NEET MDS Lessons
Pharmacology
Gastric acid secretion inhibitors (antisecretory drugs):
HCl is secreted by parietal cells of the gastric mucosa which contain receptors for acetylcholine (muscarinic receptors: MR), histamine (H2R), prostaglandins (PGR) and gastrin (GR) that stimulate the production, except PGs which inhibit gastric acid production.
Therefore, antagonists of acetylcholine, histamine and gastrin inhibit gastric acid secretion (antisecretory). On the other hand, inhibitors of PGs biosynthesis such as NSAIDs with reduce cytoprotective mechanisms and thus promote gastric mucosal erosion. Also, the last step in gastric acid secretion from parietal cells involve a pump called H+ -K+-ATPase (proton pump). Drugs that block this pump will inhibit gastric acid secretion. Antisecretory drugs include:
1. Anticholinergic agents such as pirenzepine, dicyclomine, atropine.
2. H2-receptors blocking agents such as Cimetidine, Ranitidine, Famotidine, Nizatidine (the pharmacology of these agents has been discussed previously).
3. Gastrin-receptor blockers such as proglumide.
4. Proton pump inhibitors such as omeprazole, lansoprazole.
Major clinical indications of antisecretory drugs:
• Prevention & treatment of peptic ulcer disease.
• Zollinger Ellison syndrome.
• Reflux esophagitis.
Ofloxacin : It is a quinolone antibiotic and similar in structure to levofloxacin. It is an alternative treatment to ciprofloxacin for anthrax.
Antifungal
There are several classes of antifungal drugs.
The polyenes bind with sterols in the fungal cell wall, principally ergosterol. This causes the cell's contents to leak out and the cell dies. Human (and other animal) cells contain cholesterol rather than ergosterol so are much less suceptible.
Nystatin
Amphotericin B
Natamycin
The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell wall synthesis. These drugs also block steroid synthesis in humans.
Imidazoles:
Miconazole
Ketoconazole
Clotrimazole
The triazoles are newer, and are less toxic and more effective:
Fluconazole
Itraconazole
Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis:
Terbinafine
Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase:
Caspofungin
Micafungin
Others:
Flucytosine is an antimetabolite.
Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis.
Ketoprofen
It acts by inhibiting the body's production of prostaglandin.
On the basis of Receptors, drugs can be divided into four groups,
a. agonists
b. antagonists
c. agonist-antagonists
d. partial agonists
a. Agonist
morphine fentanyl pethidine
Action : activation of all receptor subclasses, though, with different affinities
b. Antagonist
Naloxone , Naltrexone
Action : Devoid of activity at all receptor classes
c. Partial Agonist: (Mixed Narcotic Agonists/Antagonists)
Pentazocine, Nalbuphine, Butorphanol , Buprenorphine
Action: activity at one or more, but not all receptor types
With regard to partial agonists, receptor theory states that drugs have two independent properties at receptor sites,
a. affinity
The ability, or avidity to bind to the receptor
Proportional to the association rate constant, Ka
b. efficacy
or, intrinsic activity, and is the ability of the D-R complex to initiate a pharmacological effect
Drugs that produce a less than maximal response and, therefore, have a low intrinsic activity are called partial agonists.
These drugs display certain pharmacological features,
a. the slope of the dose-response curve is less than that of a full agonist
b. the dose response curve exhibits a ceiling with the maximal response below that obtainable by a full agonist
c. partial agonists are able to antagonise the effects of large doses of full agonists
Drugs used to induce vomiting
In case of poisoning with noncorrosive agents, and assuming incomplete absorption of the poison has taken place, induction of vomiting can be carried out. One of the drugs used for this purpose is emetine which causes irritation of the upper gut and, on absorption, it also acts on CTZ.
Chemotherapeutic agents (or their metabolites) can directly activate the medullary chemoreceptor trigger zone or vomiting center; several neuroreceptors, including dopamine receptor Type 2 and serotonin Type 3 (5-HT3) from cell damage(GIT and pharynx) play roles in vomiting.
DIURETICS
The basis for the use of diuretics is to promote sodium depletion (and thereby water) which leads to a decrease in extracellular fluid volume.
An important aspect of diuretic therapy is to prevent the development of tolerance to other antihypertensive drugs.
TYPES OF DIURETICS
A. Thiazide Diuretics examples include chlorothiazide
hydrochlorothiazide
a concern with these drugs is the loss of potassium as well as sodium
B. Loop Diuretics (High Ceiling Diuretics) examples include
furosemide (Lasix)
bumetanide
these compounds produce a powerful diuresis and are capable of producing severe derangements of electrolyte balance
C. Potassium Sparing Diuretics examples include
triamterene
amiloride
spironolactone
unlike the other diuretics, these agents do not cause loss of potassium
Mechanism of Action
Initial effects: through reduction of plasma volume and cardiac output.
Long term effect: through decrease in total peripheral vascular resistance.
Advantages
Documented reduction in cardiovascular morbidity and mortality.
Least expensive antihypertensive drugs.
Best drug for treatment of systolic hypertension and for hypertension in theelderly.
Can be combined with all other antihypertensive drugs to produce synergetic effect.
Side Effects
Metabolic effects (uncommon with small doses): hypokalemia,hypomagnesemia, hyponatremia, hyperuricemia, dyslipidemia (increased total
and LDL cholesterol), impaired glucose tolerance, and hypercalcemia (with thiazides).
Postural hypotension.
Impotence in up to 22% of patients.
Considerations
- Moderate salt restriction is the key for effective antihypertensive effect of diuretics and for protection from diuretic - induced hypokalaemia.
- Thiazides are not effective in patients with renal failure (serum creatinine > 2mg /dl) because of reduced glomerular filtration rate.
- Frusemide needs frequent doses ( 2-3 /day ).Thiazides can be given once daily or every other day.
- Potassium supplements should not be routinely combined with thiazide or loop diuretics. They are indicated with hypokalemia (serum potassium < 3.5 mEq/L) especially with concomitant digitalis therapy or left ventricular hypertrophy.
- Nonsteroidal antiinflammatory drugs can antagonize diuretics effectiveness.
Special Indications
Diuretics should be the primary choice in all hypertensives.
They are indicated in:
- Volume dependent forms of hypertension: blacks, elderly, diabetic, renal and obese hypertensives.
- Hypertension complicated with heart failure.
- Resistant hypertension: loop diuretics in large doses are recommended.
- Renal impairment: loop diuretics