NEET MDS Lessons
Pharmacology
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.
Benzodiazepines (BZ):
newer; depress CNS, selective anxiolytic effect (no sedative effect); are not general anesthetics (but does produce sedation, stupor) or analgesics
BZ effects:
1. Central: BZs bind GABAA receptors in limbic system (amygdala, septum, hippocampus; involved in emotions) and enhance inhibition of neurons in limbic system (this may produce anxiolytic effects of BZs)
a. GABA receptor: pentameric (α, β, δ, γ subunits)
i. Binding sites: GABA (↑ conductance (G) of Cl-, hyperpolarization, inhibition), barbiturate (↑ GABA effect), benzodiazepine (↑ GABA effect), picrotoxin (block Cl channel)
b. GABA agonists: GABA (binds GABA → Cl influx; have ↑ frequency of Cl channel opening; BZs alone- without GABA don’t affect Cl channel function)
c. Antagonists: bicuculline (competitively blocks GABA binding; ↓ inhibition,→ convulsions; no clinical use), picrotoxin (non-competitively blocks GABA actions, Cl channel → ↓ inhibition → convulsions)
2. Other agents at BZ receptor:
a. Agonists: zolpidem (acts at BZ receptor to produce pharmacological actions)
b. Inverse agonists: β-carbolines (produce opposite effects at BZ binding site-- ↓ Cl conductance; no therapeutic uses since → anxiety, irritability, agitation, delirium, convulsions)
3. Antagonists: flumazenil (block agonists and inverse agonists, have no biological effects themselves; can precipitate withdrawal in dependent people)
Metabolism: many BZs have very long action (since metabolism is slow); drugs have active metabolites
2 major reactions: demethylation and hydroxylation (both very slow reactions)
Fast reaction: glucuronidation and urinary excretion
Plasma half life: long (for treating anxiety, withdrawal, muscle relaxants), intermediate (insomnia, anxiety), short (insomnia), ultra-short (<2hrs; pre-anesthetic medication)
Acute toxicity: very high therapeutic index and OD usually not life threatening (rarely see coma or death)
Treatment: support respiration, BP, gastric lavage, give antagonist (e.g., glumazenil; quickly reverses BD-induced respiratory depression)
Tolerance: types include pharmacodynamic (down-regulation of CNS response due to presence of drug; this is probably the mechanism by which tolerance develops), cross-tolerance (with other BZ and CNS depressants like EtOH and BARBS), acquisition of tolerance (tolerance develops fastest in anticonvulsant > sedation >> muscle relaxant > antianxiety; means people can take BZs for long time for antianxiety without → tolerance)
Physical dependence: low abuse potential (no buz) but physical/psychological dependence may occur; physical dependence present when withdrawal symptoms occur (mild = anxiety, insomnia, irritability, bad dreams, tremors, anorexia; severe = agitation, depression, panic, paranoia, muscle twitches, convulsions)
Drug interactions: minimally induce liver enzymes so few interactions; see additive CNS depressant effects (can be severe and → coma and death if BZs taken with other CNS depressants like ethanol)
Azithromycin
Azithromycin is the first macrolide antibiotic belonging to the azalide group. Azithromycin is derived from erythromycin by adding a nitrogen atom into the lactone ring of erythromycin A, thus making lactone ring 15-membered.
Azithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Hemophilus influenzae.
azithromycin is acid-stable and can therefore be taken orally without being protected from gastric acids.
Main elimination route is through excretion in to the biliary fluid, and some can also be eliminated through urinary excretion
Chloramphenicol
derived from the bacterium Streptomyces venezuelae
Chloramphenicol is effective against a wide variety of microorganisms, but due to serious side-effects (e.g., damage to the bone marrow, including aplastic anemia) in humans, it is usually reserved for the treatment of serious and life-threatening infections (e.g., typhoid fever). It is used in treatment of cholera, as it destroys the
vibrios and decreases the diarrhoea. It is effective against tetracycline-resistant vibrios.It is also used in eye drops or ointment to treat bacterial conjunctivitis.
Mechanism and Resistance Chloramphenicol stops bacterial growth by binding to the bacterial ribosome (blocking peptidyl transferase) and inhibiting protein synthesis.
Chloramphenicol irreversibly binds to a receptor site on the 50S subunit of the bacterial ribosome, inhibiting peptidyl transferase. This inhibition consequently results in the prevention of amino acid transfer to growing peptide chains, ultimately leading to inhibition of protein formation.
Spectrum of activity: Broad-spectrum
Effect on bacteria: Bacteriostatic
Topical Anesthetics
Benzocaine
Benzocaine is a derivative of procaine, an ester type local anesthetic, and is poorly soluble in water and is
available only as a topical anesthetic.
- Localized allergic reactions are sometimes encountered
- Overdosing is unlikely as benzocaine is poorly absorbed into the blood, which decreases the likelihood of systemic toxicity.
- The onset of surface anesthesia is rapid requiring less than one minute.
Tetracaine
- Tetracaine is an ester type local anesthetic
- Topically applied tetracaine as opposed to benzocaine has a prolonged duration of action.
Cocaine
- Cocaine is a ester type anesthetic that is used exclusively as a topical agent.
- Cocaine is unique among topical and injectable anesthetics in that it has vasoconstrictive as well as anesthetic properties. It is used sparingly because of its abuse potential but is still used when hemostasis of mucous membranes is essential.
- Cocaine is generally available in concentrations of 2-10 % solution.
Lidocaine
- Lidocaine is an amide local anesthetic that is available in injectable and topical formulations.
- It is available in gel, viscous solution, ointment and aerosol preparations in concentrations ranging from 2-10 %.
- The onset of anesthesia is slower relative to benzocaine but, the duration is about the same.
- Absorption into the bloodstream is greater than benzocaine providing a greater risk of systemic toxicity.
Beta - Adrenergic Blocking Agents
Mechanisms of Action
- Initial decrease in cardiac output, followed by reduction in peripheral vascular resistance.
- Other actions include decrease plasma renin activity, resetting of baroreceptors, release of vasodilator prostaglandins, and blockade of prejunctional beta-receptors.
Advantages
- Documented reduction in cardiovascular morbidity and mortality.
- Cardioprotection: primary and secondary prevention against coronary artery events (i.e. ischemia, infarction, arrhythmias, death).
- Relatively not expensive.
Considerations
- Beta blockers are used with caution in patients with bronchospasm.
- Contraindicated in more than grade I AV, heart block.
- Do not discontinue abruptly.
Side Effects
- Bronchospasm and obstructive airway disease.
- Bradycardia
- Metabolic effects (raise triglyerides levels and decrease HDL cholesterol; may worsen insulin sensitivity and cause glucose intolerance). Increased incidence of diabetes mellitus.
- Coldness of extremities.
- Fatigue.
- Mask symptoms of hypoglycemia.
- Impotence.
Indications
- First line treatment for hypertension as an alternative to diuretics.
- Hypertension associated with coronary artery disease.
- Hyperkinetic circulation and high cardiac output hypertension (e.g., young hypertensives).
- Hypertension associated with supraventricular tachycardia, migraine, essential tremors, or hypertrophic cardiomyopathy.
Beta adrenergic blocker Drugs
Atenolol 25-100
Metoprolol 50-200
Bisoprolol 2.5-10
Helicobacter Pylori Agents
Antimicrobial
• Amoxicillin,
• Clarithromycin,
• Metronidozole
• Tetracycline
Antisecreteory agents accelerates symptom relief and yield healing (omeprozole)
Bismuth subsalicylate
Therapy For H. Pylori
Original
• Tetracycline
• Metronidazole (Flagyl)
• Bismuth subsalicylate
• Given for 14 days
• >90% effective in eradicating microorganisms
New triple therapy
• Amoxicillin
• Clarithromycin
• Omeprazole (Prilosec)
• Given for 7 days
• >90% effective in eradicating microorganisms
Dual Therapy
Amoxicillin or clarithromycin
Omeprazole
Given for 14 days
60-80% effective in eradication of H. Pylori