All NSAIDs, incl acetimanophen, inhibit prostaglandin synthesis via inhibition of the prostaglandin synthetase family of enzymes, specifically inhibiting cycloxygenase (COX), to one degree or another.

• All NSAIDs, except acetaminophen are anit-inflammatory

as analgesic- HA, muscle ache, joint pain,

anti-pyretic,

anti-inflammatory

treat inflamm. cond. e.g arthritis,

ASA inhibits platelet aggregation

Inhibits prostaglandin synthesis by inhibiting cyclooxygenase.  Prostaglandins normally cause hyperalgesia: make pain receptors more sensitive to other pain mediators (i.e. serotonin, substance P, bradykining)

Increase response to painful stimili, so reduce PGs will decrease response.

Inhibiting prostaglandin synthesis with both peripheral and central actions.

• PGs in hypothalamus increase body temperature via an increase in cAMP.

• ASA has a central effect to inhibit prostaglandins in hypothalamus thus decr. high body temperature by increased vasodilation and sweating.

• ASA has no effect on normal temperature.

• what role does prostaglindin play in the anti-inflammatory effect of ASA?

Relates to peripheral inhibition of cyclo-oxygenase enzyme.

Cell damage tiggers inflammation which releases PGs and others

PGs may sensitize receptors to other inflammatory mediators: 5-HT, bradykining, histamine.

• Inhibit PG synthesis effective to relieve inflamation.
• note that phagocytes migrate into area and cause lysozomal enzymes to be released with subsequent lysozomal enzymes and tissue damage that increases  inflammation. But prostaglanding inhibitors do not block this.

ASA is most effective because irreversible acetylation of the cyclooxygenase enzyme, thus  inhibits synthesis. PGs (thromboxane A2) are involved in stimulating platelet aggregation.

proven useful in decreasing risk in thrombolytic diseases

• salicylates and all NSAIDs cause GIT disturbances because harm stomach's ability to protect itself.

• Ulceration, bleeding, anemia & perforation may result.

• A prostaglandin may be protective in stomach- stimulates mucous and bicarb secretion, inhibit H+ secretion and cause vasodilation.

ASA hydrolyzes to salicylic acid (still active, 1/2 life 6-30hrs) but once deacytelated can no longer irreversibly bind to cyclooxygenase. 

ASA ( 1/2 life 30mins).

so increased dose of ASA, means more salicylic acid (metabolized in liver mainly), means slower elimination -> increased concen. and increased toxicities

GIT: upset, nausea, vomiting, ulceration,  bleeding (anemia)

• Serious overdose (esp children: note methyl salicylate/winter green oil used in baking and candy making can be toxic to kids.)
• Hypersensitivity: anaphlylaxis (cross reactive to other NSAIDs), 25% are sensitive to aspirin with no immunologic reaction. Small percetn of pts are actually allergic to aspiring: sensitized lymphocytes.
• Intoxication: Low dose = tinnitus, dizziness, HA, confusion
• Intoxication: higger doses "salicylism"= nausea, vomitting, diarrhea, hypernea, acid/base problems, hemorrhage Tx: supportive.
• Reye's syndrome: oif kids <15 get aspirin after flu/chicken pox/ viral dsease causes nerve damage and liver problems. yes give kids acetaminophen.
• (aspirin increases uric acid levels in  body, inhibits the transport mechanisms (similar to thiazides and loop diruetics)

inhibits COX enzyme but does NOT work well in periphery.

[ other non-opiate analgesics inhibit COX 1 and COX2 enzyme ]

good analgesia

fever reduction,

NO anti-inflammatory

No platelet inhibtion

NO increase in uric acid

No risk of Reye's syndrome (can use in chilren)

Problem in pts with GOUT

less water retention.

OVERDODE mainly:

APAP metabolized to toxic oxygen intermediate by p450 in the liver and the kidney; if not neuralized by gluthatione then:

hepatic necrosis

Renal necrosis

Hypoglycemia

Coma

Death

Fatal dose = 25g (all the gluthatione used up)

Acetaminophen Toxicities:

Early Symptoms of  Overdose w/in 24 hrs

Muld nausea, vomiting, anorexia, pain

Can treat early overdose with N-ACETYL CYSTEINE (antidote in first 10 hours to increase conjuction of toxic metabolite.

• Alcohol depletes glutatione; potentiates effects.

Acetaminophen Toxicities:

2 to 6 days after Overdose w/in 24 hrs

acetaminophen metabolized to highly reactive intermediates then: hepatic damage, liver failure,

bleeding,

jaundice, death

analgesic, antipyretics, anti-inflammatory.

treate Rheumatoid arthritis,

chronic inflammatory diseases..

All INHIBIT PROSTAGLANDIN SYNTHESIS (INHIBIT COX enzyme)

leukotriene, hetes and other inflammatory mediators made INSTEAD of prostaglandins.

pt can be cross senstive to NSAIDs (inhibit COX enzymes) and aspirin.

10=25% of pts that have one of the following will have aspirin sensitivity: 1. Asthma

2. Nasal Polyps,

3. Chronic uticaria.

• only 1% of poupulation have aspirin sensitivity or "aspirin tolerance"

• Fluid accummulation due to effects on kidney fct.
• increased risk of gastric problems

Sudden blur of vision,

diffuse corneal stroma deposits,

EOM abnormalities,

color vision disturbances,

toxic amblyopia.

Indomethacin (Indocin)

Sulindac (clinoril)

Ibuprofen (motrin) (Advil)

Naproxen (Naprosyn, Anaprox) (Aleve)

Diclofenac (Voltaren)

last resort NSAID drug

10-40X apirin potenscy, high tocicities

Common Toxicitiy:  GIT & HA, same ocular toxicities.

Rx only

has an active metabolite: more effective,

• less GI tox than indomethacin,
• Good for eldery px

Rx Only

More potent than aspirin,

cause less GI toxicities,

OVER THE COUNTER.

longer duration of action.

subjectively better

OTC

NSAID that decreases free arachidonic acid that results when this NSAID inhibits COX in tissues. Arachidonic acid is taken up into the cell membrane.

Used for topical ocular pain due to laser treatments

Selective COX-2 inhibtor= used as antI-inflamm, analgesic and antipyretic.

Little action on GI tract and platelet aggregation (COX-1 mediated effect).

good for pt sensitive to GI effects of other NSAIDS

kidney problems,

contraidicated in pt with aspirin sensitivity and sulfa allergies

Contraindications for ALL NSAIDs

Known Allergic Hypersensitivy,

NSAID induced asthma or utricarial

Asprin triad: asthma, nasal polyps, urticaria.

Pregnancy: (need prostaglanding production for foramen ovale in infant heart to close before birth.

Coronary Artery bypass grafting surgery- cos increased bleeding

physiologic role in glucose, aminoacid  & protein metabolism and use,

Made by beta cels of pancreatic islets of langerlans: make pro-insulin

Activate the uptake of glucose from blood plasma so we can use the energy from the glucose in our cells.

Insulin receptors at cell membrane, linked to tyrosine kinase, once  activated leads to phosphorylation of tyrosine and activation of GTP binding proteins.

cascade to stimulate transcription factor to increase glucose metabolism proteins, increase of glucose uptake molecules, increase of molecules that take glucose and convert it to glycogen

Absolute lack of insulin, insulin dependent DM:

 no beta cell production,

• Treat w/ insulin to survive

Onset: in childhood, unrelated to diet and exercise.

• Apparent lack of insulin OR decreased insulin senstivity,
• Have insulin but receptors are less sensitive to insulin,

treat w/ oral agents (or insulin)

Assoc: obesity and diet high in sugar, reduce or eliminate need for drugs with diet and exercise.

1. Human insulin (recombinant DNA dervided, injection only)
2. regular insulin (crystalline zinc or lispro) (humilin)
3. Isophane insulin suspenstion (NPH) (Humulin N or Novolin N)
4. Insulin glargine (lanthus)
5. Combo can allow better control

5-7hrs

short acting like before meals; effects last throughout the day.

18-24 hrs

Intermediate acting

36 hrs

long acting

oral agents may be sufficient enough if insulin is available ie. functional beta cells exist.

Problem: normally insulin stimulated by glucose and food ingestion so that glucose can be uptaked into tissues,  but with type 2 DM, decreased insulin sensitivity adn asynchronous release of insulin, not released appropriately so longer duration of high glucose levels.

Goal: control glucose levels that damage vasculature leading to diabetic retinopathy, kidney damage & neuropathy

sulfonylureas & biguanides,

glucosidase inhibtiors,

glitazones*

{More insulin released and more sensitive peripheral tissues}

stimulate the release of insulin from functional beta, by binding to an ATP-dependent K+ channel leading to decrease in K⁺ efflux, increase in Ca²⁺ influx, which gives greater insulin release upon stimulation by glucose.

• increased sensitivity of peripheral tissues to the actions of insulin

tolbumatide

glipizide,

glyburide,

glimepiride.

Hypoglycemia (profound)

nausea

rash

blood disorders,

jaundice,

muscle weakness and ataxia,

dizziness and mental confusion.

E.g Reaglinide (prandin)

Nateglinide (stralix)

• Same receptor sites and mechanism as sulfonyl ureas:

MOA: enter beta secretory cells,

bind to ATP-dep K+ channel,

decrease in K+ efflux & increase Ca2+ influx, increase in insulin secretion,

• increased sensitivity in peripheral tissues to insulin (includes glucose uptakes)

Hypoglycemia (less likely than sulfas)

Nausea &diarrhea

Dyspesia

NO cross allerigic hypersensitivity because these are not sulfa drugs.

short duration therefore immediately before meal

do NOT stumulate insulin release form beta cells,

much less likey to produce hypoglycemia.

MOA of metformin (glucophage),

belongs to biguanides; antihyperglycemics

• decrease glucose output from liver (gluconeogenesis) which lowers glucose plasma levels.
• Increae insulin sensitivity on muscle & fat (due to lower glucose levels), glucose uptake into cells increased.

reduce glucose output

increase sensitivity on muscle and fat

common: diarrhea, nausea, other GIT symptoms,

Rare: significant increase in lactice acidosis especially renal insufficient pt. can kill!,

megaloblastic anemia (rare)

MOA of Glucosidase inhibitors;

Antihyperglycemics

Inhibit GIT enzymes that break down complex carbs (complex carbs must be broken down or absorbed)

eg. Acarbose(Procose)

Miglitol (Glyset)

cause GIT disturbacnes. diarrhea,

pain, gas.

Acarbose (Glucobay) (precose),

Miglitol (Glyset)

anti hyperglycemic agents that increase sensitivity of insulin receptors.

• act as agonists to PPAR (peroxisome proliferator-activated receptor) to increase  gene transcription for "glucose uptake and utilization" proteins.

Increase in glut-4 (transporter for glucose), lipoprotein lipase, fatty acid transporter protein etc

Rosiglitazones (Avandia)

Pioglitazones (Actos)

• weight gain & fluid retention
• significat: hepatoxicity & congestive heart failure,

MOA of AntiHyperglycemic Agent

Liraglutide (Victoza)

Exenatide (byetta)

Liraglutide (Victoza)

Exenatide (Byetta)

MOA: a GLP-1 receptor agonist 

MOA: mimics physiologic hormone glucagon -like peptide (GLP-1) to:

• inhibit glucagon secretion,
• increase insulin secretion.
• delays gastric emptying.
• Close to normal physiologic response to a meal ingestion.

Toxicities of AntiHyperglycemic Agent

Liraglutide (Victoza)

Common: NVD

More serious & less frequent: pancreatitis

Possible thyroid carcinomaa

Common: NVD

More serious,less frequent: pancreatitis

anaphylactic reactions

MOA of Antihyperglycemics

Sitagliptin (Januvia)

Saxagliptin (onglyza)

Linagliptin (Tradjenta) which are DPP-4 inhibitors

MOA: These dipeptidyl-peptidase 4 (DPP-4) inhibitors blocks the endogenous breakdown of  GLP-1. thus increasing the duration of incretin action to stimulate insulin release and inhibit glucagon release.

(Incretin includes GLP-1 and others) 

-orally effective!!!

Toxities of Antihyperglycemia

Sitagliptin (Januvia)

Saxagliptin (onglyza)

Linagliptin (Tradjenta)

which of the following DM 2 antihyperlipidemic drugs are orally effective? pick 3

a) Sitagliptin (januvia)

b) Saxagliptin (Onglyza)

c)Linagliptin (Tradjenta)

d)Liraglutide,

e) Exenatide

Sitagliptin (januvia)

Saxagliptin (Onglyza)

Linagliptin (Tradjenta)

Toxicities of Antihyperglycemics: Sitagliptin (januvia)

Saxagliptin (Onglyza)

Linagliptin (Tradjenta)

Common: upper respirator infxn (like a cold)

Nasopharyngytis

Headache

More serious: pancreatitis, hypersenstitivity reactions

MOA of Inhibitors of type 2 sodium-glucose transporter (SGLT2) system.

MOA: inhibit SGLT2 in kidney.

Normal= glucose in filtrate reabsorbed.

Abnormal DM: too much glucose, not all rebasorbed so Polyuria.

Inhibitors of SGLT2 system prevent reabsoprtion of glucoes from the kidney, thus allowing bllood glucose levels to be low.

These are good for any pt. to lower blood glucose.