Clinical Pharmacy PDF

Clinical Pharmacy By Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy PGY1 Clinical Pharmacy B.Sc. Pharmacy ‫معهد واكاديمية النهال‬ Dr.Mohammed Ali Nameer...

Clinical Pharmacy By Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy PGY1 Clinical Pharmacy B.Sc. Pharmacy ‫معهد واكاديمية النهال‬ Dr.Mohammed Ali Nameer F.I.C.M.S Clinical Pharmacy  Chapter 1 Clinical Page |1 Anemia Anemia can be defined as a reduction from normal of the quantity of hemoglobin in the blood. The World Health Organization (WHO) defines anemia in adults as hemoglobin levels less than 130 g/L for males and less than 120 g/L for females. Epidemiology Anemia has a high prevalence worldwide. In adults, the lowest prevalence is in men. The threshold for anemia in pregnancy is lower, and anemia is more common in pregnancy. The hemoglobin level varies slightly in different altitudes and is higher in smokers. Hemoglobin is higher in males due to the influence of androgens, which increases hemoglobin production. In the elderly, therefore, the hemoglobin values in men and women are less differentiated. Hemoglobin also has some dependence on the patient’s fluid status. In dehydration, due to reduced circulating plasma volume, hemoglobin appears higher. In circumstances of higher plasma volume, such as pregnancy and splenomegaly, it will appear lower. The hemoglobin level does not always correlate with the degree of symptoms experienced by the patient. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 1 Clinical Page |2 Aetiology The low hemoglobin level that defines anemia results from two different mechanisms: Increased hemoglobin loss due to either:  Hemorrhage (red blood cell loss) or  Hemolysis (red blood cell destruction). Reduced hemoglobin synthesis due to either:  Lack of nutrient or  Bone marrow failure. Hemopoiesis and erythropoiesis Hemopoiesis Hemopoiesis is the formation of blood cells, white blood cells, red blood cells and platelets. Hemopoiesis takes place predominantly in the bone marrow of the central skeleton and in the proximal ends of the long bones. It also takes place in the liver and the spleen, particularly at times of increased need. All blood cells originate from the pluripotent haemopoietic stem cell. These stem cells have the potential to form any of the blood cells. The red blood cells (erythrocytes) are the most abundant of all the blood cells. Erythrocytes, once matured, do not contain a nucleus. This allows more capacity for the erythrocyte to carry oxygen. Erythropoiesis Erythropoiesis is the production line of red blood cells from the stem cells committed to red blood cell production (Fig. 50.1). Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 1 Clinical Page |3 1. Stem Cell Proliferation and Differentiation:  Stem cells divide and differentiate into progenitor cells. 2. Synthesis of Hemoglobin, DNA, and RNA:  Hemoglobin consists of four globin chains (α1, α2, β1, β2) each containing one haem molecule.  Haem is formed in mitochondria by combining protoporphyrin with iron (Fe2+), with pyridoxine as a co-factor.  Each haem molecule can carry one oxygen molecule. 3. Formation of Normoblasts:  Normoblasts are the last stage of production in the bone marrow.  10-15% of normoblasts die in the bone marrow without producing red blood cells.  The majority release reticulocytes into the circulation. 4. Reticulocyte Maturation:  Reticulocytes (1-3% of all red blood cells) mature into red blood cells within 48 hours.  Increased reticulocyte percentage is seen after acute blood loss.  Regulation by Growth Factors:  Erythropoiesis is regulated by erythropoietin, produced mainly in the renal cortex and, to a lesser extent, in the liver and other organs.  Erythropoietin production increases in response to reduced oxygen tension and hypoxia. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 1 Clinical Page |4  Factors Required for Erythropoiesis:  Necessary factors include iron, cobalt, vitamins B1, B6, B12, C, E, riboflavin, androgens, and thyroxine.  Hepcidin, an inflammatory protein that suppresses iron absorption, decreases during erythropoiesis.  Erythropoiesis in Chronic Conditions:  Erythropoietin production is suppressed in conditions like rheumatoid arthritis, cancer, sickle cell disease, impaired lung function, and cardiovascular dysfunction.  Renal failure leads to insufficient erythropoietin production and anemia.  Red Blood Cell Lifespan and Destruction:  Approximately 2 × 10¹¹ erythrocytes enter the circulation daily.  Normal erythrocytes survive about 120 days.  At the end of their life, red blood cells are destroyed in the spleen and bone marrow.  Iron from hemoglobin is reused, and part of the globin chains is excreted as bilirubin by the liver. Clinical manifestations 1. General Symptoms: o Tiredness o Lethargy o Exercise intolerance 2. Cerebral Symptoms: o Reduced cognition o Confusion o Headaches o Light-headedness 3. Severe or Longstanding Anemia Symptoms: o Shortness of breath o Angina o Tachycardia o Palpitations o Heart failure 4. Rapid Onset Anemia (e.g., Hemorrhage): o Shock o Collapse o Dyspnea o Tachycardia Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy Chapter 1 Clinical Page |5 Investigations 1. Medical History and Patient Evaluation: o Note medications and recent travel o Assess for liver disease, chronic renal failure, or other hematological history 2. Initial Blood Tests: o Full blood count (FBC) o Hemoglobin (Hb) o Mean corpuscular volume (MCV) o Mean cell hemoglobin (MCH) 3. MCV and MCH Analysis: o MCV: Indicates microcytic, normocytic, or macrocytic anemia o MCH: Reflects hemoglobin density, mirroring MCV o Note: MCV may appear normal if two pathologies cause different cell sizes 4. Additional Indicators: o Low leukocytes and platelet counts suggest bone marrow suppression (pancytopenia) o Consult hematology for pancytopenia o Exclude drug-related causes of bone marrow suppression 5. Blood Film Examination: o Stained blood film to examine red blood cell morphology 6. Hematinic Tests: o Vitamin B12 o Folate o Ferritin o Iron o Iron-binding capacity/transferrin (iron profile) 7. Additional Tests: o Liver function tests o Renal function tests o Thyroid function tests 8. Further Diagnostics: o Bone marrow aspiration or biopsy if the cause is not identified from peripheral blood Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 1 Clinical Page |6 Iron-deficiency anemia Etiology The commonest cause of iron deficiency is due to blood loss. In women of childbearing age, this is most commonly due to menstrual loss. Amongst adult males, the most likely cause is gastro- intestinal bleeding. Other causes of blood loss associated with iron-deficiency anemia include hemorrhoids, nosebleeds or postpartum hemorrhage. Pathophysiology 1. Iron Absorption and Regulation: o Homeostasis is maintained by controlling iron absorption, not elimination. o Iron is absorbed mainly from the duodenum and jejunum. o Haem iron (from red meat) is better absorbed than non-haem iron (from vegetables). o Phosphates and phytates in vegetables can form unabsorbable iron complexes. o Ascorbic acid increases iron absorption. o Approximately 10% of dietary iron is absorbed in healthy adults. 2. Iron Transport and Storage: o Iron is transported by transferrin. o Body contains ~50 mg/kg of iron: 65% in hemoglobin, 10% in myoglobulin, rest in liver, macrophages, and bone marrow. o Daily dietary intake of iron: ~15 mg (10% haem, 90% non-haem). o Absorbed iron (1-2 mg/day) mainly through the duodenum. o Ferrous iron (Fe2+) is more readily absorbed than ferric iron (Fe3+). 3. Iron Loss and Requirements: o Daily iron loss: 0.5–1 mg (faeces, sweat, urine). o Women lose an additional 0.5–1 mg/day due to menstruation. o Pregnancy increases iron requirement by 1–2 mg/day. o Hepcidin regulates iron uptake from the duodenum. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy Chapter 1 Clinical Page |7 4. Causes of IDA: o Occult gastrointestinal blood losses (e.g., gastric carcinoma, colonic carcinoma, benign gastric ulceration). o Malabsorption issues (e.g., coeliac disease, Helicobacter pylori). o Non-gastrointestinal blood losses (e.g., menstruation, blood donation). o Medications (e.g., aspirin, NSAIDs) causing bleeding. Clinical Manifestations of IDA 1. General Symptoms: o Fatigue o Weakness o Pallor o Breathlessness o Heart failure risk (in severe cases) 2. Chronic Iron Deficiency Symptoms: o Koilonychia (spoon-shaped nails) o Dysphagia o Pica (craving for non-nutritive substances) Investigations 1. Initial Blood Tests: o Full blood count (FBC): low MCV, low MCH. o Stained blood film: microcytic, hypochromic red blood cells, poikilocytes (abnormal shaped RBC), and target cells. 2. Definitive Markers: o Ferritin level: low ferritin (20 0 mmol/L. With eplerenone, similar contraindications exist, and therefore close monitoring of blood biochemistry and renal function must be undertaken for the use of either agent. Currently, there is no evidence available regarding the effectiveness and safety of combining an ACE inhibitor, ARB and a mineralocorticoid receptor antagonist, and such combination is avoided. Sacubitril Neprilysin breaks down endogenous vasoactive peptides (e.g. natriuretic peptides, bradykinin), meaning that neprilysin inhibition elevates plasma levels of these peptides, which in turn offset the activation of the renin– angiotensin–aldosterone system and its negative consequences on symptom control and disease progression in heart failure. Replacing ACE inhibitor therapy in suitable patients with the combination of Sacubitril/valsartan has been shown to reduce cardiovascular mortality and hospital admissions for heart failure in patients who are poorly controlled under treatment with an ACE inhibitor (or ARB), β- blockers and/or mineralocorticoid receptor antagonist. Patients shown to benefit are those with moderate to severe heart failure who have either markedly elevated plasma BNP levels or previous hospital admission for heart failure. Because both ACE inhibitors and sacubitril inhibit the breakdown of bradykinin, there is an increased risk of angioedema and hypotension with overlapping use of these agents, and therefore it is recommended that ACE inhibitor is stopped at least 36 hours before initiating sacubitril/valsartan. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 5 Clinical P a g e | 101 Ivabradine Ivabradine is a new type of medicine that reduces the pacemaker activity of the sinoatrial node. As with β-blockers, ivabradine reduces the heart rate, but it lacks negative inotropic effects, which has obvious advantages in patients with heart failure. The use of ivabradine in heart failure reduces heart failure deaths and hospitalization due to heart failure when added to usual care of patients with moderate to severe heart failure. It is recommended for use in patients who have had a hospital admission for heart failure in the preceding 12 months but have stabilized on standard therapy for at least 4 weeks. Due to the risk of severe bradycardia with the combined use of β-blockers and ivabradine, it is recommended that patients have a sinus rhythm heart rate ≥75 beats/min despite maximum tolerated doses of β-blockers. Digoxin Although the use of digoxin in heart failure in patients in sinus rhythm has no measurable impact on mortality, it reduces the number of hospital admissions. Consequently, digoxin is currently recommended for use as add-on therapy at low doses in patients with moderate to severe heart failure who remain symptomatic despite adequate doses of ACE inhibitor, β-blocker and diuretic treatment. Digoxin is a positive inotropic agent and acts by increasing the availability of calcium within the myocardial cell through an inhibition of sodium extrusion, thereby increasing sodium–calcium exchange and leading to enhanced contractility of cardiac muscle. Digoxin increases cardiac output in patients with co-existing atrial fibrillation by suppressing atrioventricular conduction and controlling the ventricular rate. Routine monitoring of serum digoxin concentrations in the pharmaceutical care of the patient is not recommended, other than to confirm or exclude digoxin toxicity or investigate issues around patient adherence. Digoxin treatment is potentially hazardous due to its low therapeutic index, it may cause bradycardia and lead to potentially fatal cardiac arrhythmias. Other symptoms associated with digoxin toxicity include nausea, vomiting, confusion and visual disturbances. Digoxin toxicity is more pronounced a. In patients with cardiac ischemia b. In the presence of metabolic or electrolyte disturbances (hypokalemia, hypomagnesaemia, hypercalcemia, alkalosis, hypothyroidism or hypoxia) Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 5 Clinical P a g e | 102 Treatment may be required to restore serum potassium, and in emergency situations, intravenous digoxin-specific antibody fragments can be used to treat life-threatening digoxin toxicity. Nitrates (Isosorbide dinitrate and sometimes mononitrate) / hydralazine Nitrates exert their effects in heart failure predominantly on the venous system, where they cause venodilation, thereby reducing the symptoms of pulmonary congestion with an arterial vasodilator such as hydralazine, which reduces the afterload. The combination increases in cardiac output, and there is evidence to show the combination is effective and associated with a reduction in mortality although the reduction is much smaller than that seen with ACE inhibitors especially in the white population. The combination has been shown to reduce mortality, heart failure hospitalization rates and quality of life in African patients, when added as an adjunct to optimum medical therapy, The combination has mainly been reserved for patients unable to tolerate or with a contraindication to ACE inhibitor therapy or for those patients of African descent. Organic nitrate vasodilators work by interacting with sulphydryl groups found in the vascular tissue. leading to the vasodilatory effect. Depletion of tissue sulphydryl groupings can occur during continued treatment with nitrates and is partly responsible for the development of TOLERANCE in patients with sustained exposure to high nitrate doses. Restoration of sulphydryl groupings occurs within hours of treatment being interrupted; therefore, nitrate tolerance can be prevented by the use of an asymmetrical dosing regimen to ensure that the patient experiences a daily nitrate-free period of more than 8 hours. In the acute setting, glyceryl trinitrate (GTN) might be administered intravenously, along with a loop diuretic, to patients with heart failure and concomitant myocardial ischaemia. ISMN is longer acting than ISDN and are both given orally. Hydralazine has a direct action on arteriolar smooth muscle to produce arterial vasodilation. Its use is associated with the risk of causing drug-induced systemic lupus erythematosus (SLE). SLE is an uncommon multisystem connective tissue disorder that is more likely to occur in patients classified as slow acetylators of hydralazine. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 5 Clinical P a g e | 103 Inotropic/Vasopressor agents The use of inotropic/vasopressor agents (except digoxin) is almost exclusively limited to hospital practice, where acute heart failure with potentially reversible cardiogenic shock (hypotension or hypoperfusion) may require the use of agents such as the sympathomimetic dopexamine in an intravenous continuous infusion. They may be used to address persisting hypotension and hypoperfusion in the critical care setting. These agents have inotrope-vasodilator effects that differ according to their action on α, β1, β2 and dopamine receptors. a. Dopexamine acts on β2 adrenoceptors in cardiac muscle with a lesser effect on peripheral dopamine receptors, which together produces a positive inotropic effect and an increase in renal perfusion. Disadvantages: Tolerance to sympathomimetic inotropic agents may develop on prolonged administration, particularly in patients with underlying ischaemia, and is also associated with a risk of precipitating arrhythmias. b. Noradrenaline (norepinephrine) is an α-adrenoreceptor agonist; its vasoconstrictor action limits its usefulness in severely hypotensive patients such as those in septic shock. c. Adrenaline (epinephrine) has β1-, β2- and α-adrenoreceptor agonist effects and is used in patients with low vascular resistance. However, it is more arrhythmogenic than dobutamine and should be used with caution. d. Phosphodiesterase inhibitors are rarely used in clinical practice as a consequence of trials showing an increased risk of mortality and there being little evidence to date to show they improve prognosis or survival. Other agents  Direct-acting vasodilators such as sodium nitroprusside are rarely used.  Patients with coronary heart disease may be candidates for calcium-blocking antianginal vasodilators. However, some of these agents can exacerbate co-existing heart failure because their negative inotropic effects offset the potentially beneficial arterial vasodilation. Amlodipine and felodipine have a more selective action on vascular tissue and, therefore, a less pronounced effect on cardiac contractility than other calcium antagonists and should be the agents of choice where appropriate.  In hospitalized patients in whom compromised respiratory function remains despite medical management of heart failure, the treatment options include mechanical ventilation, continuous positive airway pressure ventilation and the use of intra-aortic balloon pumping. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 5 Clinical P a g e | 104 Guidelines 1. All guidelines confirm that ACE inhibitors should be given to all patients with all grades of heart failure, whether symptomatic or asymptomatic, in the absence of contraindication or intolerance. In patients intolerant of ACE inhibitors, the preferred alternative is an ARB. However, it should be remembered that where ACE inhibitor intolerance is due to renal dysfunction, hypotension or hyperkalaemia, similar effects could be expected with an ARB. 2. For patients with symptomatic heart failure, a loop diuretic is usually recommended to treat oedema and control symptoms. 3. In heart failure patients who are still symptomatic despite being on optimum therapy (ACE inhibitor, β-blocker, mineralocorticoid receptor antagonist with/without a diuretic), the use of adjunctive therapies is recommended, which can include sacubitril/valsartan, ivabradine, hydralazine/nitrate combination and digoxin where the patient is still in sinus rhythm. Patient care 1- Monitoring effectiveness of drug treatment Therapeutic effectiveness is confirmed by assessing the patient for improvements in reported symptoms, such as shortness of breath and oedema, and for noticeable changes in exercise tolerance. Oedema is often visible and remarked upon by patients, especially in the feet (ankles) and hands (wrists and fingers). Increased oedema may be reflected by an increase in the patient’s body weight and can be more easily assessed if the patient routinely records his or her weight and reviews this on a daily basis. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 5 Clinical P a g e | 105 2- Potential problems with diuretic therapy Elderly patients in particular are at risk from the unwanted effects of diuretics. 1. The increase in urine volume can worsen incontinence or precipitate urinary retention in the presence of an enlarged prostate. 2. Rapid diuresis with a loop diuretic leading to more than a 1 kg loss in body weight per day may exacerbate heart failure due to an acute reduction in blood volume, hypotension and diminished renal perfusion. 3. Prolonged and excessive doses of diuretics can also contribute to symptoms of fatigue as a consequence of electrolyte disturbance and dehydration. 4. The adverse biochemical effects of excessive diuresis include uremia, hypokalaemia and alkalosis. 5. Diuretic-induced glucose intolerance may affect diabetic control in type 2 diabetes, 6. Diuretics also causes hyperuricaemia, although this may not require a change in drug therapy if symptoms of gout are absent.. 7. Hyponatraemia may occur with diuretics and is usually due to water retention rather than sodium loss. Severe hyponatraemia causes confusion and drowsiness. It commonly arises when potassium sparing agents are used in diuretic combinations. 8. Diuretics may also lead to hypokalaemia. The occurrence of hypokalaemia is hazardous for patients receiving digoxin and also for those with ischaemic heart disease or conduction disorders. Potential problems with angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker and mineralocorticoid receptor antagonist therapy 1. Both agents can predispose patients to hyperkalaemia through a reduction in circulating aldosterone; therefore, potassium supplements or potassium-retaining agents should be used with care when co-prescribed, and careful monitoring of serum potassium should be mandatory. Although potassium retention can be a problem with ACE inhibitors and ARBs, it can also be an advantage by helping counteract the potassium loss that can result from the use of diuretic therapy. However, because this effect on potassium cannot be predicted, laboratory monitoring is still necessary to confirm that serum potassium concentration remains within safe limits. a- The use of a mineralocorticoid receptor antagonist with an ACE inhibitor (or ARB if the patient is ACE inhibitor intolerant) can be safely undertaken with minimal effects on the serum potassium concentration, provided that recommended target doses Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 5 Clinical P a g e | 106 for the mineralocorticoid receptor antagonist are not exceeded. Although this is usually the case, laboratory monitoring of potassium is mandatory to ensure patient safety. b- Heparin therapy has also been shown to increase the risk of hyperkalaemia when used alongside ACE inhibitor or ARB therapy, and therefore a similar approach to monitoring should be taken when co-prescribed. 2. When initiating ACE inhibitor or ARB therapy, with diuretics this increases the risk of a large drop in blood pressure occurring after the first dose. As a consequence, diuretic treatment is usually withheld during the initiation phase of therapy in an effort to minimize this effect. 3. A dry cough, which may be accompanied by a voice change, occurs in about 10% of patients receiving an ACE inhibitor. It is more common in women and is associated with a raised level of kinins. 4. Rashes, loss or disturbances of taste, mouth ulcers and proteinuria may also occur with ACE inhibitor therapy, particularly with captopril. Potential problems with β-blocker therapy Monitoring for excessive bradycardia or rapid deterioration of symptoms is necessary to ensure patient safety while also monitoring the patient’s prescribed dose to ensure that dosage increments are gradual and that the patient is not subjected to an overall worsening of symptoms. Potential problems with sacubitril/valsartan therapy There is a need to be alert to the possible development of angioedema, particularly where there is a family history. Any swelling of the face, lips, tongue and/or throat, which may cause difficulties in breathing or swallowing, require immediate medical attention. Careful monitoring should be undertaken when switching from an ACE inhibitor to this combination, and it is important to ensure an interval of at least 36 hours between stopping the ACE inhibitor and starting the new therapy. Potential problems with digoxin therapy Digoxin use is associated with a range of adverse effects, including nonspecific signs and symptoms of toxicity such as nausea, anorexia, tiredness, weakness, diarrhoea, confusion and visual disturbances. Digoxin also has the potential to cause fatal arrhythmias. It slows atrioventricular conduction and produces bradycardia, but it may also cause various ventricular and supraventricular arrhythmias. The appropriateness of digoxin dosage should be guided by assessment of the patient’s renal function (from serum creatinine and creatinine clearance determinations) and pulse rate. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 5 Clinical P a g e | 107 Potential problems with other cardiovascular drugs Patients with coronary artery disease may be candidates for calcium-blocking antianginal vasodilators. However, some of these agents, for example, diltiazem and verapamil, can exacerbate co-existing heart failure because their negative inotropic effects offset the potentially beneficial arterial vasodilation. Symptoms of fainting or dizziness on standing may indicate a need to review diuretic or vasodilator therapy. Patients should be reassured about mild postural effects and given advice to avoid standing from a chair too quickly. Potential problems with non-cardiovascular agents A number of agents should be avoided or used with caution in patients with heart failure because of their known negative inotropic or proarrhythmic effects that may aggravate symptoms of heart failure. In particular,  the use of non-steroidal anti-inflammatory drugs (NSAIDs) should be actively discouraged where possible:  NSAIDs cause fluid retention  Put patients at increased risk of bleeding, especially if they are already taking antiplatelets or anticoagulants.  There is also an increased risk of acute renal failure, particularly in those on long- term use and in the elderly, particularly when they experience intercurrent illness (diarrhoea, vomiting, severe infections) with dehydration. Recent articles have described the synergistic/cumulative adverse renal effects of combinations of ACE inhibitors or ARBs with diuretics and NSAIDs, which are particularly common in patients with heart failure. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 108 Menstrual Cycle Disorders The onset of menstruation, known as menarche, typically occurs around 12.5 years with 95% of girls experiencing it between ages 11 and 15. Factors influencing menarche include body weight and serum leptin levels, though non-genetic influences are inconclusive. Early menarche is linked to later health issues like breast cancer, endometrial cancer, type 2 diabetes, and psychological problems. Menstruation is regulated by the central nervous system, leading to the maturation of the hypothalamic-pituitary-gonadal axis over up to two years. The menstrual cycle involves cyclic hormonal variations. During the follicular phase, estrogen thickens the endometrium. A critical estrogen level triggers a surge of luteinizing hormone, leading to ovulation. In the luteal phase, progesterone from the corpus luteum maintains the endometrium for potential implantation. If fertilization doesn’t occur, hormone levels fall, causing endometrial necrosis and menstruation. Blood loss averages 30-40 mL per period. Develop several One of them ↑ FSH ↑ Estradiol become dominant follicles 1- Follicular phase (Day 1-13) ↑ LH ↑ Androgen 2- Surge in LH Ovulation Mature follicle occurs (Just before ruptures ovulation) (day 14) 3- Luteal Phase ↑ Thickness of ↑ Progesterone uterus lining (day 15-28) If pregnancy 4- Menses ↓ Hormones Bleeding doesn’t occur Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 109 Menstrual disorders are common, including dysmenorrhea, heavy menstrual bleeding (Menorrhagia), and endometriosis, with various treatment options available. Prostaglandins and possibly leukotrienes play roles in menstruation. Premenstrual syndrome (PMS) Premenstrual syndrome (PMS) involves mood changes and physical symptoms that typically start a few days before menstruation and disappear at its onset or shortly after. However, some women may experience symptoms that persist even after menstruation begins. PMS can significantly impair daily activities, including reducing work productivity. The severity of symptoms can vary with each cycle and be influenced by stress and fatigue. The most severe form of PMS is premenstrual dysphoric disorder (PMDD), which has been recognized with full diagnostic status in the DSM-V. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 110 Epidemiology Severe PMS is more common in the 30- to 40-year age range, and married women with young children commonly seek help. Certain events may be linked with the onset of PMS, including  Childbirth,  Cessation of oral contraceptive use (incidence of reported PMS is lower in pill users),  Sterilization,  Hysterectomy or  Increasing age. PMS may be exacerbated by other stresses, typically those associated with family life. Women with a body mass index greater than 30 are more likely to suffer from PMS. There is also some evidence that crimes, accidents, examination failure, absenteeism and marital disturbances may be more common premenstrually. Etiology PMS is not seen before puberty, during pregnancy or in postmenopausal women; therefore, the ovarian hormones have been implicated. The mineralocorticoids, prolactin, androgens, prostaglandins, endorphins, nutritional factors (e.g. pyridoxine, calcium and essential fatty acids) and hypoglycemia may be involved. In addition, changes in CNS function have been implicated because cerebral blood flow in the temporal lobes is decreased premenstrually in PMS sufferers, and noradrenergic cyclicity is disrupted. There is some evidence that predisposition to PMDD may be familial. Hormones The cyclic nature of PMS suggests ovarian involvement, as it persists after hysterectomy if ovaries are intact and disappears during pregnancy and post-menopause. 1. One theory attributes PMS to a luteal phase progesterone deficiency, leading to a progesterone/estradiol imbalance, though no direct clinical evidence supports this. The issue may lie at the cellular level, such as a lack of functional steroid receptors or genetic variations in the estrogen receptor alpha gene. 2. PMS could also be due to a central control defect, as ovarian suppression by GnRH analogues alleviates symptoms but is generally not recommended due to unwanted hypo- estrogenic effects. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 111  The interaction between sex steroids and the CNS is significant, with estradiol increasing neuronal excitability and progesterone metabolites binding to the GABAA receptor, producing effects similar to benzodiazepines.  Aldosterone, linked to fluid retention, shows elevated serum levels in the luteal phase, though not significantly different between PMS sufferers and non- sufferers.  Cortisol levels, however, are elevated in PMS sufferers during the luteal phase.  Prolactin, associated with breast tenderness and stress, promotes fluid retention and affects dopamine metabolism, yet no consistent difference in prolactin levels is found between sufferers and non-sufferers.  Local hormones like prostaglandins also play a role, with imbalances contributing to PMS. Increased synthesis of PGE2, which has antidiuretic and sedative effects, and deficiencies of PGE1, which moderates prolactin actions, are implicated in the syndrome. Vitamins and minerals Pyridoxine phosphate is a cofactor in a number of enzyme reactions, particularly those leading to production of dopamine and serotonin (5-hydroxytryptamine). 1. It has been suggested that disturbances of the estrogen–progesterone balance could cause a relative deficiency of pyridoxine, and supplementation with this vitamin appears to ease the depression sometimes associated with the oral contraceptive pill. 2. Decreased dopamine levels would tend to increase serum prolactin, and decreased serotonin levels could be a factor in emotional disturbances, particularly depression. There is some evidence that premenstrual mood changes are linked to cycle-related alterations in serotonergic activity within the CNS; therefore, serotonin may be important in the pathogenesis of PMS. 3. There are also data to suggest that a variety of nutrients may play a role in the etiology of PMS, specifically calcium and vitamin D. a. Further hydroxylation of 25-hydroxyvitamin D3 [25(OH)D3)] takes place in target tissues which include the breast and the endometrium. In the Nurses’ Health Study II, high total vitamin D intake reduced risk of PMS by almost a third (Bertone-Johnson et al., 2005). b. Estrogen influences calcium metabolism by affecting intestinal absorption, as well as parathyroid gene expression and secretion, thus triggering fluctuations throughout the menstrual cycle. Disruption of calcium homeostasis has been associated with affective disorders. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 112 Essential fatty acids  Essential Fatty Acids and Prostaglandin Synthesis:  γ-Linolenic acid (GLA) is crucial for prostaglandin synthesis.  GLA is converted into di-homo-γ-linolenic acid, a precursor for prostaglandins of the 1 series (e.g., PGE1).  Role of PGE1:  PGE1 can attenuate the biological effects of prolactin.  Women with PMS may be abnormally sensitive to normal prolactin levels.  A deficiency in GLA leads to less PGE1, potentially exaggerating prolactin's effects (breast tenderness, fluid retention, mood disturbances).  Dietary Factors Affecting GLA Levels:  Excess saturated fats and cholesterol can hinder GLA conversion.  Moderate-to-high alcohol consumption negatively impacts GLA synthesis.  Zinc and magnesium deficiencies reduce GLA levels.  Conditions like diabetes, aging, and viral infections hinder the conversion of cis-linolenic acid to GLA.  Vitamins Enhancing GLA Conversion:  Pyridoxine (B6), ascorbic acid (C), and niacin (B3) enhance the conversion of GLA to PGE1.  Evidence suggests linolenic acid metabolite levels may be reduced in women with PMS Symptoms Symptoms occur 1–14 days before menstruation begins and disappear at the onset or shortly after menstruation begins. For the rest of the cycle, the woman feels well. Symptoms are cyclical, although they may not be experienced every cycle, and can be either physical and/or psychological. The symptoms of PMS tend to decrease as a woman gets closer to menopause as her ovulatory cycles become less frequent. Management Non-pharmacological strategies Maintenance of good general health is important, especially with respect to diet and possible deficiencies.  Dietary modifications that may be helpful include restricting caffeine and alcohol intake.  Smoking can also exacerbate symptoms.  Exercise may help, as may learning simple relaxation techniques.  If fluid retention is a problem, then reducing fluid and salt intake may be of value. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 113  Increasing the intake of natural diuretics such as prunes, figs, celery, cucumber, parsley and foods high in potassium such as bananas, oranges, dried fruits, nuts, soya beans and tomatoes may all be useful.  Hypoglycemia may also be involved in premenstrual tiredness, so eating small, protein-rich meals more frequently may help.  Some women do respond to pyridoxine and show improvement, particularly with respect to mood change, breast discomfort and headache.  Gastric upset and headaches have been reported at doses greater than 200 mg.  High doses over long periods have also been associated with peripheral neuropathies.  Administration: Pyridoxine should be commenced 3 days before symptom onset and continued for 2 days after menstruation has started.  Calcium supplementation has shown some activity in reducing emotional, behavioral and physical symptoms. In addition, vitamin D and magnesium nutritional status have been found to be compromised in women with PMS. There is limited evidence that supplementation with γ-linolenic acid, found in evening primrose oil, gives relief from physical symptoms, especially breast tenderness. Pharmacological management 1. Progestogens. Synthetic progestogens, in preparations such as Cyclogest, have been used in the past. However, because of the lack of convincing trial evidence and the risk of side effects, the use of progestogens is no longer recommended. Possible side effects include weight gain, nausea, breast discomfort, breakthrough bleeding and changes in cycle length. Side effects of some Progestins like Norethisterone and levonorgestrel, are because they display some affinity for glucocorticoid, mineralocorticoid and androgen receptors. 2. Combined oral contraceptives. Some women are helped by the combined oral contraceptives (COCs) pill because it prevents ovulation from taking place. However, the use of exogenous estrogen may be contraindicated because it can increase the risk of venous thromboembolism. This occurs because  Estrogen decreases blood levels of the potent natural anticoagulant antithrombin III and  Increases serum levels of some clotting factors. Some studies have reported a greater risk of venous thromboembolism in women using preparations containing the third-generation progestogens desogestrel and gestodene. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 114 However, it should be noted that the absolute risk of venous thromboembolism in women using COCs that contain these third-generation progestogens remains very small and well below the venous thromboembolism risk associated with pregnancy. In conclusion, if there is a history of thromboembolic disease at a young age in the immediate family, then disturbances of the coagulation system must be ruled out. The combination of (ethinyl estradiol with drospirenone) is also available as an oral contraceptive and appears to be useful in the management of PMS. Drospirenone is a derivative of spironolactone, with affinity for progesterone receptors, but it also acts as a mineralocorticoid antagonist. This progestogen, therefore, alleviates some of the salt-retaining effects of the ethinyl estradiol. 3. Antidepressants. The selective serotonin reuptake inhibitors (SSRIs) are becoming more popular in the treatment of PMS related depression because they are effective and well tolerated (Brown et al., 2009). Several randomized controlled trials using fluoxetine, sertraline, citalopram, fluvoxamine or paroxetine concluded that SSRIs are an effective first-line therapy for severe PMS, and the side effects at low doses are generally acceptable. SSRIs, which could be taken continuously across the cycle or restricted to only the luteal phase, can reduce the symptoms of PMS. Studies have also found that not only do SSRIs improve behavioral symptoms, but some improvement in physical symptoms has also been noted, and this is being reflected in the increased prescribing of SSRIs. Common side effects experienced include headache, nervousness, drowsiness and fatigue, sexual dysfunction and gastro-intestinal disturbances. Dose-dependent adverse effects are common (e.g. nausea and asthenia). Other agents such as tricyclic antidepressants and anxiolytics such as buspirone have been used. However, they appear to improve fewer PMS symptoms than the SSRIs. St John’s wort has been used to reduce the severity of PMS, but the available evidence is limited. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 115 4. Other treatments.  Bromocriptine:  Stimulates central dopamine receptors, inhibiting prolactin release.  Useful for breast tenderness, fluid retention, and mood changes.  Side effects often outweigh benefits.  Prostaglandin Synthesis Inhibitors (NSAID):  Improve tension, irritability, depression, headache, and general aches.  Mefenamic acid is commonly used: o Dosage: 250 mg three times a day, 12 days before period. o Increase to 500 mg three times a day, 9 days before period. o Continue until the third day of menstruation.  Mefenamic acid also acts as a PGE receptor antagonist, useful for heavy menstrual bleeding.  Best started 24 hours before symptoms, challenging with irregular cycles.  GnRH Analogues (Gonadorelin Analogues):  Manage physical symptoms but less effective for emotional symptoms.  Inhibit the hypothalamic–pituitary–gonadal axis.  Limited to short-term use (up to 6 months) due to risk of hypo-oestrogenic state and bone loss.  Bilateral oophorectomy may be beneficial if effective post-hysterectomy Dysmenorrhea Dysmenorrhea is usually subdivided into primary and secondary dysmenorrhea. Primary dysmenorrhea may also be referred to as spasmodic dysmenorrhea, which is a uterine problem and is predominantly an issue of young women. Secondary dysmenorrhea is so-called because it occurs secondary to some underlying pelvic pathology such as endometriosis or pelvic inflammatory disease (PID). Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 116 Primary dysmenorrhea Etiology and symptoms The incidence of primary dysmenorrhea peaks in women in their late teens and early 20s; the pain coincides with establishment of ovulatory cycles. Symptoms lower abdominal pain (cramping), which may radiate down into the thighs, and backache. Some women also suffer gastro-intestinal symptoms (nausea, vomiting, diarrhoea), headaches and faintness. Symptoms are intense on the first day of menses but rarely continue beyond day 1 or 2 of the cycle. Factors that appear to increase the severity include young age at menarche, extended duration of menstrual low (pain can be most severe when the low is lighter), smoking and parity (the prevalence and severity of dysmenorrhea is decreased in parous women). Other factors such as weight, length of menstrual cycle or frequency of physical exercise do not influence the condition. Studies indicate high concentrations of prostaglandins, especially PGF2α and PGE2, in sufferers, leading to increased myometrial contractility and gastrointestinal issues. Diets rich in omega-3 fatty acids, producing less potent prostaglandins (PGE3), reduce symptoms. Endothelins and vasopressin also play roles by affecting uterine blood flow and stimulating uterine activity. Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 117 Secondary dysmenorrhea Etiology and symptoms Secondary dysmenorrhea tends to afflict women in their 30s and 40s, and usually occurs as a consequence of some other pelvic pathology such as endometriosis or pelvic inflammation. In terms of symptoms, it differs from primary dysmenorrhea in that the pain may actually start before menstruation begins, continue for the duration of menses and be associated with abdominal bloating, backache and a general feeling of ‘heaviness’ in the pelvic area. Women with inflammatory bowel disease also have symptom exacerbation during menses, and it is possible that the prostaglandins are involved in this aspect of patho-etiology. The Intrauterine contraceptive device may also exacerbate menstrual pain, because it causes localized inflammation that triggers the release of prostaglandins. If the cause is endometriosis, in which endometrial tissue is found outside the uterine cavity, then this extrauterine tissue can also synthesize prostaglandins, which may in turn disrupt normal uterine function. Treatment  NSAIDs:  Most rational choice for analgesia.  Inhibit COX, reducing prostaglandin biosynthesis.  Examples: Mefenamic acid (also blocks PGE receptors).  Alternative NSAIDs:  Celecoxib and Etoricoxib effective but not licensed for dysmenorrhea.  Leukotriene Receptor Antagonists:  Montelukast may alleviate pain and reduce NSAID usage, especially effective in women without endometriosis.  Oral Contraceptive Pill:  Relieves symptoms in about 50% of sufferers.  Inhibits ovulation, reducing prostaglandin synthesis and uterine contractility.  Not suitable for all due to potential side effects (e.g., high blood pressure, obesity, history of venous thromboembolism). Dr.Mohammed Ali Alobaidy F.I.C.M.S Clinical Pharmacy  Chapter 6 Clinical P a g e | 118  Progestogenic Preparations:  Norethisterone (5 mg three times daily from day 5 to 24 of the cycle).  Progestogen-only pills, if they inhibit ovulation.  Antispasmodics:  Limited role due to poor oral bioavailability.  Examples: Hyoscine butylbromide, propantheline bromide, atropine.  Vasopressin Antagonists:  Effective, well-tolerated, do not affect bleeding patterns.  Secondary Dysmenorrhea Treatment:  Find and treat underlying cause.  PID: Treat with appropriate antimicrobial therapy.  Endometriosis: Treatment reduces symptoms.  Surgery (e.g., hysterectomy) for women not wanting to become pregnant Non-pharmacological management 1. High-frequency transcutaneous nerve stimulation and acupuncture. 2. Dietary therapies such as vitamin (e.g. vitamin B1 100 mg daily) and mineral supplementation have also been investigated. One study identified that vitamin B1 100 mg daily may be effective in relieving pain. Magnesium supplementation also shows promising results. Heavy menstrual bleeding Blood loss is considered to be excessive if it exceeds 80 mL per period, although both women themselves and clinicians find it difficult to objectively quantify blood loss. In practice, it is defined by the woman’s subjective assessment of blood loss. Physically, excessive blood loss will precipitate iron deficiency anemia (haemoglobin