Interaleukin) is a potent pro‐inflammatory cytokine:
 which is capable of inducing chondrocytes and synovial cells to
synthesize Matrix (metalloproteinases )MMPs. MMPs is responsible of
degradation of articular cartilage.
 In addition, IL‐1 inhibits synthesis of collagen II, proteoglycans and
growth factor B stimulated chondrocyte proliferation

Osteoarthritis is primarily a disease of cartilage.

3
 7/18/2022

Pathology
Pathology:
• Initial cartilage changes seen in osteoarthritis include swelling, due to an
increased influx of water in the extracellular matrix, and a loss of proteoglycans.
I response, there
In th isi increased
i d proliferation
lif ti andd activity
ti it off chondrocytes.
h d t
Eventually, though, there is an imbalance between anabolic and catabolic
activity resulting in net degradation and loss of articular cartilage.
• As osteoarthritis progresses, cartilage thins and fissures, placing the underlying
bone under great pressure. The end result is microfractures, thickening and
sclerosis of the surrounding bone.
bone
• This is more commonly seen in weight-bearing joints, indicating the
contribution of excessive stress on the pathogenesis of the disease.
• Synovitis (inflammation of the synovial membrane) and the development of
osteophytes (bony outgrowths) may also occur.

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 7/18/2022

About Osteoarthritis
• Osteoarthritis, sometimes called degenerative joint disease or
osteoarthrosis, is the most common form of arthritis. Osteoarthritis occurs
when cartilage
g in the jjoints wears down over time.
• Osteoarthritis can affect any joint in the body, though it most commonly
affects joints in hands, hips, knees and spine. Osteoarthritis typically affects
just one joint, though in some cases, such as with finger arthritis, several
joints can be affected.
• Osteoarthritis gradually worsens with time, and no cure exists. But
osteoarthritis treatments can relieve pain and help you to remain active.
Taking steps to actively manage osteoarthritis may help patient gain control
over his osteoarthritis pain.

Risk factors
 Older age : Osteoarthritis typically occurs in older adults. People under 40 rarely
experience osteoarthritis.
 Sex: Women are more likely to develop osteoarthritis, though it isn't clear why.
 Bone deformities: Some people are born with malformed joints or defective
cartilage, which can increase the risk of osteoarthritis.
 Joint injuries: Injuries, such as those that occur when playing sports or from an
accident, may increase the risk of osteoarthritis.
 Obesity: Carrying more body weight places more stress on weight-bearing joints,
such as knees. But obesity has also been linked to an increased risk of osteoarthritis
in the hands,, as well.
 Other diseases: that affect the bones and joints. Bone and joint diseases that increase
the risk of osteoarthritis include gout, rheumatoid arthritis, Paget's disease of bone
and septic arthritis.
 Heredity:
 Muscle weakness:

5
 7/18/2022

Diagnosis
Clinical Presentation: The primary symptoms are:
• Pain: which is aggravated by activity and relieved by rest. As the disease progresses, the
pain may become more persistent.
• Stiffness: May occur after a period of inactivity (e.g. in the morning), but generally persists
for less than 20 minutes.
• Limitation of movement : changes in bone may diminish its ability to withstand stress.
Swelling, caused by synovitis or osteophytes, may also restrict joint range of motion.
• Localised tenderness, warmth and swelling.
• Articular crepitus (a crackling noise or vibration heard upon joint movement) may
manifest.
if t
• Radiography changes: Joint space narrowing, subchondral bone sclerosis, subchondral
cysts, and osteophytosis.
• Other Symptoms: The pain and functional limitation associated with osteoarthritis does
have psychological impacts, including anxiety, depression and a sense of helplessness.

Osteoarthritis Rheumatoid Arthritis

• Age related progressive inflammatory • Autoimmune disorder, chronic
disease of cartilage. inflammatory condition of synovial
membrane.
• Extraticular symptoms are absent.
• Extraticular symptoms are present.
present
• Normally occurs on big weight bearing
joints. • Normally starts with small joints.
• Can occur on one side of body. • Occurs symmetrically
• Excursive, work and straineous • Inactivity is the reason of the problem.
condition cause painful condition. • Morningg stiffness is for longer
g p period
• Morning stiffness is for lesser period of of time.
time. • Disease modified rheumatoid
• Management is only for symptomatic medication can be given.
release, acute inflammation can be
controlled.

6
 7/18/2022

Management
Prevention:
 Avoiding acute joint trauma,
 modifying
dif i occupation‐related
ti l t d jjoint
i t stress
t through
th h ergonomic
i
approaches.
 preventing obesity can be recommended.
Non Pharmacological
 Hot and Cold Compression
Pharmacological :
 Analgesic and Antinflammatory
Surgery
 Knee replacement surgery

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7/18/2022

8
 7/18/2022

Group of drug Examples

Analgesics Acetaminophen and Tramadol

NSAID Aspirin, ibuprofen and naproxen

Cox‐2 inhibitors Celecoxib

Topical analgesics Cream or spray as zostrix

Corticosteroid Injectable Glucocorticoid

Vi
Visco‐supplements
l t H l
Hyaluronic
i acid
id

Bone components Glucosamine and Chondrotin Sulfate

Future therapy Degradative Enz Growth

Surgery for osteoarthritis

 Surgery is generally reserved for severe osteoarthritis that isn't relieved by other
treatments. Surgical treatments include:
• Joint replacement. In joint replacement surgery (arthroplasty), surgeon removes
damaged joint surfaces and replaces them with plastic and metal devices called
prostheses.
th J i t replacement
Joint l t surgery can h
help
l patients
ti t resume an active,
ti pain‐free
i f
lifestyle. Joint replacement surgery carries a small risk of infection and bleeding. Artificial
joints can wear or come loose, and may need to eventually be replaced.
• Debridement,is most useful in cases with a locking sensation from a torn cartilage or
loose debris Debridement is typically done arthroscopically,
• Realigning bones. Surgery to realign bones may relieve pain. These types of procedures
are typically
yp y used when jjoint replacement
p surgery
g y isn't an option,
p , such as in younger
y g
people with osteoarthritis. During a procedure called an osteotomy, the surgeon cuts
across the bone either above or below the knee to realign the leg.
• Fusing bones. Surgeons also can permanently fuse bones in a joint (arthrodesis) to
increase stability and reduce pain. The fused joint, such as an ankle, can then bear weight
without pain, but has no flexibility.

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 7/18/2022

Surgery
Arthroscopy
Mainly for knee and shoulder.
Remove of loose pieces of bone or cartilage and treatment of torn ligament or
inflamed synovial membrane

Osteotomy
Mainly for knee and hip.
For people younger to do joint replacement.
Repositioning of bone by a wedge shape cut.

Joint Replacement
For people over 50y or severe progression
Reconstruction of a joint

STRAIN AND SPRAIN

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 7/18/2022

Strain & Sprain

• Sprains and strains both refer to damage to the soft tissues in the body, including ligaments,
tendons, and muscles. They are common injuries that share some symptoms but affect
different body parts. People can often treat sprains and strains at home.
• A sprain
i is
i an overstretched,
t t h d ttorn, or twisted
t i t d ligament.
li t A ligament
li t iis a tough
t h band
b d off fibrous
fib
tissue that connects bones to other bones or cartilage. Ligaments are usually located around
joints. Commonly sprained areas include the wrists, ankles, thumbs, and knees.
• A strain is an overstretched, torn, or twisted tendon or muscle. A tendon is a tough cord of
fibrous tissue that connects muscles to bones. Commonly strained areas include the legs,
knees, feet, and back.

Strain & Sprain

 Sprain and Strain are injuries to muscles, tendons and ligaments. They are very common
sports injuries but can also happen during normal daily activity. Correct treatment given
promptly leads to the best possible recovery in shortest possible time.
 Management: RICE stands for:
• Rest: Stop any exercise or physical activities and avoid putting any weight on the affected
limb.
• Ice: Apply ice to the injury for up to 20 minutes every 2 to 3 hours. People can use bags of
frozen vegetables if they do not have ice packs.
• Compression:
p To help
p reduce swelling,g, a p
person can wrap
p the affected area with a
bandage or trainer’s tape. Loosen the wrap if the area gets numb or if the pain increases.
• Elevation: Keep the injured area raised above chest level if possible.
Pharmacological Management: NSAIDs topical, NSAIDS Orally, Cox 2 inhibitors, and Local
anesthetic spray can numb the pain

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Rheumatoid Arthritis

Rheumatoid Arthritis
 Rheumatoid arthritis (RA) is an autoimmune disease
 RA may be characterised as a lymphocyte mediated inflammatory disease,
 The most common jjoints to be involved in rheumatoid arthritis are the synovial
y
joints and the most commonly affected synovial joints are the meta‐
carpophalangeal (MCP) joints of the hand, the proximal inter‐phalangeal (PIP) joints
of the hand, the wrist, the meta‐tarsophalangeal (MTP) joints of the toes, the knee
and the shoulder.
Definition:
• It is a Chronic Systemic Inflammatory Disorder that is characterised by
inflammation and deformity of the synovial joints, and inflammation of surrounding
tissues such as tendons, ligaments and muscles.
• While it is known this is a result of an abnormal immune response, the initial
triggers for RA and its specific pathophysiology are not completely understood.

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Clinical presentation of RA
Signs and symptoms: Key features of RA in early disease are the presence of
• synovitis, manifesting as soft tissue swelling or effusion of the affected joint,
• morning stiffness in the affected joints
• local soft tissue swelling with accompanying warmth and redness.
• Usually three or more joints are affected simultaneously.
• Patients often experience weakness, fatigability, anorexia, and weight loss.
• fever can occur as a direct result of the disease.
Articular effects:
• Generalised stiffness of the affected joints is frequent and greatest after
periods of inactivity. This typically manifests in the morning and generally lasts
more than One Hour.
• Initially, pain and swelling is the cause of immobility
• joint involvement is usually symmetrical.

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Symptoms of Rheumatoid Arthritis

 Joint symptoms usually involve three or more joints.

 The most commonly affected joints are the wrists, fingers, knees, feet, and ankles.

Joint symptoms include:

 Increased pain and stiffness in the morning and after inactivity

 Morning stiffness and pain that lasts more than 30 minutes

 Pain and stiffness symmetrically

 Red, swollen, warm joints

 Deformed, misshapen joints.

Other symptoms of rheumatoid arthritis includes:

 Intense fatigue, decreased  Bumps occurring under the skin
energy (rheumatoid nodules)
 Muscle
M l aches
h  Inflamed
I fl d bl
blood
d vessels
l
 Decreased appetite  Bleeding stomach ulcers
 Weight loss  Inflammation of the heart's sac
(Pericarditis)
 Fever and sweats
 Inflammation of the heart muscle
 Depression
(Myocarditis)
 Problems sleeping
 Lung problems
 Anemia
 Eye problems

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EXTRA‐ARTICULAR FEATURES:
 Musculoskeletal :  Pulmonary :
• Subcutaneous nodules at the • Pleural effusion(commonest).
site of pressures. • Diffuse fibrosing alveolitis.
• Bursitis. • Rheumatoid nodules in the
• Tenosynovitis. lungs.
• Muscle wasting.  Cardiac :
 Ocular : • Pericarditis , myocarditis.
• Sjogren”s Syndrome.  Lymphatic :
• Keratoconjuctivitis.
Keratoconjuctivitis • Lymphadenopathy
 Haematological : • Splenomegaly
• Anaemia.  Skin
• Thrombocytosis. • Vasculitis

Causes of Rheumatoid Arthritis

 RA is caused by a combination of  Risk Factors
genetic and environmental factors • Blood Transfusions: increased risk of
developing rheumatoid arthritis
that trigger an abnormal immune
• Age ; can develop at any age, you're most
response.
p likely to develop between the ages of 25 and
45.
Possible causes: • Gender ; Women are to 3 times more likely
• Genetic factors to develop rheumatoid arthritis than men.
• Defects in the immune system can • Genetic Factors in your family with this
cause condition or with other autoimmune
• Environmental factors‐Certain infectious disorders.
agents such as some viruses or bacteria
agents, • Ethnic
t c Background:
ac g ou d White.
te
• Other factors‐Some evidence suggests • Weight: People who are obese may have an
that hormonal factors may promote RA increased risk of developing rheumatoid
arthritis.
development in combination with
• Coffee and Cigarettes may be a risk factor
genetic factors and environmental for the development of rheumatoid arthritis.
exposure.

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Biochemical Markers

Biochemical markers: The common inflammatory markers that may be used are:
 Erythrocyte sedimentation rate (ESR)
CC‐reactive
reactive protein (CRP)
 Rheumatoid factor (RhF)
 Anti‐cyclic citrullinated peptide (Anti‐CCP): is Type of Autoantibody
 Anti‐nuclear antibodies (ANA).
Important Note:
• Anti‐CCP antibodies are a newer marker for RA. Theyy are as sensitive for RA
as RhF, but have greater specificity for the disease. Anti‐CCP is a useful early
indicator for RA. Its presence is a strong predictor of progression to erosive
disease; high levels of anti‐CCP predict a more aggressive course. The
combination of anti‐CCP with RhF tests is better able to diagnose RA in its
early stages.

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Guideline for Clinical Diagnosis

Diagnose Rheumatoid Arthritis

If you have 4 of the 7 symptoms listed below for more than 6 weeks you
are considered to have rheumatoid arthritis:
 Morning stiffness that lasts over an hour
 Arthritis in at least three joints
 Arthritis of the joints of the hand
 Arthritis on both sides of the body
 A positive blood test for rheumatoid factor (RF)
 Presence of lumps under the skin, called rheumatoid nodules
 X‐rays ‐ show signs of rheumatoid arthritis affecting the joints.

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Management
 General management can be Medicines used to manage:
broadly classified into three Analgesics, Corticosteroids and DMARDs,
main areas: including biological DMARDs. ( Cytokines
 Pain management with Blockers, Immunosuppressant,
analgesics Antireumatic )
 Disease modification with Non Pharmacological Management
DMARDs or biological DMARDs  Education
(including bridging therapy and  Diet
flare control with  Exercise
corticosteroids)  Physiotherapy
 Aggressive management of co‐  Footcare
morbidities such as  Occupational therapy
cardiovascular risk factors. Surgical Management

Management Approach
Old Approach: ‘pyramid approach’.
• Prior to the 1990s, the old standard for the management of RA was known
as the ‘pyramid approach’. This approach erroneously assumed RA was a
slowly progressing,
progressing benign disease that is not life‐threatening.
life‐threatening Initial
therapy comprised a basic program of rest, exercise and education in
addition to non‐steroidal anti‐inflammatory drug (NSAID) therapy. As the
disease progressed and radiographic deterioration was evident, or trials of
several NSAIDs proved to be ineffective, disease‐modifying anti‐rheumatic
drug (DMARD) therapy was considered using the least toxic agents first,
ascending up the ‘pyramid’
pyramid to the peak and to the more toxic DMARDs.
DMARDs
• This approach did not make an impact on the functional, clinical or
radiographic progression of the disease, as effective DMARD therapy was
usually initiated late in the course of the disease, and consequently, long‐
term outcomes remained poor.

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Management Approach
New Approach‐ Saw Tooth Model:
A more aggressive approach known as the ‘saw‐tooth’ model was
implemented where one or multiple DMARDs were initiated early at
diagnosis and were maintained throughout the disease course.
course
deployment of analgesics and NSAID as adjunctive rather than "first
line" therapy.
 A ‘step‐up’ therapy approach may see a second or even a third DMARD
added to the treatment regimen which commonly consists of
methotrexate with either sulfasalazine, hydroxychloroquine or both.
Corticosteroids may be co‐prescribed as required to control short‐term
flares or as bridging therapy.
Combination therapy has been shown to reduce the progression of
erosive changes and increased the remission rate
oach
Why New Appro
W

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Treatment
 Antirheumatic and/or immunosuppressant agents
• Combinations of antirheumatics and immunosuppressants are commonly
used in an attempt to improve efficacy as often a single agent cannot control
the disease completely.
 Mild disease: Sulfasalazine or hydroxychloroquine are usually chosen first
because they are less toxic than other antirheumatic agents. Sulfasalazine is
more effective and acts sooner than hydroxychloroquine.
 Moderate
Moderate‐to‐severe
to severe disease: Low dose methotrexate is the treatment of
choice; it appears to be less toxic than other immunosuppressants, IM gold
and penicillamine. Leflunomide is used for active disease when other
antirheumatics and/or immunosuppressants (including methotrexate) are
inappropriate or ineffective.

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Biological (Cytokine blockers):

 Cytokine blockers: Inflammatory cytokines, such as interleukin‐1 (IL‐1) and TNF‐
alpha are involved in the pathogenesis of RA. They are also important in the
immune defense against tumors and infection.
 TNF‐alpha inhibitors (Etanercept, Infliximab, Adalimumab)—have a rapid onset of
action compared to older antirheumatic agents (can be within days). Used when
antirheumatic agents are inadequate. Progression of joint damage is further
slowed when they are used with methotrexate.
 TNF‐alpha inhibitors increase susceptibility to serious infections as well as they
also increase the risk of malignancy.
 IL‐1 inhibitor (anakinra)—like TNF‐alpha inhibitors, anakinra is effective in RA
refractory to treatment with antirheumatics, although it has a slower onset of
effect.

Co‐morbidity Associated with RA

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Practice Points ‐Before starting treatment

 Cardio vascular risk: Patients with rheumatoid arthritis (RA) are at increased
risk of death due to cardiovascular disease compared to the general
population. Look for and treat cardiovascular risk factors and discourage
smoking.
smoking
 Treatment that suppresses immune function consider: Presence of active
or latent infection, eg hepatitis, or tuberculosis. Immunization requirements
(especially for live vaccines) and History of malignant disease.
 Ensure that all patients with RA receive pneumococcal and annual influenza
vaccinations
i i
 There is some evidence that, compared to placebo, several months of daily
supplements of omega‐3 fatty acids or gamma‐linolenic acid reduce
severity of symptoms;

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METHOTREXATE

• A dihydrofolate
reductase
inhibitor (DHFR inhibitor)
is a molecule that inhibits
the function of
dih d f l t reductase,
dihydrofolate d t
and is a type of antifolate.
Since folate is needed by
rapidly dividing cells to
make thymine, this effect
may be used to
therapeutic advantage
advantage.

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Key points methotrexate

• Concomitant use of MTX and trimethoprim-sulfamethoxazole

can result in life-threatening myelosuppression, mucositis, and
nephrotoxicity.
nephrotoxicity

• Both folate and folinic acid reduce methotrexate toxicity and

the discontinuation rate, and decrease methotrexate-induced
hyperhomocysteinemia. Folate is less expensive, more secure and
easier to handle than folinic acid.
acid

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Cytokine Blockers

Immunosuppressants

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Antirheumatics

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