Acid-Peptic disorders

This group of diseases include peptic ulcer, gastroesophageal reflux and Zollinger-Ellison syndrome.

Pathophysiology of acid-peptic disorders

Peptic ulcer disease is thought to result from an imbalance between cell– destructive effects of hydrochloric acid and pepsin on the one side, and cell-protective effects of mucus and bicarbonate on the other side. Pepsin is a proteolytic enzyme activated in gastric acid (above pH of 4, pepsin is inactive); also it can digest the stomach wall. A bacterium, Helicobacter pylori, is now accepted to be involved in the pathogenesis of peptic ulcer.

In gastroesophageal reflux the acidic contents of the stomach enter into the oesophagus causing a burning sensation in the region of the heart; hence the common name heartburn or other names such as indigestion and dyspepsia.

However, Zollinger-Ellison syndrome is caused by a tumor of gastrin secreting cells of the pancreas characterized by excessive secretion of gastrin that stimulates gastric acid secretion.

These disorders can be treated by the following classes of drugs:

A. Gastric acid neutralizers (antacids)
B. Gastric acid secretion inhibitors (antisecretory drugs)
C. Mucosal protective agents
D. Drugs that exert antimicrobial action against H.pylori

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. 

Gabapentin (Neurontin): newer; for generalized tonic-clonic seizures and partial seizures (partial and complex)

Mechanism: unknown but know doesn’t mimic GABA inhibition or block Ca currents

Side effects: dizziness, ataxia, fatigue; drug well-tolerated and no significant drug interactions

Hydromorphone

• About 8-10 times more potent than morphine when given intravenously.
• Slightly shorter duration of action.
• More soluble than morphine, thus higher concentrations may be injected if necessary.
• Better oral/parenteral absorption ratio than morphine, but not as good as codeine or oxycodone.

• It is used for the treatment of moderate to severe pain

Class II Beta Blockers 

Block SNS stimulation of beta receptors in the heart and decreasing risks of ventricular fibrillation
– Blockage of SA and ectopic pacemakers: decreases automaticity 
– Blockage of AV increases the refractory period
- Increase AV nodal conduction ´ 
- Increase PR interval
- Reduce adrenergic activity

Treatment: Supraventricular tachycardia (AF, flutter, paroxysmal supraventricular tachycardia 
– Acebutolol 
– Esmolol 
– Propanolol 

Contraindications and Cautions 

• Contraindicated in sinus bradycardia P < 45
• Cardiogenic shock,  asthma or respiratory depression which could be made worse by the blocking of Beta receptors. 
• Use cautiously in patients with diabetes and thyroid dysfunction, which could be altered by the blockade of Beta receptors 
• Renal and hepatic dysfunction could alter the metabolism and excretion of these drugs.
 

Calcium Channel Blocking Agents 

• Act on contractile and conductive tissues of the heart and on vascular smooth muscles 
• Prevent movement of extracellular calcium into the cell 
– Coronary and peripheral arteries dilate
– Myocardial contractility decreases 
– Depress conduction system

Therapeutic Actions
• Inhibit movement of calcium ions across the membranes of myocardial and arterial muscle cells. Altering the action potential and blocking muscle cell contraction 
• Depress myocardial contractility 
• Slow cardiac impulse formation in the conductive tissues 
• Cause a fall in BP