Antagonizes the vasoconstrictive effects of angiotensin II, relaxes vascular smooth muscle promoting vasodilation, increasing renal salt water excretion, reduce plasma volume and decrease cellular hypertrophy, prevent ACE mediated degradation of bradykinin and substance p.
Hydrochlorothiazide: Decreases extracellular volume by interaction with thiazide sensitive Na-CL- cotransporter in kidney so there is fall in cardiac output and the hypotensive effect remains maintained in long term treatment because of reduced vascular resistance. .Hydrochlorothiazide opens Ca2+ activated K+ channels, leading to hyperpolarization of vascular smooth muscle cells that causes closing of L type Ca2+channel and decrease its opening so reduced Ca2+ entry and reduced vasoconstriction, inhibits vascular carbonic anhydrous which alter systolic Ph and cause opening of Ca2 activated K+ channels
Adverse drug reactions:
Irbesartan: Hypotension, hyperkalemia, reduced renal function , cough incidence is less and angioedema occurs rarely, contraindicated in pregnancy
Hydrochlorothiazide: Gout due to hyperurecemia, rapidly developing severe hypernatremia, hypercalcemia due to inhibition of calcium excretion, K+ depletion leading to polymorphic ventricular tachycardia and other cardiac problems, ischemic ventricular fibrillation leading to sudden cardiac death ,change in plasma lipid and glucose tolerance , crosses placenta but no direct effect on foetus.
Relevant Drug Interaction:
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Irbesartan: Hyperkalemia occur in conjunction with other factors that alter K+ homeostasis such as renal insufficiency, ingestion of excess K+ and drugs that cause retention of K+.
Hydrochlorothiazide: Additive with other antihypertensive, K+, Mg+ depleting action potentiate arrhythmias with digitalis toxicity, corticosteroids amplify hypokalemia, decrease lithium clearance, NSAIDS decrease antihypertensive action of hydrochlorothiazide
Irbesartan: Mostly used 150 to 300mg once daily.
Hydrochlorothiazide: 12.5 to 25 mg once daily
Rationale for use in Mrs. AB
Hydrochlorothiazide are the most important class of drug to reduce blood pressure and in most cases usually combined with other drugs like angiotensin receptor antagonist that has cardio protective effect as well as better control of blood pressure with limited side effects. (Goodman Gilman eleventh edition)
Metformin (Biguanide group) and Glibenclamide (sulfonylurea group) are oral hypoglycemic drugs that are used in the treatment of diabetes and hence used for Mrs. AB as she is a known case of diabetes.
Mechanism of action:
Metformin: Suppress hepatic gluconeogenesis and glucose output from liver.
Enhance insulin mediated glucose disposal in muscle and fat by affecting GLUT 1 transport.
Retard intestinal absorption of glucose
Interfere with mitochondrial respiratory chain so promote peripheral glucose utilization by anaerobic glycolysis
Glibenclamide: Provoke brisk release of insulin from pancreas, act on sulfonylurea receptor, on the pancreatic beta cell membrane cause depolarization by reducing conductance of ATP sensitive k+channels, enhances calcium influx and degranulation. Extrapancreatically they sensitize the target tissues to the action of insulin.
Metformin: lactic acidosis, abdominal pain, anorexia, nausea, metallic taste, diarrhea, tiredness.
Glibenclamide: Hypoglycemia, nausea, vomiting, flatulence, diarrhea, headache, weight gain, hypersensitivity
To check the blood sugar level frequently, educate the patient regarding symptoms of hypoglycemia which may mimic cardiovascular event in elderly. In case of feeling dizziness or tired patient is educated to keep something eat something sweet to correct hypoglycemia like chocolate or glucose or honey but if the patient is unconscious itâ€™s better to give intravenous glucose infusion
Rationale for its use in Mrs. AB
Sulfonylurea reduced incidence of micro vascular complications in type 2 Diabetes Mellitus but did not have significant effect on macro vascular complications. Metformin however can reduce macro vascular complications as well, it decreased death and other diabetes related endpoints in Type 2 Diabetes obese patients- its anorectic action aids in weight reduction and has the potential to lower myocardial infarction and stroke. Metformin is mostly used to supplement sulfonylureas in patient not adequately controlled by sulfonylureas alone. (K.D.Tripathy, sixth edition)
Metoprolol is eta adrenergic receptor agonist which reduces frequency and severity of attack inexertion angina and improves survival in patients who have had MI. It decreases myocardial oxygen demand and increase blood flow to ischemic reason. It reduces arterial blood pressure, negative chronoscopic and negative inotropic effect.
Therapeutic benefit in Mrs. AB: It will reduce recurrent episodes of ischemia and risk of progression to MI. In presence of adequate antiplatelet therapy and vasodilation by angiotensin receptor antagonist beta adregernic receptor antagonist is helpful.
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Adverse effects of Metoprolol: Bradycardias, complain of cold extremities, may cause or exacerbate heart failure in patients with compensated heart failure, acute MI or cardiomegaly.
Nursing precautions: Metoprolol should never be stopped abruptly after long-term treatment because risk of angina or sudden death is increased.
Warfarin: Antagonist of vitamin K so factors II, VII, IX, X are inhibited. Warfarin is effective in preventing venous thrombosis or systemic embolization in patients with acute myocardial infraction. INR is international normalized ratio which is calculated from the patientâ€™s prothrombin time to monitor efficacy and patient compliance, targeted INR is between 2 to 3.
Adverse Effects of warfarin: Bleeding is the major adverse effect of warfarin, so careful monitoring of the patients is required. Risk of bleeding is highly increased when INR becomes 4. Patient is educated regarding signs and symptoms of bleeding. Warfarin during pregnancy causes birth defects and abortion, may cause skin necrosis, reversible and sometimes painful blue tinged discoloration of the plantar surfaces, precipitates various syndromes of limb gangrene etc.
INR is international normalized ratio: a fasting blood sample is obtained 8-14 hrs after last warfarin dose and patients PT is determined along with a normal pooled plasma .
INR=PTpt/PT ref (Goodman Gilman eleventh edition)
Glyceryl Trinitrate (GTN) is a pro-drug that leads to formation of free radical nitric oxide (NO). NO activates Guanyl Cyclase increase cellular level of cGMP, activate PKG and modulate the activities of cyclic nucleotide phosphodiesterases. Ultimately the smooth muscles are relaxed leading to vasorelaxation. Low dose GTN cause relaxation of veins more than arterioles which decrease the left and right ventricular chamber size and end diastolic pressures but results in little change in vascular resistance. The Systemic arterial pressure falls slightly and heart rate is unchanged or may increase slightly. Pulmonary vascular resistance and cardiac output are slightly reduced. Dose that do not alter systemic arterial pressure often produce arteriolar dilation in face and neck so there is flushing. Higher doses cause further venous pooling and may decrease arteriolar resistance as well. Thereby systolic and diastolic blood pressure is reduced. Cardiac output is reduced and that may cause pallor, weakness, dizziness and activation of compensatory mechanisms. The reflex tachycardia and peripheral arteriolar vasoconstriction tend to restore systemic vascular resistance that is superimposed on sustained venous pooling. In patients with autonomic dysfunction and an inability to increase sympathetic outflow the fall in blood pressure consequent to veno dilatation in cannot be compensated. In these clinical context nitrates may reduce arterial pressure and coronary perfusion pressure significantly producing life threatening hypotension and even aggravating angina.
The hemodynamic mechanism responsible for have focused on the ability of organic nitrates to cause dilatation and prevent vasoconstriction of large epicardial vessels without impairing auto regulation in the small vessels which are responsible for 90 % of overall coronary vascular resistance. Vessels larger than 200micrometer in diameter are highly responsive and those less than 100 micrometers respond minimally. Analysis of coronary angiograms in humans has shown that sublingual nitroglycerin dilates epicardial vessels and reduces the resistance to flow to such areas. The resulting increase in blood flow would be distributed preferentially to ischemic myocardial regions as a consequence of vasodilatation induced by auto regulation.
Untoward response to the therapeutic use of organic nitrates is almost all secondary to actions on the cardio vascular response. Severe headache, transient episodes of dizziness, weakness due to postural hypotension may develop particularly in patients standing immobile, may occasionally lead to loss of consciousness.
Dose and route:
Sublingual route is used to terminate an attack, the tablet is crushed under the teeth and spread over buccal mucosa , it acts within 1 to 2 minutes , plasma T1/2 is 2 minutes and action depends on its availability on buccal mucosa, remaining part is spit or swallowed when no longer needed.
Routes of administration:
Sublingual tablet, sublingual spray, ointment to be applied on skin, transdermal patch, intravenous infusion. In case the sublingual GTN does not work then aspirin tablet can be chewed and swallowed. (Goodman Gilman eleventh edition).