NEET MDS Lessons
Pharmacology
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
Sympathomimetics
Beta-Adrenergic Agonists
Beta1-adrenergic agonists (dopamine, dobutamine, prenalterol, xamoterol) have been used to treat acute and chronic heart failure, but have limited usefulness in chronic CHF because of their arrhythmogenic effects, short duration of action, the development of tolerance, and necessity of parenteral administration
Dopamine (i.v.) is used in acute heart failure (cardiogenic shock) to increase blood pressure and increase cardiac output
- It has a short half-life (1 min)
- At high doses dopamine has potent peripheral vasoconstrictor effects (alpha-receptor stimulation), in addition to its inotropic effects
- Low dose dopamine has a renal artery dilating effect and may improve sodium and water excretion in patients refractory to loop diuretics
- When systolic pressure is greater than 90 mm Hg, nitroprusside can be added to reduce ventricular filling pressure and reduce afterload
- i.v. furosemide should also be administered to reduce edema
Levodopa and ibopamine, analogs of dopamine that can be administered orally, have been shown to improve symptoms in some patients, but can exhibit arrhythmogenic side-effects and tachyphylaxis
Dobutamine is a somewhat selective beta1-adrenergic agonist that lacks vasoconstrictor activity and causes minimal changes in heart rate
- It is frequently added to nitroprusside when blood pressure is adequate to increase cardiac output
- It is administered as an i.v. infusion to treat acute severe heart failure
- It has a short half-life (2.4 min) and is only used on a short-term basis, although long-term beneficial effects on cardiac function have been noted
- After 72 hours of therapy, tolerance can develop to dobutamine necessitating switch to other inotropic support (e.g. milrinone)
- Dobutamine can enhance AV conduction and worsen atrial tachycardia
Prenalterol and xamoterol are partial beta1-adrenergic agonists that may simultaneously stimulate beta1-receptors and block the receptors from stimulation by endogenous catecholamines, thereby protecting against beta1-receptor down-regulation
Anticonvulsants: include carbamazepine (use when lithium not tolerated; may not be as effective) .
valproic acid (use when lithium not tolerated; rapid onset)
Nalidixic acid:
Nalidixic acid is the basis for quinolone antibiotics. It acts bacteriostatically (that is, it inhibits growth and reproduction) or bactericidally (it kills them) on both Gram positive and Gram negative bacteria, depending on the concentration. It is especially used in treating urinary tract infections, caused for example by Escherichia coli, Proteus, Enterobacter and Klebsiella.
Fourth Generation:
These are extended spectrum antibiotics. They are resistant to beta lactamases.
Cefipime
Clarithromycin Used to treat pharyngitis, tonsillitis, acute maxillary
sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia (especially atypical pneumonias associated with Chlamydia pneumoniae or TWAR), skin and skin structure infections, and, in HIV and AIDS patients to prevent, and to treat, disseminated Mycobacterium avium complex or MAC.
Unlike erythromycin, clarithromycin is acid-stable and can therefore be taken orally without being protected from gastric acids. It is readily absorbed, and diffused into most tissues and phagocytes.
Clarithromycin has a fairly rapid first-pass hepatic metabolism, i.e it is metabolised by the liver. However, this metabolite, 14-hydroxy clarithromycin is almost twice as active as clarithromycin.
Contraindications Clarithromycin should be used with caution if the patient has liver or kidney disease, certain heart problems (e.g., QTc prolongation or bradycardia), or a mineral imbalance (e.g., low potassium or magnesium levels).
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
The actions of Angiotensin II include an increase in blood pressure and a stimulation of the secretion of aldosterone (a hormone from the adrenal cortex) that promotes sodium retention. By preventing the formation of angiotensin II, blood pressure will be reduced. This is the strategy for development of inhibitors. Useful inhibitors of the renin-angiotensin system are the Angiotensin Converting Enzyme Inhibitors
First line treatment for: Hypertension , Congestive heart failure [CHF]
ACE-Inhibitor’s MOA (Angiotensin Converting Enzyme Inhibitors)
Renin-Angiotensin Aldosterone System:
. Renin & Angiotensin = vasoconstrictor
. constricts blood vessels & increases BP
. increases SVR or afterload
. ACE Inhibitors blocks these effects decreasing SVR & afterload
. Aldosterone = secreted from adrenal glands
. cause sodium & water reabsorption
. increase blood volume
. increase preload
. ACE I blocks this and decreases preload
Types
Class I: captopril
Class II (prodrug) : e.g., ramipril, enalapril, perindopril
Class III ( water soluble) : lisinopril.
Mechanism of Action
Inhibition of circulating and tissue angiotensin- converting enzyme.
Increased formation of bradykinin and vasodilatory prostaglandins.
Decreased secretion of aldosterone; help sodium excretion.
Advantages
- Reduction of cardiovascular morbidity and mortality in patients with atherosclerotic vascular disease, diabetes, and heart failure.
- Favorable metabolic profile.
- Improvement in glucose tolerance and insulin resistance.
- Renal glomerular protection effect especially in diabetes mellitus.
- Do not adversely affect quality of life.
Indications
- Diabetes mellitus, particularly with nephropathy.
- Congestive heart failure.
- Following myocardial infraction.
Side Effects
- Cough (10 - 30%): a dry irritant cough with tickling sensation in the throat.
- Skin rash (6%).
- Postural hypotension in salt depleted or blood volume depleted patients.
- Angioedema (0.2%) : life threatening.
- Renal failure: rare, high risk with bilateral renal artery stenosis.
- Hyperkalaemia
- Teratogenicity.
Considerations
- Contraindications include bilateral renal artery stenosis, pregnancy, known allergy, and hyperkalaemia.
- High serum creatinine (> 3 mg/dl) is an indication for careful monitoring of renal function, and potassium. Benefits can still be obtained in spite of renal insufficiency.
- A slight stable increase in serum creatinine after the introduction of ACE inhibitors does not limit use.
- ACE-I are more effective when combined with diuretics and moderate salt restriction.
ACE inhibitors drugs
Captopril 50-150 mg
Enalapril 2.5-40 mg
Lisinopril 10-40 mg
Ramipril 2.5-20 mg
Perindopril 2-8 mg
Angiotensin Receptor Blocker
Losartan 25-100 mg
Candesartan 4-32 mg
Telmisartan 20-80 mg
Mechanism of action
They act by blocking type I angiotensin II receptors generally, producing more blockade of the renin -angiotensin - aldosterone axis.
Advantages
• Similar metabolic profile to that of ACE-I.
• Renal protection.
• They do not produce cough.
Indications
Patients with a compelling indication for ACE-I and who can not tolerate them because of cough or allergic reactions.