NURS 1650: Lecture #5 (Inflammation Medications)

Histamine is released by what two cells?

Mast cells and basophils

What are the two major effects of histamine when released?

1) Vasodilation

2) Increased permeability

What does histamine act through?

H1 receptors

What happens when H1 receptors are activated

1) Increased alertness

2) Itching and pain

3) Mucus secretion

What is histamine associated with? What can massive releases of histamine cause?

Histamine is associated with allergic reactions and it can lead to bronchoconstriction, hypotension, and anaphylaxis

What type of receptor is H1

GPCR

What is the mechanism of action of antihistamines?

Selectively antagonize H1 receptors

What is the main difference between first generation and second generation antihistamines? Why?

First gen antihistamines tend to be more sedating as they cross the BBB easier

What is our primary antihistamine medication?

Diphenhydramine (Benadryl)

What class is diphenhydramine and its mechanism of action

H1 blocker/antihistamine and its mechanism of action is an H1 receptor antagonist

What are the adverse effects of diphenhydramine

Sedation, anticholinergic effects, paradoxical CNS excitation

When is diphenhydramine contraindicated during pregnancy/lactation?

Not contraindicated during pregnancy itself, but contraindicated in neonates and premature infants and breastfeeding

What are some drug interactions for diphenhydramine? What is the recommendation for older adults

CNS depressants, other anticholinergics and avoid/minimize in older adults

How does diphenhydramine half-life change with age?

The older someone is the longer half-life diphenhydramine has

What are the anticholinergic effects

1) A lot of things get dry

2) Drowsiness/sedation

3) Dizziness

4) Dry mouth, mucus, membranes, and eyes

5) Hypotension

6) Palpitations

7) Urinary retention

8) Constipation

9) Blurry vision

10) Confusion

What is the first, most critical drug to be used for anaphylaxis and how should it be administered and what does it do?

Epinephrine (IM) and it is a vasoconstrictor and bronchodilator?

When would/would not an antihistamine help in an allergic reaction?

Antihistamines can be given for hives and itching but will NOT relieve bronchospasm, hypotension or shock.

What should one do if they inject epinephrine into their finger? Why?

They should go to the ER as it can cause ischemia

What do NSAIDs do?

1) Block COX-1 or COX-2

2) CAUSE RENAL IMPAIRMENT (hypertension or edema)

3) Increase risk of bleeding (if COX-1 is inhibited)

4) Increase GI bleeding tendencies, even if they selectively inhibit COX-2

6) All except aspirin increase risk of MI and stroke

7) All except low-dose aspirin can cause oligohydramnios so AVOID as much as possible between 20-30 weeks

How do NSAIDs generally act by?

Inhibiting cycooxygenase (COX)

What is the general difference between immunosuppressants and immunomodulators

IS drugs have a broad effect and tamp down the immune response and IM drugs target a specific cytokine or signaling pathway, IS also has a HIGHER risk of infection and cancer (but IM still has this risk just lesser)

What are the roles of COX throughout the body

1) At site of local injury, catalyzes production of PGE2 and

PGD2 which promotes inflammation, sensitizes to pain

2) In stomach, promotes PGE2 and PGI2, which have a protective role and keep gastric mucosa healthy

3) In platelets, promotes synthesis of TXA2, which stimulates platelet aggregation

4) In blood vessels, promotes synthesis of PGI2 (prostacyclin) in healthy endothelial cells, which causes vasodilation and prevents platelet aggregation

5) In kidneys, promotes PGE2 and PGI2, which promote vasodilation and renal blood flow

6) In brain, mediates fever and perception of pain

7) In uterus, promotes contractions.

Where is COX-1 found? COX-2?

COX-1 is found in practically all tissues and COX-2 is found mainly at sites of tissue injury, produces in response to cytokines

What are some functions of COX-1?

1) Protecting gastric mucosa

2) Supporting renal function

3) Promoting platelet aggregation via TXA2

What are the largely harmful effects that occur when you inhibit COX-1

1) Gastric ulceration

2) Bleeding

3) Renal impairment (both COXs')

What are the beneficial effects that occur when you inhibit COX-1

Protection against myocardial infarction, and stroke by reducing clotting

What are the functions of COX-2?

1) Mediates inflammation

2) Sensitizes receptors to painful stimuli

3) Promotes vasodilation via PGI2

4) Can contribute to colon cancer

5) Supports renal function

What are the largely beneficial effects that occur when you inhibit COX-1

1) Suppression of inflammation

2) Alleviation of pain

3) Reduction of fever

4) Protection against colorectal cancer

What are the harmful effects that occur when you inhibit COX-1

1) Renal impairment

2) Promotes MI and stroke (suppresses vasodilation and production of PGI2 and not suppressing platelet aggregation

All NSAIDs should be avoided in what populations?

1) CKD

2) Uncontrolled hypertension

3) Active peptic ulcer disease

4) Other bleeding tendencies

5) Severe liver disease (if cirrhosis)

6) contraindicated at 30+ weeks gestation

What class is aspirin?

NSAID (More COX 1 > COX 2)

What is the mechanism of aspirin?

Irreversibly inhibits COX and effects last until new molecules are synthesized

How does aspirin irreversibly inhibit COX

By attaching an acetyl group to COX enzyme and inhibiting platelet aggregation by preventing the production and release of TXA2

What are the adverse effects of aspirin?

1) Bleeding (including GI)

2) Renal dysfunction

3) Tinnitus

4) Reye syndrome (aspirin is contraindicated <18)

5) Hypersensitivity reactions

What is the rule regarding aspiring during pregnancy? When can it be used?

 Avoid in pregnancy esp at 20+ wks, contraindicated at 30+ wks; however, a low-dose may be prescribed to prevent preeclampsia

What are the drug interactions with aspirin?

1) Anticoagulants and antiplatelet drugs

2) Glucocorticoids (gastric ulcer)

3) Alcohol (gastric ulcer)

4) Other NSAIDs

When should one discontinue aspirin

7-10 days before surgery

What is salivate? What is it responsible for?

Aspirin's active metabolite that is responsible for general anti-inflammatory effects, anti-fever, and pain-relief

What are some reasons a low dose of aspiring might be used?

1) Prevent preclampsia during pregnancy

2) Second MI and stroke

What is the drug class of ibuprofen?

NSAID (COX-1 and COX-2 equally)

What is the mechanism of ibuprofen?

Inhibits COX 50/50

What are the adverse effects of ibuprofen?

Bleeding, tinnitus, renal dysfunction, increased risk of MI/stroke

What durg interactions does ibuprofen have?

Aspirin, glucocorticoids, other NSAIDs, anticoagulant, and antiplatelet

When should one discontinue ibuprofen?

3 days before surgery

When is ibuprofen contraindicated for pregnancy?

30+ weeks

Is COX-2 present on platelets?

NO!!!

What class is Celecoxib?

NSAID

What is the mechanism of Celecoxib

Selectively inhibits COX-2

What are the adverse effects of Celecoxib

Renal impairment & risk of MI/stroke

What should you have caution with for Celecoxib

a sulfonamide allergy

When is Celecoxib contraindicated for pregnancy?

Past 30 wks gestation

What interactions does Celecoxib have

anticoagulation/bleeding drugs and other COX inhibitors

What are the two subclasses of corticosteroids and what is the primary thing of each?

Mineralocorticoids (aldosterone) and glucocorticoids (cortisol)

How do corticosteroids exert their effect?

Bind to steroid receptors in the cytoplasm and then the receptor-steroid complex migrates to the cell nucleus, here it has gene transcription effects (NOT rapid)

What are corticosteoroids? What are they made of? Where? What regulates their synthesis?

They are steroids made of cholesterol in adrenal cortex regulated by the HPA axis

What are the very broad physiological effects of glucocorticoids?

1) Metabolic effects

2) Cardiovascular and hematologic: Maintains blood pressure,

decreases most immune cells w/exception of neutrophils,

increases RBCs.

3) Respiratory: Promotes maturation of neonate's lungs.

4) CNS: affects mood and CNS excitability

5) Response to stress: Critical for this function! Deficiency can

cause circulatory collapse and death in severe stress.

6) Decreases prostaglandin synthesis. Overall

anti-inflammatory, decreased immune response.

How do glucocorticoids inhibit prostaglandin synthesis?

Inhibits phospholipase that form ACA from phospholipids

What are glucocorticoid drugs mimetics of?

Cortisol

What are glucocorticoids most potent effects?

Anti-inflammatory and immunosuppressant effects

What class is prednisone?

Glucocorticoid

What is the mechanism of prednisone?

 Inhibits pro-inflammatory mediatory synthesis via gene transcription mechanism

Is prednisone a prodrug? If so how is it excreted?

Prednisone is a prodrug converted via CYP3A4 to active metabolite then renal excretion

What is the onset/duration of prednisone?

Hours/days, it is not rapid as it is done via gene transcription

What are the interactions with prednisone?

NSAIDs, diabetes medications (inc blood glucose), and grapefruit juice

What are the short/medium term effects of prednisone?

 Increased appetite, hyperglycemia, insomnia, delayed wound healing, GI ulcers/bleeding, blood clots, infection

What are the medium/long-term effects of prednisone?

Osteoporosis, iatrogenic Cushing syndrome, adrenal suppression

What is required for extended use of prednisone?

Tapering

What are the S/S of Iatrogenic Cushing Syndrome?

1) Hyperglycemia

2) Osteoporosis

3) Muscle weakness

4) Inc. risk of infection

5) Fluid, electrolyte disturbances

6) Cutaneous striations

7) Rounded face, fat pads on back of the neck, enlarged abdomen

What can adrenal suppression be caused by?

Long-term glucocorticoud use w/ abrupt cessation

What does adrenal suppression result from?

Results from neg feedback caused by glucocorticoids as suppression of CRH and ACTH occurs and adrenal glands will atrophy, stop synthesizing corticoids due to the amount of glucocorticoids

What could severe stress or trauma lead to in a patient with adrenal suppression?

Hypotension, circulatory collapse, and death

True or false: It may take up to 1 month for adrenals to recover after tapering and stopping meds and supplemental glucocorticoids will be needed in times of stress

FALSE: It will take 1 year

What are some general roles for glucocorticoud dosage

1) Start low and go slow (highy individualized)

2) Smallest effective amount for long-term use: extremely important principle

3) Gradual weaning: also extremely important

What is the most important patient teaching point for glucocorticoids?

THEY MUST BE TAPERED OR YOU WILL DIE

What is a DMARD and what does it do?

It is a Disease Modifying Antirheumatic Drug that modifies he underlying disease process, rather than simply treating the resulting inflammation; however, it may suppress immune function

How fast does it act compared to NSAIDs? How toxic is it compared to NSAIDs?

It has a slower action and may potentially be more toxic than NSAIDs

What class is metrotrexate?

Non-biologic DMARD

What is the indication for methotrexate?

rheumatoid arthritis

Is methotrextate a prodrug? Why?

It is a prodrug as intracellularly it has many glutamates added to it and then those forms are the actually active drug

What is the mexhanism of methotrexate?

Not fully understood

How often is dosing for methtrexate?

ONCE WEEKLY (patient teaching)

What is the onset for methotrexate?

3-6 weeks (PATIENT TEACHING)

When is methotrexate contraindicated? Why?

It is contraindicated in severe liver disease as its mode of elimination is hepatic

What are some adverse effects of methotrexate

Hepatic fibrosis, bone marrow suppression, GI ulceration

What is required every 8-12 weeks with methotrexate?

CBC, platelet count, LFTs

What is recommended for adverse effects for methotrexate? Why?

A folic acid supplement to minimize hepatic, GI and hematological adverse effects

What is the recommendation for methotrexate regarding pregnancy and lactation

It is CONTRAINDICATED in pregnancy as it is tetratogenic and causes fetal death and congenital abnormalities

What interactions does methotrexate have?

Other immunosuppressants and immunomodulators (EXCEPT infliximab)

What is a monoclocal antibody?

Antibodies that are identical because they were produced by clones of a single parent cell and they are very expensive

What antagonist is a biological DMARD?

A TNF-a antagonist?

Why would one want to target and block TNF-a?

1) Pro-inflammatory cytokine released by macrophages 

2) Found in high concentrations in synovial fluid of patients w/ RA

3) Stimulates osteoclast activity

What is the class of infliximab

Biologic DMARD; immunomodulator

What is the mechanism of infliximab?

TNF-a antagonist (Binds and inhibits receptor-bound TNF-α, and inhibits binding of soluble TNF-α with its receptors, reducing inflammation and altering immune response.)

What routes can infliximab be administered?

IV ONLY!

What are some adverse effects of infliximab?

1) Risk of severe infection

2) Risk of lymphoma and other malignancies

3) Risk of activation of latent TB or new TB infection

4) Formation of antibodies to the drug

5) Infusion reaction, ranging from mild to anaphylaxis.

What should you do prior to starting infliximab

Test of latent TB

What should you do when you take infliximab? Why?

You should take it with concomitant methotrexate to improve efficacy

What interactions does infliximab have?

1) Immunosuppressant

2) Immunomodulators

3) Corticostreroids

4) Vaccines