Analgesics I: Peripherally Acting Analgesics

Describe Peripherally Acting Analgesics (general)

non-opioid, non-sedating analgesics ==> act on PNS (so not sedating like analgesics that act on CNS)

ex: - NSAID

-Acetaminophen

-corticosteroids

Describe Centrally Acting Analgesics (general)

analgesics that act on the central nervous system to cause low & slow vitals

ex: -opioids (narcotics)

NSAID Classification

-Non-selective COX Inhibitors (traditional NSAIDs)

>Naproxen

> Salicylic Acid (aspirin)

>ibuprofen & indomethacin 1

>ketorolac

>diclofenac

-Selective COX 2 Inhibitors --> celecoxib (celebrex)

-Analgesic-Antipyretic, w/ poor anti-inflammatory action --> acetaminophen/tylenol/paracetamol

Non-selective COX Inhibitors

Traditional NSAIDs = NSIKD

-Naproxen

-salicyclic acid

-ibuprofen & indomethacin 1

-ketorolac

-diclofenac

What is the general mechanism of action of NSAIDs?

inhibition of COX-1 & COX-2 to block the synthesis of prostaglandins (cause pain, fever, & inflammation)

-analgesic

-anti-inflammatory

-antipyretic

-antiplatelet --> inhibit TXA2 (thromboxane) synthesis thereby inhibiting platelet aggregation

Why is bleeding a risk of NSAID use?

NSAIDs (esp Aspirin) is pro-bleeding because it inhibits COX-1 more than it inhibits COX-2 (COX-2 pathway is antithrombic & COX-1 promote platelet aggregation ==> inhibiting COX-1 more means that COX-2 antithrom dominates)

Describe prostaglandin synthesis via COX-1 pathway.

cell membrane phospholipids converted to arachidonic acid via phospholipase A2--> COX1 metabolizes arachidonic acid --> prostaglandins & thromboxane produced in stomach, intestine, kidney, & platelets --> mucosal protection, renal blood flow & haemostasis

*creates housekeeping prostaglandins

**Arachidonic acid can also go down the COX2 & Lipoxygenase Pathway

Describe prostaglandin synthesis via COX-2 pathway

cell membrane phospholipids converted to arachidonic acid via phospholipase A2--> COX2 metabolizes arachidonic acid --> produces prostaglandins at inflammatory sites, macrophages, synovocytes--> induce inflammation, pain, & fever

*Arachidonic acid can also go down the COX1 & Lipoxygenase Pathway

Describe leukotriene synthesis pathway

cell membrane phospholipids converted to arachidonic acid via phospholipase A2--> lipoxygenase metabolizes arachidonic acid to leukotrienes at inflammatory sites --> induce inflammation

*Arachidonic acid can also go down the COX1 & COX2 pathway

Why are NSAIDs contraindicated in asthma patients?

NSAIDS block COX1 & COX2 thereby forcing the lipoxygenase pathway to dominate and metabolize arachidonic acid into leukrotrienes that are inflammatory & bronchioconstricters

*NSAIDs aren't a good choice for asthma pt

How do prostaglandins promote pain?

prostaglandins sensitize nerve endings to painful actions of bradykinin & histamine ==> make nerve endings more sensitive to pain signals

Why do NSAIDS reduce prostaglandin synthesis to decrease pain?

to block the sensitization of nerve endings = blocking the painful actions of bradykinin & histamine

How does an infection/inflammation cause fever?

bacteria release toxins = exogenous pyrogens --> recognized by toll-like receptors & MHC on leukocytes --> release inflammatory cytokines IL-1B, TNF-A, IL-6 = endogenous pyrogens --> travel to the thermoregulatory center of the hypothalamus --> upregulate phospholipase A2 --> produce arachidonic acid --> converted into PGE2 via COX-2 --> acts on thremoreg center to increase peripheral vasodilation --> body temp increases from 37C to 39C

*NSAIDS are antipyretic b/c they block COX-2 from synthesizing PGE2 in thermoreg center of hympothalamus

exogenous pyrogens

micorbial toxins that cause fever due to promotion of inflammatory cytokines that induce pro-fever PGE2 prostaglandin synthesis in the thermoregulatory center of hypothalamus

endogenous pyrogens

host inflammatory cytokines released in response to bacterial pyrogens (toxins) that induce pro-fever PGE2 prostaglandin synthesis in the thermoregulatory center of hypothalamus

-IL-1B

-TNF-A

-IL-6

thromboxane A2

prostaglandin synthesized by COX-1 in platelets that promotes platelet aggregation

*COX-1 is prothrombotic; blocking COX-1 is anti-thrombotic

prostacyclin (PGI2)

prostaglandin synthesized by COX-2 in vascular epithelium that blocks platelet aggregation

*COX-2 is antithrombotic, blocking COX-2 is prothrombotic

Why does aspirin have the greatest effect on platelet aggregation of all the NSAIDs?

-aspirin irreversibly binds to COX-1 w/in platelets --> COX-1 doesn't work for the duration of the platelet's life

-other NSAIDs reversibly inhibit--> have less effect on platelet aggregration

How does aspirin act as a blood thinner?

aspirin has an antithrombotic effect b/c it inhibits COX-1 a little more than it inhibits COX-2 --> more COX-2 pathway--> more PGI2 that blocks platelet formation--> increased bleeding

Why are peptic ulcers & GI bleeding a common side effect of NSAIDs?

NSAIDs inhibit COX-1 (& COX-2)==> COX-1 in GI mucosa produces PGE2 that increases mucus secretion, bicarbonate secretion, & mucosal blood flow for gastric protection

*inhibition of COX-1 reduces gastric protection

Why are kidney disorders & hypertension a common side effect of NSAIDs?

NSAIDs inhibit COX-1 & COX-2 ==> COX-1 & 2 in the kidney produces PGE2 & PGI2 that increases afferent arteriolar vasodilation (increased GFR) & Na/water excretion

*inhibition of COX -1&2 = Na & water retention, hypertension, hemodynamic acute kidney injury

What are the cardiovascular effects of NSAIDs?

NSAIDs inhibit COX-1 & COX-2 (but COX-1 a lil more ==> COX-1 produces TXA2 that promotes platelet aggregation & vasoconstriction; COX-2 produces PGI2 that promotes vasodilation & inhibit platelet aggregation

*Disturbs the balance bwtn COX-1 & COX-2 causing bleeding

What does it mean that Aspirin irreversibly inhibits platelet COX-1?

COX-1 will remain inhibited for the duration of the platelets life ==> functional COX-1 will arise after stem cells in bone marrow will need to differentiate into new platelets & replace the inhibited ones

Which drugs can potentially interact with NSAIDs & result in additive effects on upper GI bleeding?

-SSRIs --> prozac, paxil, celexa, zoloft

-anticoagulants --> warfarin, pradaxa, eliquis

-antiplatelet drugs --> plavix

-alcohol

Prozac can potentially interact with NSAIDs and cause ________________.

additive effects on upper GI bleeding

Paxil can potentially interact with NSAIDs and cause ________________________.

additive effects on upper GI bleeding

Celexa can potentially interact with NSAIDs and cause _____________________.

additive effects on upper GI bleeding

Zoloft can potentially interact with NSAIDs and cause ____________________.

additive effects on upper GI bleeding

The anticoagulant Warfarin can potentially interact with NSAIDs and cause __________________.

additive effects on upper GI bleeding

The anticoagulant Pradaxa can potentially interact with NSAIDs and cause ___________________.

additive effects on upper GI bleeding

The anticoagulant Eliquis can potentially interact with NSAIDs and cause ___________________________.

additive effects on upper GI bleeding

Antiplatelet drugs like Plavix can potentially interact with NSAIDs and cause _____________________.

additive effects on upper GI bleeding

Alcohol can potentially interact with NSAIDs and cause ___________________________.

additive effects on upper GI bleeding

What are the potential drug-drug interactions bwtn low dose aspirin taken for cardioprotection & NSAIDs?

NSAIDs antagonize the cardioprotective effect of low-dose aspirin thru competition for the NSAID binding site of COX-1 in platelet.

*patient should be advised to take the aspirin first & then other NSAIDs 2 hrs later (to avoid competition)

What are the potential drug-drug interactions bwtn insulin/hypoglycemic agents & aspirin?

Aspirin displaces insulin/hypoglycemic agents from plasma protein binding sites --> increases active insulin/hypoglycemic agents in plasma levels --> promotes hypoglycemia

ACE-inhibitors may interact with NSAIDs and _____________________.

diminish the antihypertensive effect of ACE inhibitors

*ACE inhibitors are used to Tx hypertension & NSAIDs decrease their effectiveness

How does NSAIDs effect furosemide?

NSAIDs reduce the natriuretic effect of diuretics

How does NSAIDs effect thiazides?

NSAIDs reduce the natriuretic (excess sodium removal) effect of diuretics (urine removal)

Why are their contraindications for managing pain with NSAIDs in patients with bipolar affective disorder?

Some bipolar patients are treated with lithium--> NSAIDs increase serum lithium levels & reduce lithium clearance --> acute lithium intoxication

*symptoms = tremor, increased reflexes, trouble walking, kidney problems, & altered level on consciousness

Potential Contraindications for NSAID Use

-ulcers

-bleeding disorders, taking anticoagulants, or taking antiplatelets

-inflammatory bowl disease (more flare ups when using NSAIDs)

-asthma

-increase risk of heart attack/stroke w/ selective COX-2 inhibitors

-pregnancy (esp last trimester)

-severe renal or liver disease

-elderly pts more susceptible to GI & renal effects

-aspirin intolerance, hypersenstivity, & allergies

-Chamomile, Ginseng, Gingko --> antiplatelets activity that's additive when taken w/ NSAIDs

What are the potential contraindications of NSAIDs and certain herbal medications?

certain herbal meds like chamomile, ginseng, & gingko have some antiplatelet activity that's additive with the effects of NSAIDs on platelets

What are the toxic effects of NSAIDs?

-GI bleeding

-tinnitus

-nausea & vomiting

-metabolic acidosis

-hyperventilation

-teratogenic effects

-liver toxicity

-allergy

-analgesic nephropathy

True or False: Aspirin has more toxic effects than the other NSAIDs

True ==> in addition to the toxic effects that all NSAIDs share, aspirin also can cause salicylism & exacerbation of Reye's Syndrome

-salicylism ==> pt develops a group of symptoms including tremor, tinnitus, metabolic/respiratory alkalosis immediately or after prolonged use (recommended pt stop taking aspirin immediately)

-exacerbation of Reye's Syndrome ==> hepatic toxicity & encephalopathy that leads to coma in children under 12 yrs old.

ceiling effect

where the analgesic effect on the body plateaus ==> at the point taking higher doses doesn't increase analgesic effect but it increases anti-inflammatory effect

Ibuprofen

-analgesic component has a ceiling effect (plateau of effectiveness at a certain pt)

-has lowest incidence of GI adverse effects of all nonselective NSAIDs

ex: Advil, Motrin

True or False: The analgesic effect of all NSAIDs have a ceiling effect

True

Naproxen Sodium

NSAID w/ similar efficacy to ibuprofen but w/ longer duration of action (up to 7 hrs of pain relief ==> more suitable for pts w/ chronic pain)

ex: Aleve

Ketorolac (Toradol)

strongest NSAID in terms of efficacy (was developed as NSAID equivalent to morphine)

-oral (limit dosing to 5 days) , intranasal, & IV forms

-indicated for short-term management of moderate to severe pain ( up to 5 days ) ==> b/c it's the most problematic of the NSAIDS in terms of GI ulceration

-avoid in pts w/ renal insufficiency

Celecoxib (Celebrex)

Selective COX-2 inhibitor NSAID

-created to spare COX-1 to reduce gastrointestinal toxicity

-common side effects = insomnia, abdominal pain, flatulence, headache, nausea, & diarrhea

-multiple contraindications

> reduces effectiveness of codiene

>use of fluconazole (antifungal) doubles celecoxib levels in blood --> CYP2D6 that metabolizes celecoxib

>ppl with allergy to NSAIDS or sulfonamides shouldn't take

>increase risk of heart attack & stroke --> blocking COX2 makes COX1 pro-clotting pathway dominate

Rofecoxib (Vioxx)

a selective COX-2 inhibitor NSAID that was withdrawn from the market in 2004 due to excessive increased risk of heart attacks & strokes with long term use

Valdecoxib (Bextra)

a selective COX-2 inhibitor NSAID that was withdrawn from the market in 2004 due to excessive increased risk of heart attacks & strokes with long term use

Meloxicam

"selective COX-2 inhibitor" that has some COX-1 inhibition

*released in South Africa

How does celecoxib effect codeine?

celecoxib inhibits CYP2D6 ==> codeine needs to be metabolized by CYP2D6 become effective

*celecoxib reduces the effectiveness of codeine by inhibiting CYP2D6

What are the contraindications of antifungal drug fluconazole & celecoxib?

fluconazole inhibits CYP2C9 ==> CYP2C9 metabolizes celecoxib to be marked for excretion

*inhibition of CYP2C9 doubles celecoxib levels in the blood = increased toxicity

Should patients who are allergic to sulfonamides use celecoxib?

not recommended these pts use selective COX-2 inhibitor like celecoxib b/c. they may experience an allergic reaction.

What are the pros of Acetaminophen use opposed to NSAIDs?

-pain relief equivalent to that of aspirin & ibuprofen for mild pain

-no GI upset --> ulcer pts can use

-No effects on bleeding--> ok in anti coagulated pts or patients w/ bleeding disorders

-doesn't increase blood pressure so it's safe for hypertensive patients

-no allergic reactions --> ok in aspirin sensitive patients

What are the cons of Acetaminophen use opposed to NSAIDs?

-most common drug taken in overdose

-as little as 12g can be fatal (therapeutic dose is 2.6gm/24hr)

-it's a hepatic & renal toxin = Centrolobular Necrosis

-more toxic if liver enzymes have reduce ability to conjugate toxin (ex: alcoholics, phenytoin, phenobarbitone)

-safety of tylenol depends on glutathione (GSH) & other thiol-containing substances required to detox its toxic metabolite (NAPQI)

Describe the metabolism of acetaminophen

acetaminophen is metabolized down 3 different pathways = Glucuronidation + Sulphation + CYP2E1

-Glucuronidation ==> major pathway that converts tylenol into a nontoxic compound for excretion

-Sulphation ==> major pathway that converts tylenol into a nontoxic compound for excretion

-CYP2E1 ==> normally less common pathway that converts tylenol into toxic metabolite NAPQI --> conjugated to gluthathione--> made into nontoxic compound for excretion ( if not , it will go cause liver, kidney, pancreas, & heart damage)

Factors that adversely affect acetaminophen metabolism

-upregulation/induction of CYP2E1 activity (the enzyme that coverts tylenol into toxic NAPQI that damages liver, kidneys, panceras, & heart) --> smoking, barbituates, rifampin, carbamazepine, phenytocin, alcohol

-decreased glutathione storage (due to malnutrition) --> GSH binds NAPQI to make it nontoxic

-frequent dosing intervals --> more opportunity to make NAPQI

-prolonged duration of excessive dosing --> more opportunity to make NAPQI

Describe how smoking affects acetaminophen metabolism.

upregulation/induction of CYP2E1 activity ==> the enzyme that coverts tylenol into toxic NAPQI that damages liver, kidneys, panceras, & heart

How does barbituates affect acetaminophen metabolism?

upregulation/induction of CYP2E1 activity (the enzyme that coverts tylenol into toxic NAPQI that damages liver, kidneys, panceras, & heart)

How does rifampin affect acetaminophen metabolism?

upregulation/induction of CYP2E1 activity (the enzyme that coverts tylenol into toxic NAPQI that damages liver, kidneys, panceras, & heart)

Describe how carbamazepine affects acetaminophen metabolism?

upregulation/induction of CYP2E1 activity (the enzyme that coverts tylenol into toxic NAPQI that damages liver, kidneys, panceras, & heart)

Describe how phenytoin affects acetaminophen metabolism?

upregulation/induction of CYP2E1 activity (the enzyme that coverts tylenol into toxic NAPQI that damages liver, kidneys, panceras, & heart)

How does alcohol affect acetaminophen metabolism?

upregulation/induction of CYP2E1 activity (the enzyme that coverts tylenol into toxic NAPQI that damages liver, kidneys, panceras, & heart)

How can being malnutrition affect acetaminophen metabolism?

decreased glutathione (GSH) storage due to malnutrition = increased liver, heart, pancreas, and kidney toxicity due to tylenol ==> CYP2E1 metabolizes tylenol to toxic NAPQI --> GSH binds it to make it nontoxic

*GSH shortage = increased tylenol toxicity