INTRODUCTION:

Hypertension or high blood pressure, is a very common and serious condition that can lead to or complicate many health problems. The risk of cardiovascular morbidity and mortality is directly correlated with blood pressure. Risks of stroke, MI, angina, heart failure, Kidney failure or early death from a cardiovascular cause are directly correlated with BP.¹

Hypertension is often called " the silent killer" because it generally has no symptoms until serious complications develop.¹

There are two general types of hypertension. Primary hypertension, Secondary hypertension.¹

Normal blood pressure is 120/80 mmHg, Systolic BP is the maximum BP during the ventricular systole-120 mmHg and the diastolic BP is the maximum BP during the ventricular diastole- 80 mmHg. During the hypertension increass BP. Systolic BP increase during the ventricular systole -140 mmHg and the diastolic BP increass during the ventricular diastole- 90 mmHg.[1]

Formulation:

To achieve the rapid action, Bolourtchian et Al developed sublingual tablets of Captopril which was effective and safe method of lowering arterial blood pressure in patient with hypertensive emergencies. More rapid attainment of plasma concentrations and more rapid onset of pharmacological effect have been observed after sublingual administration of Captopril than oral route.^2-3

Various pharmacological approaches have been made to design long acting device to administer once a day formulation as controlled and sustained release systems to deliver the drug. The different methodologies applied and their limitations are described as follows.^2-3

(1) Matrix tablets:

Various methods are available to formulate water soluble drug in to sustained release dosage forms by retardation the dissolution rate. One of the method used to control the drug release and there by prolonging therapeutic activity is to use of hydrophilic or lipophilic polymers. In recent years, the considerable attention has been focused on hydrophilic polymer in the design of oral controlled drug delivery systems because of their flexibility to obtains a desirable drug release profile, cost effectiveness, and broad regulatory acceptance. Among the hydrophilic polymers, cellulose derivatives such as methyl cellulose, hydroxyl propyl methyl cellulose, and sodium carboxy methyl cellulose are generally considered to be stable and safe as release retardant excipients in the development of oral controlled release dosage forms. These semisynthetic polymers are quite expensive when compared with natural polymers such as guar gum, alginates, and so forth. The natural polymers are nontoxic and easily available.^2-4 The cellulose derivative polymers are suitable for preparing formulations with soluble or insoluble drug and at high or low dosage levels. Hydration of polymers results in the formation of gel layer that controls the release rate of the drug^2-5.

Ali Nokhodchi et Al described the effects of various polymers such as hydroxy propyl methyl cellulose (HPMC), ethyl cellulose (EC) and sodium carboxy methyl cellulose and surfactants on the release rate of Captopril from matrix tablets. This work has showed that surfactants can be used to control the release rate of Captopril from HPMC - EC matrices. However, they are not able to produce the zero order release pattern for Captopril matrices. The magnitude of the increase or decrease of release rate remarkably depends on the type of surfactant and on concentration. The results also show that the surfactants are able to change the mechanism of Captopril release from the matrices. The principal mechanism by which surfactants retard drug release from HPMC- EC matrices is the drug / surfactant ionic interaction [2-6].

(2) Coated tablets:

It is a classical technique to control the drug release. The drug has cross the barriers before it reaches the physiological fluids. The type and composition of the barriers is the release delermining step. Barriers are mainly come of hydrophilic or hydrophobic polymers and that is due to the compatibility of these substances beside their in Vivo safety even when used in large amounts².

Guittard et Al described a coated tablet formulation of Captopril capable of showing in Vivo sustained release pattern and that was by making use of a semi permeable coat prepared from a mixture of micro crystalline cellulose acetate, poly vinyl pyrrolidine (PVP) and Tri propyl citrate. The core tablet consisted of Captopril blended with HPMC, Micro crystalline cellulose, PVP and magnesium stearate and wetted with anhydrous ethanol, dried and compressed^2-7.

MECHANISM OF ACTION:

The benefits of Captopril in hypertension and heart failure result primarily from suppression of the renin - angiotensin- aldosterone system (RAAS)^8-9. As angiotensin- converting enzyme (ACE) inhibitor, it inhibits ACE, which converts angiotensin 1 to angiotensin 2. Angiotensin 2 binds to AT1 receptors on smooth muscles to produce vasoconstriction of precapillary arterioles and potcapillary venules, inhibits the reuptake of norepinephrine, and release of catecholamines from the adrenal medulla which all increases blood pressure. Angiotensin 2 also stimulates the adrenal cortex to secrete aldosterone. Aldosterone causes the distal tubules collecting ducts of the kidneys to reabsorb water and sodium in exchange for potassium, which results in an expansion in extracellular volume and an increase in blood pressure^8-10.

Inhibition of ACE leads to decreased plasma angiotensin 2, leading to vasodilation and decreased aldosterone secretion. Small increase in serum potassium, as well as sodium and fluid loss, may occur due to a decrease in aldosterone secretion^8-11.

Administration of Captopril results in a reduction of peripheral arterial resistance in hypertensive patients. Regarding the cardiovascular system, ACE inhibitors reduce preload by causing vasodilation and natriuresis, reduce afterload by inhibiting the formation of angiotensin 2. The overall effect is the improvement of cardiac output and reduce blood pressure [8-12]. ACE also metabolizes bradykinin, a peptide that cause vasodilation. ACE inhibitors impede the breakdown of bradykinin, resulting in vasodilation and a bradykinin- evoked cough. The only two ACE inhibitors that do not have to be activated in the body to be effective are lisinopril and Captopril while others need to be activated in order to be effective^8-12.

Dosage:

The early clinical study protocols provided for Captopril daily dosages of 75 mg (in three divided doses) that were increased at weekly intervals to 150,300 and 450 mg/day (also in three divided doses). These doses were employed before a diuretic or other antihypertensives agent (usually a Bita blocker) was introduced. Since the maximum sustained antihypertensive effect of Captopril may not be achieved for two to three weeks, excessive doses of the drug due to rapid titration were frequently employed in these early studies. Later studies demonstrated that when diuretic were introduced before these maximum permitted doses of Captopril were reached, a marked synergistic antihypertensive effect could be expected. There for, higher doses of Captopril (300mg/day and 450 mg/day) were probably only rarely required for adequate pressure control¹³.

Because Captopril is excreted completely by renal mechanisms, lower doses should be administered to patients with impaired renal function. Such adjustment were made rarely during the early clinical trials, and since 26% of all patients in these studies had renal impairment, it is not surprising that the frequency of side effects was relatively and at times unacceptably, high¹³.

Adverse Effects:

· Paroxysmal cough (1% to 10%)^8-12.

· Proteinuria (1 of 100 patients) which subsides or clears within six months even when Captopril therapy is continued⁸.

· Renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency (1 to 2 of 1000 patients)⁸.

· Neutropenia (less than 1000/mm³) or agranulocytosis with myeloid hypoplasia⁸.

· Rash with pruritus and occasionally with fever, arthralgia, and eosinophila (4 to 7 of 1000 patients)⁸.

· Dysgeusia (diminution or less of taste perception) which is reversible and usually self - limited (2 to 4 of 100 patients)⁸.

· Anaphylactoid and other related reactions due to the invitation of the metabolism of eicosanoids and polypeptides, including bradykinin⁸.

In terms of angioedema, it can occur in any region such as the intestine but angioedema of the tongue, glottis, or larynx cause obstruction of the airway. The prevalence of angioedema is higher in the African- American population. Treatment for angioedema involving the airway involves immediate stabilization with an endotracheal tube until the swelling resolves. Many pharmacological agents like diphenhydramine, methylprednisolone, epinephrine or bradykinin blocking agents have been tried as treatment without a definitive answer^8-12.

· Intestinal angioedema- abdominal pain with or without nausea vomiting⁸.

· Flushing or pallor⁸.

· Tachycardia, chest pain, and palpitations⁸.

· Hypotension^8-12.

ACE inhibitors may cause hyperkalemia. Individuals who are more prone to developing hyperkalemia have a history of renal impairment and lot diabetes, concurrent use of potassium- sparing diuretic, and or potassium supplements. Treatment takes into consideration factors such as the level of potassium, EKG changes, and the patient's renal function and urine production^8-12. There has been one cause of sudden death in a patient who was taking an ACE inhibitor and trimoxazole at the same time. Hyperkalemia was assumed to be the cause since it can trigger lethal arrhythmias^8-12. Symptoms of hyperkalemia can range from nausea, palpitations, muscle pain, or paresthesia. Electrocardiography (ECG) monitoring is required in patients with serum potassium > 6.5 mmol/L. ECG changes may present as non specific repolarization abnormalities, peaked T- waves, widening of QPR as well as ST- segment depression. Treatment involves immediate stabilization of cardiac myocytes with calcium gluconate, dextrose and insulin infusion, or the use of beta - agonists. The last step involves the removal of total body potassium using loop diuretics, kayexalate, or hemodialysis [8].

USE:

Captopril is used to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks and kidney problems. It is also used to treat heart failure, protect the kidneys from harm due to diabetes and to improve survival after a heart attacks¹⁴.

Captopril is an ACE inhibitor and works by relaxing blood vessels so that blood can flow more easily [14].

CONCLUSION:

As has been described, all the controlled release dosage forms available for Captopril claims to release the drug upto 8hr. These need the drug administration for two to three times a day which is not feasible to for once a formulation. In some cases, the optimum release of drug was shown but with in vitro data only. The in Vivo release was studied under animals only. Further clinical studies are needed to assess the utility of these systems for patients suffering from hypertension. Only by considering these factors collectively, it is feasible to formulate a controlled release dosage form to deliver Captopril, however extensive studies are required to examine the factors that play role in development of controlled release formulations of Captopril. Surprisingly, despite of all these review article, there are likely to be no well established Captopril controlled release fromulations reported to be in the market.

REFERENCE:

1. Siyad. A.R, Hypertension- Journal for drug and medicines, H.J.D. Med: vol- 3; April- October 2011.

2. C.Nithya Shanthi, Rakesh Gupta, Arun Kumar Mahato, International Journal of drug Development and Research: vol- 2; April- June- 2010.

3. Bolourtchian N, Hadifi N, Foroutan S M, Faghi, BS. Formulation and Optimization of Captopril D- optimal design. Iran. J. Pharma Res 2008:7:256-67.

4. Al- Saidan SM, Krishnaiah YSR, Patrol SS, Satyanarayana V. Invitro and Invivo evaluation of Guar gum matrix table for oral controlled release of water-soluble Diltiazem Hydrochloride. AAPS. Pharmacological. Sci. Tech. 2005;6: E14-21.

5. Ojoe E, Miyauchi EM, Kaneko TM, Velasco MVR, Consiglieri Vo. Influence of cellulose polymers type on invitro controlled release tablets containing the ophylline. Brazil. J. Pharm. Sci. 2007; 43: 572-579.

6. Nokhodchi A, Zadeh DH, Zadeh FM, Zadeh NT. Effect of various surfactants and their concentration on controlled release of Captopril from polymer matrices. Acta.Pharm. 2008;58:151-162.

7. Guittard GV, Carpenter HA, Quan ES, Wong PS, Hamel LG. Dosage form for delivery drug in short time period. 1993; U.S. Patent 5178867:12 Jan.

8. Https://www.ncbi.n/m.nih.gov/books/NBK 535386/

9. Gan Z, Huang D, Jiang J, LiY, LiH, KeY. Captopril alleviates hypertension induced renal damage, inflammation, and NF-KB activation. Braz J Med Biol Res. 2018; Sep 03;51:e7338.

10. Lezama- Martinez D, Flores- Monroy J, Fonseca- Coronado S, Hernandez- Campos ME, Valencia- Hernandez I, Martinez- Aguilar L. Combined Antihypertensive Therapies that Increase Expression of Cardioprotective Biomarkers Associated with the Renin- Angiotensin and Kallikrein- kinin Systems.J Cardiovasc Pharmacological. 2018; Dec; 72:291-295.

11. Chen YJ, Li LJ, Tang WL, Song JY, Qiu R, Li Q, Xue H, Wright JM. First- line drug inhibiting the Renin-Angiotensin system versus other first- line antihypertensive drugs classes for hypertension. Cochrane Database syst Rev.2018; Nov 14;11:CD008170.

12. Herman LL, Padala SA, Annamaraju P, Bashir K. Statpearls (internet). Statpearls Publishing; Treasure Island (FL): Jun22, 2020. Angiotensin converting Enzyme Inhibitors (ACEI).

13. http://archinte.jamanetwork.com/on 05/20/2012.

14. www.webmd.com>drugs>details.

Received on 16.01.2021 Modified on 19.02.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(2):157-160.

DOI: 10.52711/0975-4377.2021.00028