Indomethacin

commonly used to reduce fever, pain, stiffness, and swelling. It works by inhibiting the production of prostaglandins, molecules known to cause these symptoms.

Indications

ankylosing spondylitis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, Reiter's disease, Paget's disease of bone, Bartter's disease, pseudogout, dysmenorrhea (menstrual cramps), pericarditis, bursitis, tendonitis, fever, headaches, nephrogenic , diabetes insipidus (prostaglandin inhibits vasopressin's action in the kidney)

Indomethacin has also been used clinically to delay premature labor, reduce amniotic fluid in polyhydramnios, and to treat patent ductus arteriosus.

Mechanism of action

Indomethacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2, enzymes that participate in prostaglandin synthesis from arachidonic acid. Prostaglandins are hormone-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation.

Prostaglandins also cause uterine contractions in pregnant women. Indomethacin is an effective tocolytic agent, able to delay premature labor by reducing uterine contractions through inhibition of PG synthesis in the uterus and possibly through  calcium channel blockade.

Indomethacin easily crosses the placenta, and can reduce fetal urine production to treat polyhydramnios. It does so by reducing renal blood flow and increasing renal vascular resistance, possibly by enhancing the effects of vasopressin on the fetal kidneys.

Adverse effects

Since indomethacin inhibits both COX-1 and COX-2, it inhibits the production of prostaglandins in the  stomach and intestines which maintain the mucous lining of the

gastrointestinal tract. Indomethacin, therefore, like other nonselective COX inhibitors, can cause ulcers.

Many NSAIDs, but particularly indomethacin, cause lithium retention by reducing its excretion by the kidneys.

Indomethacin also reduces plasma renin activity and aldosterone levels, and increases

sodium and potassium retention. It also enhances the effects of vasopressin. Together these may lead to:

edema (swelling due to fluid retention)

hyperkalemia (high potassium levels)

hypernatremia (high sodium levels)

hypertension (high blood pressure)

Sulindac:  Is a pro‐drug closely related to Indomethacin. 

Converted to the active form of the drug. 

Indications and toxicity similar to  Indomethacin

Midazolam -Intravenous Anesthetics
 Midazolam is a benzodiazepine used for preoperative sedation, induction of anesthesia, or maintenance of anesthesia in short procedures.

Buspirone

1. Short half-life (2–4 hours).
2. Relieves anxiety.
3. Does not act as an anticonvulsant.
4. Is not a good muscle relaxant.
5. Minimum abuse potential.

Distal (Potassium Sparing) Diuretics

Agents:

spironolactone
triamterene

Mechanism of action

Inhibition of Na/K exchange at aldosterone dependent distal tubular site

Spironolactone - competes with aldosterone for regulatory site

Triamterene - decreases activity of pump directly
•    Either mechanism decreases potassium wasting
•    Either mechanism produces poor diuresis (when used alone)
o    relatively unimportant Na recovery site

Diurectic activity increased if:

•    sodium load (body) is high 
•    aldosterone concentrations are high 
•    sodium load (tubule) is high - secondary to diuresis

Other electrolytes unaffected

Toxicity

•    spironolactone may produce adrenal and sex hormone effects with LONG-TERM use
•    Both drugs may produce electrolyte imbalance
 

Ketoprofen

It acts by inhibiting the body's production of prostaglandin.

Pharmacokinetics

Pharmacokinetics is the way that the body deals with a drug - how that drug moves throughout the body, and how the body metabolizes and excretes it.  The factors and processes involved in pharmacokinetics must be considered when choosing the most effective dose, route and schedule for a drug's use.

The four processes involved in pharmacokinetics are:

Absorption:  The movement of a drug from its site of administration into the blood.

Several factors influence a drug's absorption:

• Rate of Dissolution:  the faster a drug dissolves the faster it can be absorbed, and the faster the effects will begin.
• Surface Area:  Larger surface area = faster absorption.
• Blood Flow:  Greater blood flow at the site of drug administration = faster absorption.
• Lipid Solubility:  High lipid solubility = faster absorption
• pH Partitioning:  A drug that will ionize in the blood and not at the site of administration will absorb more quickly.

Distribution:  The movement of drugs throughout the body.

Metabolism:  (Biotransformation) The enzymatic alteration of drug structure.

Excretion:  The removal of drugs from the body.

As a drug moves through the body, it must cross membranes.  Some important factors to consider here then are:

Body's cells are surrounded by a bilayer of phospholipids (cell membrane).

There are three ways that a substance can cross cell membranes:

• Passing through channels and pores: only very small molecules can cross cell membranes this way.

• Transport Systems:   Selective carriers that may or may not use ATP.

• Direct Penetration of the Cell Membrane: