Unknown terms.

❖ A sprain is an overstretched, torn, or twisted ligament. A ligament is a tough band

of fibrous tissue that connects bones to other bones or cartilage.
❖ 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.
Describe the inflammation cascade and the role of the chemical mediators.

Extra Information
1. Neutrophils are highly mobile phagocytic specialists that engulf and destroy
unwanted materials(bacteria).
2. Eosinophils secrete chemicals that destroy parasitic worms and are involved in
allergic reactions.
3. Basophils release histamine and heparin and also are involved in allergic
reactions.
4. Monocytes are transformed into macrophages, which are large, tissue-bound
phagocytic specialists.
5. Lymphocytes are of two types.
a. B lymphocytes (B cells) are transformed into plasma cells, which secrete
antibodies that indirectly lead to the destruction of foreign material (antibody-
mediated immunity).
b. T lymphocytes (T cells) directly destroy virus-invaded cells and mutant cells by
releasing chemicals that punch lethal holes in the victim cells (cell-mediated
immunity)
Inflammatory chemical release
❖ The inflammatory process begins with a chemical ‘alarm’ – a flood of
inflammatory chemicals released into the extracellular fluid.
❖ Inflammatory chemicals are released by injured or stressed tissue cells, and
immune cells. Clot=fight=repair.
Role of the inflammatory chemicals
Mast cells
➢ Release the potent inflammatory chemical histamine.
Histamine
➢ Source: Mast cells and basophils. Released in response to mechanical injury,
presence of certain microorganisms and chemicals released by neutrophils.
➢ Promotes vasodilation of local arterioles. Increases permeability of local
capillaries, promoting formation of exudate (fluid that seeps out of the BV into
inflammation area?).
Macrophages
➢ Have special membrane receptors that allow them to recognize invaders and
sound a chemical alarm. The receptors are called Toll-like receptors.
Kinin (bradykinin and others)
➢ Same as for histamine.
➢ Also induce chemotaxis of leukocytes and prompt neutrophils to release
lysosomal enzymes, thereby enhancing generation of more kinins.
➢ Induce pain.
Prostaglandins
➢ Same as for histamine.
➢ Also induce neutrophil chemotaxis.
➢ Induce pain.
They sensitize sensory nerve endings to nociceptive stimuli and thereby amplify the
generation of pain impulses. They also promote tissue inflammation by stimulating
inflammatory cell chemotaxis, causing vasodilation, and increasing capillary
permeability and edema.
Complement
➢ A group of bloodborne proteins that, when activated, lyse microorganisms,
enhance phagocytosis by opsonization, and intensify inflammatory and other
immune responses.
Cytokines
➢ They are a lot do not even know if it is necessary.

Inflammatory Steps
Phagocyte mobilisation

Steps:
1) Leukocytosis.
Injured cells release chemicals called leukocytosis-inducing factors. In response,
neutrophils enter blood from red bone marrow and within a few hours, the number of
neutrophils in blood increases four- to fivefold. This leukocytosis, the increase in
white blood cells (WBCs), is characteristic of inflammation.
2) Margination
➢ Inflamed endothelial cells sprout cell adhesion molecules (CAMs) that signal “this
is the place.” As neutrophils encounter these CAMs, they slow and roll along the
surface, eventually achieving an initial foothold. When activated by inflammatory
chemicals, CAMs on neutrophils bind tightly to endothelial cells.
➢ Margination refers to this phenomenon of phagocytes clinging to the inner walls
(margins) of the capillaries and postcapillary venules.
3) Diapedesis.
Continued chemical signalling prompts the neutrophils to flatten and squeeze
between the endothelial cells of the capillary walls—a process called diapedesis.
The movement is mediated by chemokines.
4) Chemotaxis
➢ Inflammatory chemicals act as homing devices, or more precisely chemotactic
agents. Neutrophils and other WBCs migrate up the gradient of chemotactic
agents to the site of injury (positive chemotaxis).
➢ Within an hour after the inflammatory response has begun, neutrophils have
collected at the site and are devouring any foreign material present.

Overview of Inflammation
The inflammatory response is triggered whenever body tissues are injured by
physical trauma (a blow), intense heat, irritating chemicals, or infection by viruses,
fungi, or bacteria.
The inflammatory response has several beneficial effects.
❖ Disposes of cell debris and pathogens.
❖ Alerts the adaptive immune system.
❖ Prevents the spread of damaging agents to nearby tissues.
❖ Sets the stage for repair.
The four cardinal signs of short-term, or acute, inflammation are.
❖ Redness
❖ Heat
❖ Swelling
❖ Pain
❖ Some authorities consider the fifth to be impaired function.
For instance, movement in an inflamed joint may be hampered temporarily, forcing it
to rest, which aids healing.

Discuss the pharmacological treatment of sport injuries.

First things first
❖ cyclooxygenase (COX), an enzyme that catalyses the first step in the synthesis of
prostaglandins from arachidonic acid and other precursor fatty acid.
❖ Prostaglandins play an important role in the development of pain, inflammation,
and fever.
COX-1
❖ It is a constitutive or housekeeping enzyme that is found in relatively constant
levels in various tissues.
❖ Participates in the synthesis of prostaglandins that have a cytoprotective effect on
the gastrointestinal (GI) tract.
❖ It also catalyses the formation of thromboxane A2 in platelets, leading to platelet
aggregation and haemostasis.
COX-2
❖ COX-2 is an inducible enzyme.
❖ It is detected upon stimulation in the monocyte, macrophage, neutrophil, and
endothelial cells.
❖ COX2-release is triggered by cytokines, mitogens, and endotoxins in the
inflammatory cells, and is responsible for prostaglandin production in inflamed
tissue.

NSAIDs
❖ NSAIDs have a strong anti-inflammatory, antipyretic, and analgesic effect. While
Acetaminophen has a strong antipyretic and analgesic effect but weak anti-
inflammatory effect.
❖ All NSAIDs relieve fever by inhibiting prostaglandin synthesis in the
hypothalamus, but these drugs are not capable of reducing body temperature
below normal.
Examples
Brenner
Non – selective COX inhibitors Selective COX 2 inhibitors
Aspirin Celecoxib
Ibuprofen Rofecoxib (withdrawn)
Acetaminophen Valdecoxib (withdrawn)

Indomethacin
Ketoprofen
Ketorolac
Naproxen

Indications
❖ Lower doses of NSAIDs are usually sufficient to treat mild to moderate pain and
counteract fever, whereas higher doses are generally needed to relieve
inflammation associated with arthritic disorders and injuries.
❖ NSAIDs are widely used in the treatment of postoperative pain, either alone or in
combination with an opioid.
Contraindications
❖ NSAIDs during the second half of pregnancy is generally not recommended,
however, because of potential adverse effects on the foetus.
GPPR
❖ These effects result from prostaglandin inhibition and include GI bleeding, platelet
inhibition, renal dysfunction, and premature closure of the ductus arteriosus.
Interactions
LMAP
❖ Inhibit the renal excretion of lithium and can increase lithium serum levels and
toxicity.
❖ Reduce the clearance of methotrexate and aminoglycoside drugs.
❖ Interfere to varying degrees with the antihypertensive effect of diuretics, β-
adrenoceptor antagonists, angiotensin inhibitors, and other antihypertensive
drugs.
❖ When given with potassium-sparing diuretics, NSAIDs can cause potassium
retention and lead to hyperkalaemia.
Side effects
GPR
❖ Their long-term use is associated with several adverse effects, including GI
bleeding, peptic ulcers, and renal and hepatic dysfunction.
Mechanism of action
❖ NSAIDs decrease COX activity primarily by competitive inhibition; however,
aspirin forms a covalent, irreversible inhibition of COX. The net effect of NSAID
administration is a decrease in the production of prostaglandins and other
autacoids.

Nonselective cyclooxygenase inhibitors

Aspirin (analgesic, antipyretic, and anti-inflammatory effect)
Indications
❖ In adults, the salicylates can be used in the management of pain, fever, and
inflammation, as well as in the prophylaxis of myocardial infarction, stroke, and
other thromboembolic disorders.
❖ In children, the use of salicylates should be avoided, because the risk of Reye
syndrome appears to be increased in virus-infected children who are treated
with these drugs.
Notes
❖ The oral dosage of aspirin that is needed to inhibit platelet aggregation is
somewhat lower than the oral dosage needed to obtain analgesic and antipyretic
 effects, and it is much lower than the oral dosage needed to relieve inflammation
caused by arthritic and other inflammatory disorders.

Pharmacokinetics
CAHAM
❖ Concurrent administration with antacids may slow its absorption rate, it does not
significantly reduce its bioavailability.
❖ Aspirin is rapidly hydrolysed to salicylic acid (salicylate) by plasma esterase, and
this accounts for its short plasma half-life (about 15 minutes).
❖ Aspirin itself, however, is responsible for irreversible inhibition of platelet COX
and platelet aggregation.
❖ Most of the salicylic acid formed from aspirin and other salicylate drugs is
conjugated with glycine to form salicyluric acid.
Moa
❖ Mentioned above.
❖ The analgesic, antipyretic, and anti-inflammatory effect of aspirin and other
salicylates result from nonspecific inhibition of COX in peripheral tissues and the
CNS.
❖ Aspirin irreversibly acetylates platelet COX and has a longer-lasting effect on
thromboxane synthesis than do other salicylates.
Moa of GI effect (Lippincott)
❖ Normally, prostacyclin (PGI2) inhibits gastric acid secretion, whereas PGE2 and
PGF2 alpha stimulate synthesis of protective mucus in both stomach and small
intestines.
❖ In the presence of aspirin. These prostanoids are not formed, resulting in
increased gastric secretions and diminished mucus protection. This may cause
epigastric distress, ulceration, and haemorrhage.
Side effects
❖ The Reye syndrome in children.
❖ Therapeutic doses of aspirin can cause gastric irritation and contribute to GI
bleeding and peptic ulcers.
❖ Moderately high therapeutic doses can cause tinnitus.
❖ Hyperventilation is caused by direct and indirect stimulation of the respiratory
centre in the medulla, and it often leads to increased exhalation of carbon dioxide
and respiratory alkalosis.
❖ Higher plasma salicylate concentrations can cause fever, dehydration, and
severe metabolic acidosis. If not treated promptly, these events can culminate in
shock, coma, organ system failure, and death.
Aspirin overdose
Patho
❖ The rate of metabolism and the rate of excretion of salicylate are proportional to
the drug’s plasma concentration (first-order elimination). When an excessive
dose is taken, the elimination pathways become saturated, giving rise to zero-
order elimination.
❖ For this reason, larger doses can rapidly elevate plasma salicylate concentrations
to toxic levels, especially in the elderly, who are at greatest risk of aspirin toxicity.
Presentation
CTV MR HM
❖ vomiting, tinnitus, confusion, hyperthermia, respiratory alkalosis, metabolic
acidosis, and multiple organ failure (coma).
The treatment of salicylate poisoning may include the following:
(1) induction of vomiting and gastric lavage to remove unabsorbed drug.
(2) intravenous administration of sodium bicarbonate to counteract metabolic
acidosis, increase the ionization of salicylate in the kidneys, and thereby enhance
the rate of excretion of salicylate
(3) administration of fluids, electrolytes, and other supportive care.
❖ Treatment is with activated charcoal and alkaline diuresis or haemodialysis.
(MSD manual)

Acetaminophen
Indications
❖ Mild pain and fever.
❖ Unlike aspirin use, acetaminophen use has not been associated with Reye
syndrome, so acetaminophen can be safely given to children with fever caused
by viral illnesses.
❖ Low doses of acetaminophen can be safely used for analgesia and antipyresis
during pregnancy.
❖ (Lippincott) Suitable substitute for the analgesic and antipyretic effects of aspirin
for patients with gastric complaints and in those whom prolongation of bleeding
time would be a disadvantage or who do not require the anti-inflammatory action
of aspirin.
Pharmacokinetics
❖ A small amount of acetaminophen is converted by cytochrome P450 to a
potentially hepatotoxic quinone intermediate.
❖ When a therapeutic dose of acetaminophen is taken, the quinone intermediate is
rapidly inactivated by conjugation with glutathione.
❖ Toxic doses of acetaminophen, however, deplete hepatic glutathione, cause
accumulation of the quinone intermediate, and lead to hepatic necrosis.
❖ To prevent liver damage, patients who ingest an overdose and are determined to
be at risk for hepatotoxicity can be given acetylcysteine, a sulfhydryl compound
that conjugates the quinone intermediate and renders it harmless.
Moa
❖ it inhibits prostaglandin synthesis and act Central on hypothalamic heat,
regulating Centre to produce peripheral vasodilation which increases blood flow.
❖ inhibits Cox-3 which has a role in mediating pain and fever. (Confirmed in
Brenner)
❖ (Lippincott) Acts by inhibiting prostaglandin synthesis in the CNS. This explains
their antipyretic analgesic properties. They have less effect on the COX in
peripheral tissues, which accounts for their weak anti-inflammatory effects. Does
not affect the platelet function or increase blood clotting time.
Treatment of Acetaminophen Overdose.
❖ Because hepatotoxicity gradually progresses over several days after an
acetaminophen overdose, prompt treatment with acetylcysteine can prevent or
significantly reduce hepatotoxicity.
❖ The metabolic pathway of detoxification that becomes increasingly important in
paracetamol toxicity is…Cytochrome P450.
Moa of treatment
two mechanisms. First, N-acetylcysteine acts as a precursor for the synthesis of
glutathione and, therefore, maintains cellular glutathione at a level sufficient to
inactivate NAPQI. This is thought to be the main mechanism by which N-
acetylcysteine acts in the early stages of paracetamol toxicity. (Not confirmed in
Brenner).

Ibuprofen, Ketoprofen, and Naproxen

❖ By reversibly and nonselectively inhibiting COX isozymes, these drugs exert
analgesic, antipyretic, and anti-inflammatory effects.
❖ Ibuprofen and related drugs produce dose-dependent gastric irritation, nausea,
dyspepsia, and bleeding.
❖ Among the serious effects that have been reported are hepatic toxicity and renal
toxicity.

Selective Cyclooxygenase-2 Inhibitors

❖ The selective COX-2 inhibitors are a new group of drugs that provide potent anti-
inflammatory activity without causing significant GI toxicity.
Indications
❖ is a potent analgesic, antipyretic, and anti-inflammatory agent. This drug does not
inhibit platelet aggregation, because platelets contain only the COX-1 isozyme.
Pharmacokinetics
❖ The drug is rapidly absorbed from the gut, is metabolized by cytochrome P450
isozyme CYP2C9, and is excreted in the faeces and urine. The half-life is about
11 hours.
❖ Because celecoxib is metabolized by CYP2C9, drugs such as fluconazole,
Fluvastatin, and zafirlukast may inhibit its metabolism and increase its serum
concentration.
Side effects
❖ Besides the risk of cardiovascular events, celecoxib appears to cause a low
incidence of adverse reactions, the most common of which are diarrhoea,
dyspepsia, and abdominal pain.
❖ (Ignore, this my notes) Cardiovascular events: inhibit Cox-2 in endothelium,
which is responsible for anti-thrombotic and vasodilatory effect, thus, the favours
pro-thrombotic (blood clots) and vasoconstriction brought by Cox-1.
Centrally acting muscle relaxant
❖ Examples: Baclofen, cyclobenzaprine, tizanidine
❖ Baclofen is a GABAB (gamma-aminobutyric acid-B) receptor agonist, and these
G protein–coupled receptors (GPCRs), when activated, reduce motor neuron
excitability.
❖ Baclofen is available in oral, injectable, and intrathecal infusion formulations.
❖ Patient should not take baclofen with alcohol because they have additive CNS
depressant effects.
❖ Patients should be warned that drowsiness and ataxia may occur.

Discuss the non-pharmacological management of sports injuries e.g.,

cold/heat packs.
Heat therapy
Heat therapy is the application of heat to the body resulting in increased tissue
temperature. Superficial modes of heat therapy include hot water bottles, heat pads,
electric heat pads, heat wraps, heated stones, soft heated packs filled with grain,
poultices, hot towels, hot baths, sauna, paraffin, steam, and infrared heat lamps. An
alternative mode of heat therapy is deep-heat therapy, which involves conversion of
another form of energy to heat (e.g., shortwave diathermy, microwave diathermy,
ultrasound).
Cold therapy
Cold therapy, also known as cryotherapy, is the application of any substance or
physical medium to the body that removes heat, decreasing the temperature of the
contact area and adjacent tissues. Cold therapy is used in the management of acute
injury/trauma, chronic pain, muscle spasm, DOMS, inflammation, and oedema.
Acute ankle sprains are a prototypic injury for which cold therapy is used, generally
within the context of rest, ice, compression, and elevation (RICE) therapy. Many
devices are available for application of cold therapy, including bags of crushed ice,
commercially available ice and gel packs, ice massage, cold compression units, and
cold whirlpool. The efficacy of each mode of cold therapy for lowering the
temperature within deep and surface tissues may vary.
For example, wetted ice is more effective than cubed ice or crushed ice in lowering
skin surface temperature (17.0 ºC, 14.1 ºC, and 15.0 ºC, respectively) and
intramuscular temperatures (6.0 ºC, 4.8 ºC, and 4.3 ºC, respectively) over a 20-
minute application period.
Methods of application of cryotherapy
Ice packs: Ice in this method is crushed, shaved, or chipped and put in a plastic bag
applied directly to the injured area. Several authors agree that some form of
protection be used to prevent frostbite. Ice pack with temperature at 0 o C (32 o F)
can be applied directly to the skin to maximize the effectiveness of the cold
application.
Cold-gel packs: A gelatinous substance enclosed in a vinyl cover containing water,
and antifreeze (such as salt).
Chemical cold packs: These consist of two chemical substances, one in a small
vinyl bag within a larger bag. Squeezing the smaller bag until it ruptures and spills its
contents into the larger causes a chemical reaction producing the cold. They are
ideally utilized for emergency use.
Ice immersion: A container is filled with ice and water, and the body part is
immersed in it. Immersion is recommended for extremities.
Ice massage: A cube of ice is rubbed over and around the underlying muscle fibre
until numb.
Ice should be used for a period of 5 minutes if being used as first aid. Prolong period
of application could cause blood vessels dilation resulting into increase in
haemorrhage.
At chronic stage of injury, ice may be used for 10 minutes. An individual experiences
cold burning sensation-aches-numbness during the application of ice.
When an exercise or manual therapy is to be used for a patient, ice is usually applied
to serve as local anaesthesia to reduce pain.

Mechanism of Cold and Heat therapy

Cold Therapy
❖ Cold therapy has multiple physiological effects on injured tissue.
❖ Decreasing temperatures of skin and muscle reduces blood flow to the cooled
tissues by activating a sympathetic vasoconstrictive reflex.
❖ Cold induced decreases in blood flow reduce oedema and slow the delivery of
inflammatory mediators (e.g., leukocytes), reducing inflammation of the affected
area.
❖ Decreasing tissue temperature also reduces the metabolic demand of hypoxic
tissues, potentially preventing secondary hypoxic damage in injured tissue.
(Facilitator’s version) Cold limits the pain by decreasing impulse transmission from
pain receptors and tendon receptors to the muscles. It reduces tissue destruction by
decreasing cellular metabolism, vasodilation which happens when there is heat,
occurs after removal of the cold substance and circulation increases once more.
Heat promotes circulation which eases pain, promotes relaxation of spasms and
facilities movement, and is used more in chronic conditions.
Heat Therapy
❖ Includes pain relief. Increases in blood flow and metabolism, and increased
elasticity of connective tissue.
❖ Increasing tissue temperature stimulates vasodilation and increases tissue blood
flow, which is thought to promote healing by increasing the supply of nutrients
and oxygen to the site of injury.
❖ The rate of local tissue metabolism is also increased by warming, which may
further promote healing.
Non-pharmacologic therapy consisting of rest, ice, compression, and elevation
(RICE) along with non-prescription oral and/or topical analgesics can be used during
the first 1 to 3 days after an injury. RICE therapy promotes healing and helps reduce
swelling and inflammation associated with muscle and joint injuries. Heat therapy is
an alternative for non-inflammatory pain and may help with stiffness.
Describe the physical interventions used in the treatment of broken bones,
sports injuries.
Forms of Mobilization
Cast - Immobilise broken bone.
Splint: Immobilise dislocated joint
Sling: Supports arm after fracture
Braces: Hold body parts in correct position
Collars: Neck injury
Fractures may be classified by
Position of the bone ends after fracture: In nondisplaced fractures, the bone ends
retain their normal position. In displaced fractures, the bone ends are out of normal
alignment.
Completeness of the break: If the bone is broken through, the fracture is a complete
fracture. If not, it is an incomplete fracture.
Whether the bone ends penetrate the skin: If so, the fracture is an open (compound)
fracture. If not, it is a closed (simple) fracture.
Repair and Treatment
Treatment involves reduction, the realignment of the broken bone ends.
In closed (external) reduction, the physician’s hands coax the bone ends into
position. In open (internal) reduction, the bone ends are secured together surgically
with pins or wires.
After the broken bone is reduced, it is immobilized either by a cast or traction to allow
healing. A simple fracture of small or medium-sized bones in young adults heals in
six to eight weeks, but it takes much longer for large, weight-bearing bones and for
bones of elderly people (because of their poorer circulation).
Extra info
Orthotic devices
Orthotic devices are needed during early onset of sport injuries to provide rest and
support for the damaged structures, especially joints. The devices provide support,
or correct deformities and improve the movement of joints, spine, or limbs. They also
provide stability of joints by limiting abnormal or excessive joint mobility. Ankle foot
orthosis is commonly used to protect the ankle joints at acute stage.
Therapeutic exercise
All these exercises have been found to bring about relief of pain with or without any
other therapeutic analgesic modalities.
Massage
Massage is the systematic, mechanical stimulation of the soft tissues of the body by
means of rhythmically applied pressure and stretching using hands. It’s performed to
produce mechanical or reflexive effects such as improved range of motion, to
increase circulation and lymphatic drainage, to induce general relaxation and reduce
pain.
Discuss the role of the pharmacist in the management or outcomes of
musculoskeletal injuries.
What must Pharmacist do...
❖ Explain to patients who are eligible for self-treatment the expected benefits of
medication, appropriate dose and administration schedule, application directions,
potential adverse reactions, potential interactions, and self-monitoring techniques
for assessing response.
❖ Counsel patients to prevent injuries by warming up and stretching muscles before
physical activity, ensuring proper hydration, and wearing appropriate footwear.
❖ Must ask appropriate questions to identify the types of pain for which patients are
seeking treatment, to achieve a better understanding of their pain complaints,
and to identify risks that preclude self-treatment.

Appendix
Inflammation Flow Chart

Vasodilation and increased vascular permeability.

❖ Vasodilation accounts for two of the cardinal signs of inflammation.
❖ The redness and heat of the inflamed region are both due to local hyperaemia
(congestion with blood) that occurs when arterioles dilate. Inflammatory
chemicals also increase the permeability of local capillaries.
❖ Consequently, exudate (fluid containing clotting factors and antibodies causes
the local swelling that presses on adjacent nerve endings, contributing to a
sensation of pain. Pain also results from the release of bacterial toxins and the
sensitizing effects of released prostaglandins and kinins.