Pharm Exam PDF

PRIMARY PREVENTION AND DRUGS THAT LOWER CHOLESTEROL Dr. Adam Gratton NMT150 MSc ND April 6, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used positively affect lipid profiles - HMG-CoA Reductase Inhibitors -...

PRIMARY PREVENTION AND DRUGS THAT LOWER CHOLESTEROL Dr. Adam Gratton NMT150 MSc ND April 6, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used positively affect lipid profiles - HMG-CoA Reductase Inhibitors - Bile Acid-Binding Resins - Cholesterol Absorption Inhibitors - Fibrates - Niacin Define primary prevention in terms of cardiovascular disease Describe the impact and adverse effects of the main evidence-based treatment options to reduce the risk of serious or fatal cardiovascular events PRIMARY PREVENTION Vascular disease is one of the top contributors to mortality and morbidity in Canada Many modifiable risk factors exist, yet remain undertreated Prevention requires early recognition Evidence supporting primary preventive interventions quite low compared to secondary prevention RISK ASSESSMENT/FACTORS Modifiable Non-modifiable Diabetes Diet Age Dyslipidemia Family history Hypertension Assigned male at birth Lack of physical activity Obesity Tobacco use RISK ASSESSMENT TOOLS There are many validated tools Framingham risk score is most commonly used Provides an estimate of the chance of experiencing a vascular event (coronary heart disease, cerebrovascular disease, peripheral vascular disease, heart failure) in the next 10 years Score 10 or lower – Low risk, 11 – 19 – Intermediate, 20 or higher - High A LESSON ON RISK Absolute Risk (AR) - the number of events (good or bad) in a treated (exposed) or control (non-exposed) group, divided by the number of people in that group Absolute Risk Reduction (ARR) - the AR of events in the control group minus the AR of events in the treatment group A LESSON ON RISK Number Needed to Treat (NNT) - a measurement of the impact of a medicine or therapy by estimating the number of patients that need to be treated to have an impact on one person Number Needed to Harm (NNH) - a measure of how many people need to be treated (or exposed to a risk factor) for one person to have a particular adverse effect A LESSON ON RISK https://bestpractice.bmj.com/info/toolkit/learn- ebm/how-to-calculate-risk/ PHARMACOLOGIC CHOICES Antihypertensive therapy Statin therapy Low-dose ASA ANTIHYPERTENSIVE THERAPY Myocardial infarction ARR = 0.7% NNT = 143 Stroke ARR = 1.3 % NNT= 77 With 4-5 years of therapy RR reduction ~ 20-40% for first major vascular event vs placebo Adverse effects related to the specific medications used STATIN THERAPY Cardiovascular event ARR = 1.39% NNT = 52 Myocardial infarction ARR= 0.81% NNT = 123 Stroke ARR= 0.38% NNT = 263 With 2 – 5 years of therapy Most common adverse effect is myalgia LOW DOSE ASA THERAPY Major cardiovascular event ARR = 0.41% NNT = 241 Myocardial infarction ARR = 0.28% NNT = 361 Major bleeding ARI 0.47% NNH 210 With 5 years of therapy Major bleeding is usually within the GI tract LIPID LOWERING DRUGS HMG-CoA Reductase Inhibitors Atorvastatin Bile Acid-Binding Resins Cholestyramine Cholesterol Absorption Inhibitor Ezetimibe Fibrates Fenofibrate Niacin LIPID ABSORPTION HMG-COA REDUCTASE INHIBITORS Aka statins The generic naming convention of these drugs includes “statin” at the end of the name Atorvastatin The most common cholesterol lowering drug used in clinical practice The only drug approved for primary prevention of cardiovascular disease HMG-COA REDUCTASE INHIBITORS Cholesterol synthesis involves several steps to take acetyl CoA and acetoacetyl CoA and ultimately convert them to a molecule of cholesterol. The rate-limiting step occurs early in the biosynthesis pathway where HMG-CoA is converted to mevalonate via the enzyme HMG CoA reductase Statins inhibit this enzyme and substantially slow down the biosynthesis of cholesterol HMG-COA REDUCTASE INHIBITORS Reduced cholesterol results in reduced hepatic secretion of VLDL Reduced cholesterol also stimulates transcription for LDL receptors Increased LDL receptors result in more binding of circulating LDL to increase hepatic cholesterol ATORVASTATIN The second-most potent statin available The first statin to be approved for use in 1987 although atorvastatin had been studied in Japan since the mid-70s as an isolate of the mold Monascus purpureusi aka Red Yeast which grows on rice. RYRE produces a number of statin-like compounds, including the drug lovastatin, which is less potent than other statins INDICATIONS Lowering LDL-C Primary prevention of CVD Statins, in general, lower LDL-C by 20-60% and increase HDL-C by 5-15%  ADVERSE EFFECTS The most serious adverse effect is rhabdomyolysis (potentially fatal skeletal muscle toxicity) - 0.2% of all patients taking a statin will experience this - Myalgia and myositis may also be caused by statins The potential for muscle-related adverse effects increases with dose Additional factors: Being assigned female at birth, renal and hepatic disease, hypothyroidism, and use of CYP3A4 inhibitors Muscle-related side effects resolve with discontinuation of the medication Common adverse effects are GI related ABSORPTION INHIBITION Dietary lipids are absorbed as small micelles into enterocytes via a transporter called Niemann-Pick C1-Like 1 (aka NPC1L1) among others (step 3b in previous image on slide 9) Mechanistically, drugs that prevent the function of transport proteins, bind dietary lipids and prevent incorporation into micelles or compete with lipids for micelle carriage could all reduce absorption ABSORPTION INHIBITION Transport protein inhibition - Specifically NPC1L1 - Ezetimibe Binding dietary lipids preventing incorporation into micelles - Cholestyramine EZETIMIBE Currently a class unto itself Inhibits NPC1L1 and prevents absorption of cholesterol from the intestinal lumen This inhibits the absorption of cholesterol from the diet as well as cholesterol secreted as bile Reduced cholesterol increases LDL receptors and takes LDL-C out of circulation Administered as a prodrug which needs to be metabolized to the active form ezetimibe-glucuronide which localizes to the small intestine EZETIMIBE Adverse effects are uncommon and it has a low potential for drug interactions Because it is a prodrug, moderate to severe hepatic impairment substantially decreases its effect Magnitude of benefit – reduces LDL-C by 14-25% and increases HDL-C by 1% CHOLESTYRAMINE A bile acid-binding resin – a high molecular weight polymer that can bind bile acids Binding to bile acids prevents reabsorption in the small intestine and forces the excretion of cholesterol This also forces the liver to create new bile acids using cholesterol already in the body Decreased cholesterol then increases LDL receptors and use of LDL-C by the liver CHOLESTYRAMINE Completely unabsorbed and works entirely within the digestive tract Adverse effects include: constipation, fecal impaction, rash, decreased absorption of fat-soluble vitamins Magnitude of benefit – reduces LDL-C by 10-30% and increases HDL-C by 3-10% CHOLESTYRAMINE Drug interactions Has the capacity to bind other drugs like digoxin, thyroxin, and warfarin Decreases absorption of ezetimibe FIBRATES Whereas the rest of the drugs discussed are indicated for hypercholesterolemia, fibrates, as a class, have a more modest effect at reducing LDL-C Better suited for increasing HDL-C and reducing triglycerides - Diabetic dyslipidemias - Benefit seems to be best in diabetic populations FENOFIBRATE Activator of PPAR-α (peroxisome proliferator activated receptor) Activation of PPAR-α increases lipolysis and elimination of triglyceride-rich particles from plasma Activation also changes lipoprotein ratios – increase apoprotein AI and AII which increases HDL and reduces apolipoprotein B which reduces VLDL and LDL FENOFIBRATE Magnitude of benefit – lowers LDL-C by 5-20%, increases HDL-C by 10-35% More potent at lowering triglycerides by 20-50% FENOFIBRATE Adverse Effects Can cause myopathy and rhabdomyolysis like statins, especially when the two are combined Can also cause decreased platelets and white blood cells, allergic reactions, and cholelithiasis Contraindicated in patients with hepatic dysfunction and pre- existing gall bladder disease NIACIN Has the broadest spectrum of lipid-altering effects of any agent Dose required is quite large 1.5-4 g/d Given the flushing response (erythema and pruritus) to mg doses it is not routinely used Works by inhibiting lipolysis in adipose tissue which results in reduced formation and secretion of hepatic VLDL (which is a precursor to LDL) May also cause liver damage and hepatitis, hyperuricemia, and gout, and aggravate peptic ulcers SAMPLE QUESTION Which of the following drugs can cause rhabdomyolysis as an adverse effect? A. Niacin and cholestyramine B. Cholestyramine and fenofibrate C. Fenofibrate and atorvastatin D. Atorvastatin and niacin ANTIHYPERTENSIVE DRUGS Dr. Adam Gratton NMT150 MSc ND March 27 and 30, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used to treat hypertension - Angiotensin converting enzyme inhibitors - Angiotensin receptor blockers - Direct renin inhibitors - Alpha blockers - Beta blockers - Calcium channel blockers - Centrally acting sympatholytics - Diuretics INTRODUCTION Hypertension is the leading cause of death or disability globally Approximately 23% of Canadian adults have a diagnosis of hypertension Blood pressure targets are reached in approximately 65% of those with a diagnosis Control in women has decreased over the last ten years and is now under 50% INTRODUCTION Regulation of blood pressure is complex and controlled by several physiological systems Two major drivers of elevated blood pressure are obesity (primarily in younger adults) and vascular stiffness (primarily in older adults) Commonly considered a risk factor for future cardiovascular sequelae, like stroke, myocardial infarction, heart failure, chronic kidney disease, and dementia RENIN-ANGIOTENSIN- ALDOSTERONE DRUGS Short and long-term control of blood volume is determined by the kidneys using blood pressure and fluid volume as the driving force Drug classes include: angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor antagonists (ARB), direct renin inhibitors ACE INHIBITORS Exemplar drug: Quinapril Generic naming convention: -pril Binds the zinc atom at the active site of ACE and prevents angiotensin I from accessing it inhibiting production of angiotensin II Angiotensin II is a potent vasoconstrictor and acts at the adrenal cortex to release aldosterone ACE INHIBITORS Decreases both arterial and venous pressure, which reduces cardiac afterload and preload, respectively Prevention of compensatory increase in sodium retention that can occur with other drugs that reduce blood pressure Renal sodium retention is decreased, therefore renal potassium retention is increased (serum potassium levels typically increased by ~0.5mEq/L) ACE is also involved in the metabolism of bradykinin QUINAPRIL Food reduces absorption by 25-30%, particularly with high-fat meals Like many ACEi it is administered in prodrug form Long-lasting effects permitting once or twice daily dosing QUINAPRIL A member of a commonly used class of drugs for a number of diseases: Hypertension Diabetes Ischemic heart disease Post myocardial infarction Chronic kidney disease QUINAPRIL ADVERSE EFFECTS Dry cough is the most limiting adverse effect. If present, it usually forces the patient off of the medication as there is no effective way to manage it Hyperkalemia Angioedema (less often) Can precipitate renal failure in renovascular disease, volume depletion, or those receiving NSAIDs Not to be combined with potassium supplements or potassium-sparing diuretics QUINAPRIL All ACEi are contraindicated in pregnancy and caution should be used if the patient could become pregnant Low doses (50% of initial dose) should be used if the patient is also on a diuretic Renal function and potassium levels should be monitored regularly ANGIOTENSIN II RECEPTOR BLOCKERS Exemplar drug: candesartan Generic naming convention: -sartan In terms of use, they are very similar to ACEi Act as an antagonist and angiotensin II receptors and therefore block angiotensin II signalling which Inhibits vasoconstriction, aldosterone secretion and sodium reabsorption CANDESARTAN Identical adverse effects and contraindications as seen with ACEi (quinapril) All ARBs are contraindicated in pregnancy Indications are very similar to quinapril The primary difference between quinapril and candesartan is that since candesartan does not interfere with bradykinin metabolism reducing the potential to cause cough ARBs may have greater antihypertensive effects than ACEi Combining ACEi and ARB is not recommended DIRECT RENIN INHIBITOR Exemplar drug: aliskiren Binds to the active site of renin which prevents cleavage of angiotensinogen and therefore inhibits formation of angiotensin I (and II) ALISKIREN Incidence of cough and hyperkalemia is low compared with ACEi or ARB Most common adverse effect is diarrhea Not to be combined with ACEi or ARB Contraindicated in pregnancy and use is cautioned in those that can become pregnant It is a fairly new drug so long term safety data is lacking CALCIUM CHANNEL BLOCKERS All CCBs function as L-type calcium channel antagonists L-type calcium channels are expressed in cardiac myocytes, pacemaker cells and arteries In cardiac myocytes, L-type calcium channels permit calcium entry upon depolarization which activates ryanodine receptors in the sarcoplasmic reticulum releasing stored calcium (calcium-induced calcium release) resulting in muscular contraction  CALCIUM CHANNEL BLOCKERS In pacemaker cells, like the sinoatrial node, L-type calcium channels are involved in the steep depolarization phase of the action potentials generated there CALCIUM CHANNEL BLOCKERS Dihydropyridine: amlodipine More affinity for L-type calcium channels in the vasculature Non-dihydropyridine Phenylalkylamine class: verapamil More affinity for L-type calcium channels in the heart Benzothiazepine class: diltiazem Affinity for L-type calcium channels in both vasculature and the heart CALCIUM CHANNEL BLOCKERS Why 2 different classes? Dihydropyridines, being selective for the vasculature, have the tendency to cause rebound tachycardia because of the pronounced vasodilation and hypotension Detrimental for ischemic diseases as this results in greater myocardial oxygen demand Since they don’t have the capacity to alter cardiac function they are better when cardiac function is compromised (like with heart failure) or when altering it is not needed (uncomplicated hypertension) CALCIUM CHANNEL BLOCKERS Nondihydropyridines have less affinity for the vasculature and therefore do not exhibit the rebound tachycardia and can be used in ischemic conditions or for arrythymias, due to their higher affinity for cardiac L-type calcium channels All three classes typically have short half lives (under 6 hours) and long acting formulations (sustained release) are generally used, particularly within the context of treating hypertension  CALCIUM CHANNEL BLOCKERS Drug Coronary Blood Heart Rate and AV Conduction Flow Contractility Velocity Amlodipine ↑↑ No change or No change or ↑(reflex) ↑(reflex) Diltiazem ↑↑ ↓ ↓ Verapamil ↑↑ ↓ or ↓↓ ↓ or ↓↓  Amlodipine Verapamil Diltiazem Ankle edema, Headache, dizziness, Headache, dizziness, bradycardia, flushing, headache, bradycardia, heart block, new heart block, new onset or worsening hypotension, onset or worsening of heart of heart failure tachycardia failure, constipation Inhibits metabolism of statins Inhibits metabolism of statins Additive inotropic effects with Additive negative inotropic effects beta-blockers and digoxin with beta blockers and digoxin Not recommended in patients Not recommended in patients with with heart failure or 2nd or 3rd heart failure or 2nd or 3rd degree heart degree heart block without a block without a functioning functioning pacemaker pacemaker SYMPATHOLYTIC DRUGS Essentially interfere with adrenergic signalling, either centrally (in the CNS) or peripherally Drug classes α-adrenoreceptor antagonists – prazosin β-adrenoreceptor antagonists – atenolol Centrally acting drugs - clonidine  ADRENERGIC RECEPTORS Alpha Receptors Beta Receptors α1 α2 β1 β2 Constriction Glucose Heart Smooth muscle of blood metabolism - Increases heart rate relaxation vessels (skin, Presynaptic - Increases impulse (respiratory tract, GI, kidney, regulation of conduction bladder, uterus) brain) NE - Increases force of Increases renin contraction release by Increases renin juxtaglomerular cells release from Glucose metabolism juxtaglomerular cells Lipolysis “ALPHA BLOCKERS” Exemplar drug: prazosin A selective α1-adrenoreceptor antagonist Inhibition of signalling results in decreased vasoconstriction which decreases peripheral resistance PRAZOSIN Indications: Primarily reserved for the treatment of hypertension that does not respond to other medications PRAZOSIN ADVERSE EFFECTS May cause reflex activation of the sympathetic nervous system which leads to increased heart rate, force of contraction, and circulating levels of NE (leads to increased myocardial oxygen requirements) Renal artery dilation leads to increased sodium and fluid retention Orthostatic hypotension, headache, drowsiness, palpitations, nasal congestion. “First dose” syncope (especially with diuretics) “BETA BLOCKERS” Generic naming convention: -lol Exemplar drug: atenolol Drugs within this class have varying affinities for β1 and β2 adrenergic receptors (some are more selective than others) Some also have some effect on α1 receptors Some also have the capacity to act as both agonist and antagonist at β1 receptors (dose-dependent) called intrinsic sympathomimetic activity ATENOLOL A selective β1 receptor antagonist This drug is primarily going to act on the heart to decrease heart rate, impulse conduction and force of contraction Also acts on juxtaglomerular cells inhibiting renin secretion which reduces angiotensin II and therefore reduces aldosterone Also appears to reduce sympathetic outflow from the CNS ATENOLOL Due to the many mechanisms and sites of action there are multiple indications Hypertension (not a first-line option) Heart failure Post myocardial infarction Coronary heart disease Arrhythmias ATENOLOL ADVERSE EFFECTS Fatigue, bradycardia, decreased exercise capacity, headache, impotence, and vivid dreams are common May also cause hyperglycemia, depression, heart failure, heart block May cause rebound hypertension with abrupt discontinuation ATENOLOL Not generally used as initial therapy May be appropriate for patients over the age of 60 Avoid use in patients with asthma Avoid in patients with severe peripheral arterial disease Contraindicated in patients with second- or third-degree heart block in the absence of a pacemaker CENTRALLY ACTING SYMPATHOLYTICS Exemplar drug: clonidine α2-adrenergic receptor agonist Stimulation of α2 receptors REDUCES sympathetic outflow from the CNS (brainstem) Reduced NE results in decreased peripheral resistance, heart rate, and blood pressure CLONIDINE Due to the fact it acts within the CNS it has much more potential for adverse effects than those that act in the periphery Adverse effects include: Sedation, dizziness, dry mouth, orthostatic hypotension Rebound hypertension with abrupt withdrawal CLONIDINE Not routinely used for cardiovascular diseases May potentially be used for hypertension during pregnancy Has many other indications for a wide variety of disorders where reducing in sympathetic activity would be desirable: treatment of substance withdrawal (nicotine, opioids, alcohol) ADHD DRUGS THAT REDUCE BLOOD VOLUME The diuretics can be split into categories based on the area in the nephron where they work Loop diuretics (Loop of Henle) Thiazide diuretics (distal convoluted tubule) K+ sparing diuretics (collecting duct) DIURETICS LOOP DIURETICS Drug: Furosemide Inhibition of Na/Cl/K symport Decreased sodium and potassium reabsorption in ascending loop Increased water excretion FUROSEMIDE Indications Mainly for anything that causes a lot of edema, such as heart failure, cirrhosis, pulmonary edema Can be used to treat hypertension and hypercalcemia but not routinely used for this purpose FUROSEMIDE Has the greatest potential to cause diuresis of all the diuretic classes Also increase magnesium and calcium excretion May cause ototoxicity Other adverse effects include: major electrolyte imbalances, blood cell deficiencies, increased cholesterol, glucose, or uric acid, and photosensitivity FUROSEMIDE Diuretic effect is decreased by NSAIDs Combination with ACEi may cause excessive hypotension The only diuretic class that can be used when renal function is substantially decreased THIAZIDE DIURETICS Drug: Hydrochlorothiazide Inhibition of Na/Cl symport Decrease Na reabsorption Increased water excretion HYDROCHLOROTHIAZIDE Typically the diuretic of choice for hypertension Seems particularly effective in African-American populations and the elderly Leads to calcium retention and may be helpful when a patient also has osteoporosis or nephrolithiasis Patient must have sufficient renal function for the drug to work HYDROCHLOROTHIAZIDE Particularly effective in patients with isolated systolic hypertension More effective in elderly and black patients HYDROCHLOROTHIAZIDE Adverse effects Leads to marked potassium and magnesium excretion Common: Hypotension, weakness, muscle cramps, impotence, hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hyperlipidemia. Drug Interactions NSAIDs reduce the hypotensive effect Reduced efficacy of antihyperglycemic drugs POTASSIUM SPARING DIURETICS Drug: Spironolactone Inhibition of downstream effects of aldosterone binding to nuclear mineralocorticoid receptor Aldosterone stimulates sodium reabsorption and potassium excretion Inhibition blocks this, resulting in sodium excretion and potassium reabsorption SPIRONOLACTONE Minimal use within the context of cardiovascular disease May be used in combination with a thiazide or loop diuretics to prevent hypokalemia and hypomagnesemia in patients being treated for heart failure Adverse effects Antiandrogenic effects (which is why it’s sometimes used for acne) can cause gynecomastia SPIRONOLACTONE Drug Interactions ACEi, ARBs, potassium supplements NSAIDs reduce the diuretic effect SUMMARY OF DIURETICS Thiazide diuretics are first-line therapy for uncomplicated hypertension Loop diuretics are only really valuable when the patient is experiencing significant edema, which often occurs with heart failure TREATMENT STANDARDS For patients with hypertension and the absence of other comorbidities, a thiazide diuretic, beta-blocker, ACEi, ARB, or long-acting calcium channel blocker are all considered first-line therapy depending on patient factors For patients with hypertension and diabetes with additional risk factors, an ACEi or ARB should be started first SAMPLE QUESTION Which of the following antihypertensive drugs works by modifying the renin-angiotensin-aldosterone system? A. Atenolol B. Candesartan C. Clonidine D. Amlodipine SAMPLE QUESTION Which of the following antihypertensive drugs is considered first-line therapy for a hypertensive patient with type 2 diabetes who smokes one pack of cigarettes per day? A. Atenolol B. Hydrochlorothiazide C. Amlodipine D. Candesartan STOMACH ACID SUPPRESSION AND H. PYLORI ERADICATION Dr. Adam Gratton NMT150 MSc ND March 23, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used to alleviate the effects of, or suppress excess stomach acid secretion - Antacids and alginates - H2 receptor antagonists - Proton pump inhibitors - Prostaglandin analogues Describe quadruple therapy within the context of H. pylori eradication Describe the adverse effects of quadruple therapy GI DISORDERS Dyspepsia - pain or discomfort located in the upper abdomen Gastroesophageal reflux disease (GERD) – acid reflux into the lower esophagus most commonly associated with heartburn and regurgitation ranging from silent to severe Peptic ulcer disease (PUD) - the development of breaks in the mucosa of the stomach (gastric ulcers) and/or proximal duodenum (duodenal ulcers). ALGINATES Natural polysaccharide polymers derived from seaweed Precipitate into a gel on contact with gastric acid Gel floats on top of stomach contents forming a physical barrier between acid and the lower esophageal sphincter Gel refluxes instead of acid ALGINATE/MAGNESIUM HYDROXIDE Tablet form Typically 2 – 4 tablets chewed PRN after meals followed by a glass of water Adverse effects include nausea, vomiting, eructation, flatulence ANTACIDS Just acid-neutralizing agents Aluminum and magnesium hydroxides, in combination, are one of the most common Aluminum hydroxide causes constipation Magnesium hydroxide causes diarrhea Often only work for a short time as acid is involved in the negative feedback of acid regulation ALUMINUM AND MAGNESIUM HYDROXIDE COMBINATION Typically administered PRN after meals Adverse effects include constipation and diarrhea H2 RECEPTOR ANTAGONISTS Generic naming convention: -tidine Histamine is a potent inducer of acid secretion Structurally similar to histamine but do not activate H2 receptors on parietal cells resulting in competitive inhibition Results in potent inhibition of both meal-stimulated secretion and basal secretion of gastric acid RANITIDINE Have no effect on gastric emptying time, esophageal sphincter pressure, or pancreatic enzyme secretion Indications: Dyspepsia/GERD/heartburn Peptic ulcer disease: at doses that raise gastric pH above 4 for at least 13 hours a day Require 6-8 weeks of continuous therapy to heal 90% of ulcers RANITIDINE Adverse effects include diarrhea, constipation, headache, fatigue, confusion (most commonly in elderly patients with reduced renal function), cardiac effects, rash Dose: 150 mg BID – QID PO or 300 mg QHS PO PROTON PUMP INHIBITORS Generic naming convention: -prazole Prodrugs administered orally as sustained-release, enteric- coated preparations as they are inactivated by stomach acid Activated by protonation, which occurs in areas of the body below their pKa (~4.0) The only place that happens is in the parietal cell canaliculi Once activated they bind to H+/K+ ATPase and irreversibly inactivate the pump OMEPRAZOLE Must be taken 30 minutes before a meal to ensure pumps are active when peak concentration of PPI are present in the blood Takes about 3 days to reach steady state inhibition (after factoring in the inactivation of active pumps, stimulation of inactive pumps, and creation of new pumps) Rapid CYP2C19 metabolizers may require higher doses OMEPRAZOLE Indications Peptic ulcer disease Better than H2 antagonists Heal 80-90% of ulcers in 2 weeks or less Drug of choice for Zollinger-Ellison syndrome Most effective for treating dyspepsia/GERD/heartburn May be used to prevent ulcers in patients taking NSAIDs OMEPRAZOLE Common adverse effects include headache, nausea, diarrhea, abdominal pain, constipation, dizziness, fatigue, rash, pruritis May cause allergic reactions, kidney disorders, dementia (inconclusive) Long-term use associated with pneumonia, GI infections, vitamin and mineral deficiencies (B12, iron, Mg), osteoporosis, and fractures OMEPRAZOLE Dose: 20 – 40 mg once daily PO 30 minutes AC If partial or no response, dose BID AC Half the usual dose may be enough for less severe symptoms or for maintenance after remission CYTOPROTECTIVE DRUGS The two common drugs here are sucralfate and misoprostol Sucralfate is essentially a chemical bandage Sucrose sulfate and aluminum hydroxide complex that binds to ulcers creating a physical barrier from stomach acid Misoprostol has a more complicated mechanism of action MISOPROSTOL Prostaglandin E1 analog Binds to prostaglandin receptors in the stomach and enhances mucus production, mucosal blood flow, and bicarbonate secretion in epithelial cells Binds to prostaglandin receptors on parietal cells and inhibits adenylate cyclase (decreases cAMP) which downregulates H+/K+ ATPase and decreases acid secretion MISOPROSTOL Indicated for gastric and duodenal ulcers in patients taking NSAIDs long-term. Rather expensive and typically reserved for high-risk patients (elderly and those with a previous history of ulcer disease) Contraindicated in pregnancy as it can stimulate uterine contractions and induce labour MISOPROSTOL Adverse effects include dose-related diarrhea, abdominal cramps, flatulence Risk of diarrhea increased when used alongside magnesium-based antacids Dose: 200 mcg QID PO HELICOBACTER PYLORI Most infections are asymptomatic When symptoms do occur, they are typically related to gastritis or peptic ulcers Infection significantly increases the risk of gastric cancer First line management for eradication is “quadruple therapy” for 14 days QUADRUPLE THERAPY First-line First-line or prior treatment failure PPI BID PPI BID Amoxicillin BID Bismuth subsalicylate QID Metronidazole BID Metronidazole TID - QID Clarithromycin BID Tetracycline QID QUADRUPLE THERAPY Both regimens achieve a minimum eradication rate of at least 85% Risk of reinfection after successful eradication is about 1% a year QUADRUPLE THERAPY Adverse effects are generally related to the component parts Headache and diarrhea are most commonly reported Clarithromycin can cause altered taste, GI upset, and diarrhea Amoxicillin can cause diarrhea and rash Bismuth can lead to darkening of stool and tongue, nausea, and constipation Adverse effects are more common with quadruple therapy containing PPI, bismuth, metronidazole, tetracycline SAMPLE QUESTION Which of the following drug options is the best for treating peptic ulcer disease? A. Alginate B. Misoprostol C. Ranitidine D. Omeprazole DRUGS THAT AFFECT GI MOTILITY Dr. Adam Gratton NMT150 MSc ND March 9, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action and indications of bulk-forming, osmotic, and stimulant laxatives Describe the adverse effects associated with bulk-forming, osmotic, and stimulant laxatives Describe the antidiarrheal mechanism and indication of opioid agonists Describe the adverse effects of opioid agonists Describe the intestinal motility effects of tricyclic antidepressants and selective serotonin receptor inhibitors INTESTINAL TRANSIT TIME How long it takes for food to move through the GI tract Average transit time is 30 – 40 hours Increased transit time can lead to constipation Reduced transit time can result in diarrhea BULK-FORMING LAXATIVES Agents that retain fluid in the stool itself Increase stool weight and improve consistency Generally soluble fibers that gel when mixed with water Do not alter peristalsis PSYLLIUM Most commonly discussed bulk-forming laxative Generally a first-line recommendation when dietary fiber intake is inadequate (25 – 30 g/d) Indicated for both constipation and diarrhea PSYLLIUM Commercial psyllium products are powdered preparations of the mucilaginous portion (psyllium hydrophilic mucilloid) Recommended dose: 3.4 g once daily to TID PO Time to onset: 12 – 72 hours PSYLLIUM Adverse effects: bloating, flatulence, abdominal discomfort In rare instances: allergic reactions and esophageal and colonic obstruction Must be taken with a minimum of 250 mL water Do not take within 2 h of other medications OSMOTIC LAXATIVES Poorly absorbed agents that draw water into the intestines Hydrates and softens stool Increase colonic peristalsis MAGNESIUM Citrate, hydroxide, and sulfate salts all have osmotic laxative effects Use with caution in patients with renal dysfunction as they can result in hypermagnesemia Mild: Weakness, nausea, dizziness and confusion Moderate: hyporeflexia, worsening confusion and sedation, bladder paralysis, flushing, headache, constipation MAGNESIUM CITRATE Dose: 3.75 – 7.5 g daily PO for acute purgative effect (preoperatively) Time to effect: 30 min – 6 h More commonly used in much smaller doses and tailored to patient tolerance STIMULANT LAXATIVES Stimulate the myenteric plexus and Auerbach plexus Increase intestinal secretions and motility Decrease absorption of water from the bowel lumen SENNA Generally only recommended for short-term treatment of constipation May be necessary to use long-term, particularly with opioid therapy SENNA Can cause abdominal pain and cramps Can cause benign, reversible pigmentation of the colonic mucosa called pseudomelanosis coli SENNA Most commercial preparations are 8 mg per tablet Dose: 16.2 – 32.4 mg (2 – 4 tablets) at bedtime PO Maximum 64.8 mg (8 tablets) per day Time to effect: 6 – 12 h OPIOID AGONISTS Opioids typically cause constipation as an adverse effect when used for their analgesic effect Tolerance to constipation does not develop, unlike many of the other adverse effects Interacts with intestinal mu-opioid receptors which reduces intestinal motility, increases transit time and water and electrolyte reabsorption LOPERAMIDE Indicated for diarrhea Some caution when used for microbial etiologies as use may enhance infection LOPERAMIDE Adverse effects include sedation, nausea, and abdominal cramps. Lowest addiction potential of all opioids Reports of loperamide being abused as an opioid substitute In high doses can cause cardiac dysrhythmia and death Not to be used in children under 2 years of age due to increased risk of respiratory depression and serious cardiac adverse effects LOPERAMIDE Usually formulated in 2 mg doses (tablets, wafers, etc.) Dose: 4 mg PO followed by 2 mg after each unformed stool Maximum 16 mg per day ANTIDEPRESSANTS Often used within the context of irritable bowel syndrome Effect for IBS seems to be independent of their effect on mood May alter pain perception and reduce visceral hypersensitivity Alter GI transit TRICYCLIC ANTIDEPRESSANTS More robust evidence for TCAs vs SSRIs Increase colonic transit time and may be more effective for diarrhea-dominant IBS (IBS-D) and concomitant depression Used in much lower doses than for treating psychiatric conditions AMITRYPTALINE Dose: 25 – 100 mg QHS PO May cause drowsiness, dry mouth and headache Recommended to start with low doses and increase gradually SSRI Mechanism similar to that of TCAs Decrease colonic transit time and may be more effective for constipation-dominant IBS (IBS-C) and concomitant depression CITALOPRAM Dose: 20 mg daily PO Adverse effects include: nausea, dry mouth, sleep disturbance, somnolence, sweating, sexual dysfunction, increased risk of GI bleeding Recommendation to start with lower doses and titrate based on response SAMPLE QUESTION Which of the following drug pairs increase intestinal transit time? A. Loperamide and citalopram B. Citalopram and amitryptaline C. Amitryptaline and senna D. Senna and loperamide OPIOIDS Dr. Adam Gratton NMT150 MSc ND March 9, 2023 LECTURE COMPETENCIES Describe the proposed mechanism of action of opioid agonists Describe the adverse effects associated with opioid agonists Describe the mechanism of action of opioid antagonists Describe the adverse effects of opioid antagonists Describe the symptoms of opioid withdrawal OPIOIDS AND LOW BACK PAIN Not generally recommended for acute low back pain Potential increased risk of disability at 6 months when used early on Should not really be used unless there has been no benefit seen with other pain medications (NSAIDs, GABA derivatives, etc.) OPIOIDS AND LOW BACK PAIN With chronic low back pain opioids may only provide modest, short-term alleviation of pain Small doses should be used (no more than 50 morphine equivalents per day) Initial prescriptions should only be for 3 – 5 days Should not be used within the context of anxiety, depression, PTSD, history of substance abuse PATHOPHYSIOLOGY OF PAIN Enkephalins, endorphins, and dynorphins are the endogenous ligands of the opioid receptors Enkephalins are released throughout the pain axis There are three main types of opioid receptors: Mu (μ), delta (δ), and kappa (κ) Most clinically useful opioid analgesics have strong selectivity for the μ- opioid receptor PATHOPHYSIOLOGY OF PAIN μ-opioid receptors are inhibitory G-protein coupled receptors Activation leads to increased inhibitory activity via inhibition of adenylate cyclase which leads to decreased cAMP Increased potassium conductance via the opening of membrane-bound potassium channels Decreased intracellular calcium via blockage of membrane-bound calcium channels Ultimately decreased neurotransmitter release OPIOID CLASSES Full Opioid Agonists (Morphine, Codeine) Fentanyl>>Morphine>Codeine (100:1:0.15) Partial Opioid Agonists (Tramadol) Opioid Antagonists (Naloxone) OPIOID AGONISTS Opioids have a wide range of physiological effects CNS: Analgesia, euphoria, cough inhibition, miosis, dependence, respiratory depression, sedation CVS: Decreased myocardial oxygen demand, vasodilation, hypotension GI: Constipation, increased biliary sphincter tone, nausea, vomiting GU: Increased bladder sphincter tone, prolongation of labour OPIOID AGONISTS Neuroendocrine: Inhibition of LH, stimulation of ADH and prolactin Immune: Suppression of NK cell activity Skin: Flushing, pruritis, urticaria FULL VS PARTIAL AGONISTS Strong opioid agonists are generally well tolerated when given at dosages sufficient to relieve severe pain Compared to moderate opioid agonists, like codeine, that have more side effects in higher dosages. Strong opioids have a high affinity for opioid receptors which undergo a significant conformational change to produce the maximal effect Partial agonists cause less conformational change and receptor activation, however analgesic activity plateaus with higher dosages (and side effect activity does not) MORPHINE The principal alkaloid of opium poppy Well absorbed from the GI tract but extensively metabolized during first-pass Principal metabolite (~90%) is morphine-3-glucuronide which is inactive Morphine-6-glucuronide (~10%) is more active than morphine with a longer half-life and contributes to analgesic effectiveness Duration of action: 4 hours MORPHINE Primarily excreted in urine and a small amount is enterohepatically recycled from biliary excretion Standard of comparison for all other opioid analgesics Can be administered orally (but in much higher dosages) and intravenously TRAMADOL Partial μ-opioid agonist Also inhibits neuronal reuptake of serotonin and norepinephrine Relationship to analgesic effect not determined May potentiate the inhibitory effect these have on spinothalamic tract neurons Has long been incorrectly considered the “safe” opioid, due to a lower potential to cause dependence TRAMADOL Analgesic effect mediated by the M1 metabolite (O- desmethyltramadol) which is dependent on CYP2D6 CYP2D6 is highly polymorphic Given the dual nature of the drug it’s like giving morphine and venlafaxine in unknown ratio TRAMADOL Side effects include: hypoglycemia, decreases seizure threshold, orthostatic hypotension, hallucinations Interacts with antidepressants (SSRIs, TCAs) and increased risk of serotonin syndrome Duration of action: 4 hrs Half life: 6 hrs OPIOID ANTAGONISTS Competitive opioid receptor antagonists rapidly reverse the effects of opioid agonists Indicated for opioid overdose, treatment of alcohol and opioid dependences, decreasing opioid-induced constipation Bind to opioid receptors and prevents conformational change necessary for activation and agonist activity NALOXONE Administered intravenously Half life: 2 hrs Repeated administration often needed for longer-lasting opioid agonists Low bioavailability so not given orally on its own Sometimes added to oral opioid agonists to curb crushing tablets and using them intravenously Indicated for opioid overdose treatment ADVERSE EFFECTS Headache, hypertension, muscle spasms, serious allergic reactions, nasal dryness, Can cause opioid withdrawal symptoms Cardiac arrhythmias, nausea, vomiting, diarrhea, irritability, nervousness, aggressive behaviour SAMPLE QUESTION Which of the following drugs is an opioid receptor antagonist? A. Codeine B. Morphine C. Tramadol D. Naloxone