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. 

Antimania Drugs

MANIC SYMPTOMSMANIC SYMPTOMS

Elevated  or irritable mood
Increased activity or psychomotor agitation
Reduced need for sleep
Inflated self esteem or grandiosity
Increased or pressure of speech
Flight of ideas

These drugs are used to treat manic-depressive illness.

1. Lithium
2. Carbamazepine
3. Valproic acid

Mechanisms of action

1. Lithium works inside the cell to block conversion of inositol phosphate to inositol.
2. Carbamazepine blocks sodium channels 
3. Valproic acid blocks sodium and calcium channels

PHARMACOKINETICS

Absorbed readily and almost completely from the GI tract; peak concentrations in 1-2 hrs

Lithium toxicity

1. Nausea, diarrhea, convulsions, coma, hyperreflexia, cardiac arrhythmias, hypotension.
2. Thyroid enlargement; increases thyroid stimulating hormone (TSH) secretion; may cause hypothyroidism.
3. Polydipsia, polyuria (lithium inhibits the effect of antidiuretic hormone on the kidney).

Clinical applications concerning lithium 

- Patients must be warned against sodium-restricted diets because sodium restriction leads to greater retention of lithium by the kidney.
- Patients must have regular (e.g., monthly) blood checks because the margin of safety is narrow.

Endocrine Effects – Goitre and hypothyroidism commonly

Cardiac Effects:– ECG changes(common) - T-wave flattening/inversion and appearance of U wavesflattening/inversion and appearance of U waves

Li and Pregnancy -1st Trimester:Cardiovascular anomalies of the newborn, especially Ebstein's malformation
- 3rd Trimester: Neonatal goiter, CNS depression, hypotonia ("floppy baby" syndrome)

Drug–drug interactions of lithium
Diuretics and newer nonsteroidal anti-inflammatory drugs (NSAIDs) reduce lithium excretion and may cause lithium toxicity.

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

Fentanyl (Sublimaze)

• Related chemically to meperidine.
• Approximately 80 times more potent than morphine.
• Duration of action very short (t1/2 20 min).
• Used mainly following general anesthesia.
• Neurolept analgesia: Fentanyl & Droperidol (Innovar)
• fentanyl in analgesic (2-10 µg/kg), or anaesthetic (30-100 µg/kg) doses seldom causes significant decreases in blood pressure when given alone, even in patients with poor LV function
• hypotension following fentanyl is mostly due to bradycardia and can be prevented by the use of anticholinergics, sympathomimetics or agents such as pancuronium this is more likely to occur in patients with high pre-existing sympathetic tone
• hypertension is the commonest disturbance with high dose fentanyl anaesthesia, usually accompanying intubation, sternotomy, or aortic root dissection

Methadone

Pharmacology and analgesic potency similar to morphine.

• Very effective following oral administration.
• Longer duration of action than morphine due to plasma protein binding (t1/2 approximately 25 hrs).
• Used in methadone maintenance programs for drug addicts and for opiate withdrawal. Opiate withdrawal is more prolonged but is less intense than it is following morphine or heroin.

NATURAL ANTICOAGULANTS:

       1. PGI-2.

       2. Antithrombin.

       3. Protein-C.

       4. TFPI.

       5. Heparin.

       6. Fibrinolytic system.