Nervous System - Drugs for Inflammation

What is acute inflammation?

Inflammation that typically lasts for 8-10 days, followed by repair and healing

Usually caused by minor physical injury, chemical damage, infection, or antigens

Usually self-limiting

What is chronic inflammation?

Inflammation that occurs when the body is not able to contain or neutralize the trigger of the initial inflammation.

Causes perpetual cycle of inflammation leading to cell damage leading to further inflammation

What is the general treatment strategy for acute inflammation?

Consider non-pharmacological methods first, use topical anti-inflammatories before considering systematic ones

What is the role of the mast cell in the inflammation response?

Releases chemical mediators, such as histamine, bradykinin, complement factors, leukotrienes, and prostaglandins.

Mast cells also activate nociceptors, resulting in pain, which is why inflammation and pain are linked

What is the role of thromboxane A2 in the arachidonic acid pathway?

Activated by COX-1 (protective), stimulates platelet aggregation

What is the role of lipoxygenase in the arachidonic acid pathway?

Converts arachidonic acids into leukotrienes, which are responsible for activation of the immune system and bronchoconstriction

Why can aspirin, a non-selective COX inhibitor, lead to anaphylaxis when given to a patient with asthma?

Aspirin inhibits both COX-1 and COX-2 enzymes, which results in arachidonic acids being converted into leukotrienes by lipoxygenase. Leukotrienes activate the immune system and cause bronchoconstriction, the latter of which is the cause of anaphylaxis.

What are the two primary anti-inflammatory drug classes?

1. NSAIDS - mild to moderate pain, inflammation, and fever

2. Glucocorticoids - severe or disabling inflammation

What is the cause of most of the adverse effects from NSAIDS?

Most NSAIDS are non-specific, meaning that prostaglandin synthesis from COX-1 and COX-2 enzymes are both inhibited

COX-1 enzyme prostaglandins are protective as they protect gastric mucosa by inhibiting gastric secretion, support kidney function, and promote platelet aggregation (Thromboxane A2)

Therefore, NSAIDS can lead to side effects, such as increased bleeding from platelet aggregation inhibition and peptic ulcer disease from increased gastric acid secretion

Why are selective COX-2 inhibitor NSAIDS not commonly prescribed?

Associated with many adverse effects, most notably asymptomatic hypertension, which increases risk for myocardial infarction and stroke.

It therefore cannot be prescribed to a patient with hx of myocardial infarction or stroke

How do enteric coated aspirin pills work?

Aspirin pills are enteric coated so that they are not absorbed in the stomach and are instead absorbed in the small intestine. This prevents the adverse effects of aspirin in the stomach, however, since the pill is acidic, it is slowly absorbed in the small intestine

How do stomach guard aspirin pills work?

A buffer is provided that contains ions to decrease gastric acidity of the stomach, preventing risk of peptic ulcers from forming, and results in the pill being slowly absorbed

What is systemic glucocorticoid therapy for management of inflammation? (Use, Mechanism of Action, Route of Administration, Dose, Adverse Effects)

Use

Used for short-term management of severe or disabling inflammation

Mechanism of Action

Blocks activity of phospholipase A2 which converts arachnoid esters into arachnoid acids, and COX-2 enzymes, which produces "bad" prostaglandins (pain, inflam)

Inhibits immune response by suppressing phagocytic activity, IL2, IL3, and PAF

Route of Administration

Preferred topical route -> Inhaled, Creams, or intranasal

Dose

Low dose, shortest duration for management of inflammation due to huge adverse effect profile

Adverse Effects

-Adrenal insuffficiency

-Hyperglycemia

-Mood changes

-Osteoporosis

-Immunosuppresion

What is the use of systemic glucocorticoid therapy for management of inflammation?

Used for short-term management of severe or disabling inflammation

What is the mechanism of action of systemic glucocorticoid therapy for management of inflammation?

Blocks activity of phospholipase A2 which converts arachnoid esters into arachnoid acids, and COX-2 enzymes, which produces "bad" prostaglandins (pain, inflam)

Inhibits immune response by suppressing phagocytic activity, IL2, IL3, and PAF

What is the preferred route of administration of systemic glucocorticoid therapy for management of inflammation?

Preferred topical route -> Inhaled, Creams, or intranasal, less adverse effects - avoid administration routes that have systemic effects

What is the preferred dosing regimen of systemic glucocorticoid therapy for management of inflammation?

Low dose, shortest duration for management of inflammation due to huge adverse effect profile

What are the two primary anti-pyretic drug classes?

1. NSAIDS

2. Acetaminophen (preferred in children)

What is the mechanism of action of acetaminophen as an anti-pyretic?

Enacts direct action on the hypothalamus and causes dilation of peripheral blood vessels, resulting in sweating and dissipation of heat

Why should aspirin never be prescribed for children?

Can result in Reye's syndrome in some children between the ages of 4-14 yr and with a previous Hx of a viral illness.

Use of aspirin in these patients can cause brain inflammation, fatty deposits in the liver, and death within days

What are antihistamines? (Use, Mechanism of action, Adverse Effects, Contraindications?

Use

Used to provide symptomatic treatment of allergic rhinitis -> including sneezing, and itchy eyes and throat

Mechanism of Action

Blocks action of histamine at the H1 receptor

Adverse Effects

Anticholinergic effects

-Dry mouth

-Headache

-Dizziness

-Urinary retention

-Thickening of bronchial secretions

-Nausea

-Vomiting

Prolonged QT interval for 2nd gen

Contraindications

-Liver and kidney dysfunction

-1st gen -> caution with pregnancy

-2nd gen -> 3rd trimester, dysrhythmias

^ can cross breast milk and placenta ^

What are 1st generation antihistamines and associated contraindications?

1st generation antihistamines produce a sedative effect and includes drugs such as diphenhydramine

Contraindications include

-Liver and kidney dysfunction

-Pregnancy caution

What are 2nd generation antihistamines and associated contraindications?

2nd generation antihistamines do not produce a sedative effect and includes drugs such as loratadine

Contraindications include

-Liver and kidney dysfunction

-Dysrhythmias - can cause prolonged QT interval

-3rd trimester of pregnancy

What is anaphylaxis?

Hyperimmune and hyperinflammatory response to an antigen, with the body responding within minutes and releasing massive amount of inflammatory mediators, resulting in

-itching, hives, tightness in throat and chest

-swelling of larynx

-rapid fall in bp, reflex tachycardia, and difficulty breathing -> bronchoconstriction

What is the treatment response for a patient with anaphylaxis?

Epinephrine IM injection - repeat if no response after 5 min

Hypotensive - Supplement oxygen + normal saline infusion

Inadequate response after 2-3 doses - IV epinephrine infusion

Continued upper airway obstruction - nebulized epinephrine

Persistent wheeze - beta2 adrenergic agonists

What is the treatment response for a patient with anaphylaxis and is hypotensive?

Provide epinephrine IM injection, supplemental oxygen, and normal saline infusion

What is the treatment response for a patient with anaphylaxis and an inadequate response to IM epinephrine after 2-3 doses?

Provide IV epinephrine infusion

What is the treatment response for a patient with anaphylaxis and continued upper airway obstruction?

Provide nebulized epinephrine

What is the treatment response for a patient with anaphylaxis and a persistent wheeze?

Provide IM epinephrine injection and beta2 adrenergic agonists such as salbutamol

What is the mechanism of action of epinephrine used during anaphylaxis?

Epinephrine is an adrenergic agonist

Binds to...

Alpha 1 receptor (bvs) - causes increased BP

Beta1 receptor (heart) - increased cardiac output

Beta 2 receptor (lungs) - bronchodilation