NEET MDS Lessons
Pharmacology
Distribution
Three major controlling factors:
Blood Flow to Tissues: rarely a limiting factor, except in cases of abscesses and tumors.
Exiting the Vascular System: Occurs at capillary beds.
- Typical Capillary Beds - drugs pass between cells
- The Blood-Brain Barrier- Tight junctions here, so drugs must pass through cells. Must then be lipid soluble, or have transport system.
- Placenta - Does not constitute an absolute barrier to passage of drugs. Lipid soluble, nonionized compounds readily pass.
- Protein Binding: Albumin is most important plasma protein in this respect. It always remains in the blood stream, so drugs that are highly protein bound are not free to leave the bloodstream. Restricts the distribution of drugs, and can be source of drug interactions.
Entering Cells: some drugs must enter cells to reach sites of action.
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