Pharmacology 2.1 PDF by NAC, RPh

PHARMACOLOGY 2.1 BY: NOVOCHINO CASTILLO, RPh I. Adrenergic Agonists and Antagonists a. Adrenergic Receptors b. Alpha and beta-adrenergic agonists c. Alpha and beta-adrenergic antagonists II. Drugs Acting in the Renal System a. Diuretics b. Inhibitors of Sodium-Glucose Sympo...

PHARMACOLOGY 2.1 BY: NOVOCHINO CASTILLO, RPh I. Adrenergic Agonists and Antagonists a. Adrenergic Receptors b. Alpha and beta-adrenergic agonists c. Alpha and beta-adrenergic antagonists II. Drugs Acting in the Renal System a. Diuretics b. Inhibitors of Sodium-Glucose Symport: SGLT2 inhibitors (-gliflozins) c. Inhibitors of the Nonspecific Cation Channel: Natriuretic Peptides d. Adenosine Receptor Antagonists III. Water Homeostasis and the Vasopressin System a. Vasopressin Physiology b. Vasopressin Receptor Agonists c. Diseases Affecting the Vasopressin System d. Clinical Use of Vasopressin Agonists e. Clinical Use of Vasopressin Antagonists OUTLINE I. ADRENERGIC AGONISTS AND ANTAGONISTS A. ADRENERGIC RECEPTORS ALPHA RECEPTORS Alpha 1 Alpha 2 vasoconstriction control release if NE increased BP (-) Ach and insulin release mydriasis feedback inhibition closure of bladder sphincter I. ADRENERGIC AGONISTS AND ANTAGONISTS A. ADRENERGIC RECEPTORS BETA RECEPTORS Beta 1 Beta 2 Beta 3 vasodilation increased heart rate decreased peripheral resistance increased myocardial contractility bronchodilation lipolysis increased release of renin glycogenolysis closure of bladder sphincter uterine relaxation I. ADRENERGIC AGONISTS AND ANTAGONISTS  PHENYLEPHRINE activates beta receptors at higher concentrations used as a nasal decongestant and mydriatic METARAMINOL acts directly on vascular alpha receptors acts indirectly through stimulation of MIDODRINE NE release prodrug (AM: desglymidodrine) treatment of hypotensive states treatment for autonomic insufficiency and postural hypotension can cause supine hypertension B. ADRENERGIC AGONISTS Alpha 1 selective agonists I. ADRENERGIC AGONISTS AND ANTAGONISTS CLONIDINE transient vasoconstriction (IV) treatment for hypertension; hypertensive urgency (SL) common off-label uses: - diarrhea in DM patients - treatment and preparing patients for withdrawal from narcotics, alcohol, and tobacco - reducing hot flashes (menopause) - ADHD A/E: dry mouth, sedation, lethargy, constipation B. ADRENERGIC AGONISTS Alpha 2 selective agonists I. ADRENERGIC AGONISTS AND ANTAGONISTS  MOXONIDINE mixed α2 receptor and imidazole I1 receptor agonist reduce sympathetic outflow from the CNS has analgesic properties- treatment for neuropathic pain APRACLONIDINE, BRIMONIDINE administered ocularly to lower intraocular pressure, specifically for patients with glaucoma, ocular hypertension, or patients who undergo surgery like iridectomy Brimonidine- can cross the BBB and produces hypotension and sedation TIZANIDINE muscle relaxant for the treatment of spasticity associated with cerebral and spinal disorders B. ADRENERGIC AGONISTS Alpha 2 selective agonists I. ADRENERGIC AGONISTS AND ANTAGONISTS B. ADRENERGIC AGONISTS Nonselective beta agonists 1. ISOPROTERENOL used in emergencies to stimulate heart rate in patients with bradycardia or heart block A/E: palpitations, tachycardia, headache, flushing; cardiac ischemia and arrhythmia in patients with underlying coronary diseases 2. DOBUTAMINE indicated for the short-term treatment of cardiac decompensation that may occur after cardiac surgery or in patients with congestive heart failure or acute myocardial infarction I. ADRENERGIC AGONISTS AND ANTAGONISTS  B. ADRENERGIC AGONISTS Beta 2 selective agonists Short- Acting Long-Acting Very-Long Acting (SABA) (LABA) (VLABA)* Metaproterenol Albuterol Levalbuterol Salmeterol Indacaterol Pirbuterol Formoterol Olodaterol Terbutaline Aformoterol Vilanterol Fenoterol Procaterol *have been developed primarily for treating COPD I. ADRENERGIC AGONISTS AND ANTAGONISTS B. ADRENERGIC AGONISTS Beta 3 selective agonists MIRABEGRON, VIBEGRON prevents voiding and provides relief for those with an overactive bladder and urinary incontinence Mirabegron- used in clinical trials for induction of brown fat in humans and also heart failure I. ADRENERGIC AGONISTS AND ANTAGONISTS C. ADRENERGIC ANTAGONISTS I. ADRENERGIC AGONISTS AND ANTAGONISTS C. ADRENERGIC ANTAGONISTS Beta-adrenergic receptor antagonists NON-SELECTIVE BETA-BLOCKERS BETA 1 SELECTIVE BLOCKERS BETA 1 BLOCKERS WITH ISA BETA 1 BLOCKERS WITH MSA NSTPPP CINBBEAAM CLAPP PPALM Celiprolol Nadolol Isoprolol Nevibolol- most cardioselective Carteolol Propranolol Sotalol Bisoprolol Labetalol Pindolol Timolol Betaxolol Acebutolol Acebutolol Propranolol- prototype Esmolol Pindolol Labetalol Pindolol Atenolol Penbutolol Metoprolol Penbutolol Acebutolol Metoprolol I. ADRENERGIC AGONISTS AND ANTAGONISTS C. ADRENERGIC ANTAGONISTS Beta-adrenergic receptor antagonists I. ADRENERGIC AGONISTS AND ANTAGONISTS II. DRUGS ACTING IN THE RENAL SYSTEM II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS drugs that increase the rate of urine flow through the excretion of sodium (natriuretic) and water (aquaretic) Diuretic braking- compensatory mechanisms that bring Na+ excretion in line with Na+ intake - activation of the sympathetic nervous system - activation of the renin-angiotensin-aldosterone axis - decreased arterial blood pressure (reduces pressure natriuresis) - renal epithelial cell hypertrophy - increased renal epithelial transporter expression - alterations in natriuretic hormones II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 1. Carbonic Anhydrase Inhibitors - acetazolamide - dorzolamide - dichlorphenamide - methazolamide Site: proximal convoluted tubule (PCT) potently inhibit both the membrane- bound and cytoplasmic forms of carbonic anhydrase, and can cause nearly complete abolition of NaHCO3 reabsorption in the proximal tubule. II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 1. Carbonic Anhydrase Inhibitors Uses: - open-angle glaucoma - high altitude sickness or mountain sickness - epilepsy (anticonvulsant) - vasodilatory - resistance to diuretic monotherapy (acetazolamide + HCTZ) - metabolic alkalosis A/E: sulfa-like toxicity (bone marrow depression, skin toxicity, sulfonamide-like renal lesions, and allergic reactions), drowsiness, paresthesia, metabolic acidosis C/I: COPD, chronic liver disease (increased ammonia- encepalopathy) II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 2. Osmotic Diuretics - glycerin (PO) - isosorbide (PO) - mannitol (IV) - urea (IV) Site: proximal convoluted tubule (PCT); Loop of Henle (primary) limits the osmosis of water into the interstitial space, thereby reducing the luminal Na+ concentration to the point that net Na+ reabsorption ceases (PCT); diminishes the passive reabsorption of NaCl in the thin ascending Loop of Henle (Loop of Henle) increase urinary excretion of nearly all electrolytes, including Na+, K+, Ca2+, Mg2+, Cl−, HCO3- , and phosphate II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 2. Osmotic Diuretics Uses: - control intraocular pressure - reduce cerebral edema and brain mass - dialysis disequilibrium syndrome - treatment and prevention of AKI A/E: florid pulmonary edema, hyponatremia, dehydration C/I: anuric patients, patients with impaired liver function (urea), hyperglycemia (glycerin), active cranial bleeding (mannitol and urea) II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 3. Loop Diuretics (high-ceiling diuretics) *Sulfonamide moiety - furosemide (PO/IV) - bumetanide (PO/IV) *Phenoxyacetic acid derivative - ethacrynic acid (PO) *Sulfonylurea - torsemide (PO) Site: thick ascending limb (TAL) inhibits Na+-K+-2Cl− symporter , bringing salt transport in this segment of the nephron to a virtual standstill II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 3. Loop Diuretics (high-ceiling diuretics)- Bartter Syndrome II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 3. Loop Diuretics (high-ceiling diuretics) Uses: - acute pulmonary edema and other edematous conditions - drug overdose - hypercalcemia (w/ NSS) - hyponatremia (w/ hypertonic saline) NOT considered first-line diuretics for the treatment of hypertension A/E: hyper-Glycemia,Lipidemia,Uricemia, serious depletion of total-body Na+, ototoxicity (more prominent in ethacrynic acid) C/I: postmenopausal women, serious volume depletion, anuria, patients who are allergic to sulfonamides II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 3. Loop Diuretics (high-ceiling diuretics) Drug Interactions: - aminoglycosides, carboplatin, paclitaxel- synergism of ototoxicity - cisplatin- increased risk of diuretic-induced ototoxicity - digitalis glycosides- increased digitalis-induced arrhythmias - lithium- increased plasma levels of Li+ - propranolol- increased plasma levels of propranolol - sulfonylureas- hyperglycemia - NSAIDs- blunted diuretic response and salicylate toxicity with higher doses - probenecid- blunted diuretic response - thiazide diuretics- synergism of diuretic activity (profound diuresis) - amphotericin B- increased potential for nephrotoxicity II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 4. Thiazide and Thiazide-Like Diuretics *Thiazide diuretics - hydrochlorothiazide (HCTZ)- prototype - chlorothiazide (IV) - bendroflumethiazide - methyclothiazide *Thiazide-like diuretics - chlorthalidone - indapamide - metolazone Site: distal convoluted tubule (DCT) II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 4. Thiazide and Thiazide-Like Diuretics inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+ /Cl− transporter (called ENCC1 or TSC); enhance Ca2+ reabsorption Uses: - edema - hypertension - heart failure - nephrolithiasis due to idiopathic hypercalciuria - nephrogenic diabetes insipidus - Br- intoxication A/E: hyper-GLU + Calcemia, sulfa allergic reactions, erectile dysfunction C/I: patients who are allergic to sulfonamides II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 4. Thiazide and Thiazide-Like Diuretics- Gitelman Syndrome Drug Interactions DECREASE EFFECTIVENESS OF INCREASE EFFECTIVENESS OF INCREASE RISK OF HYPOKALEMIA THIAZIDES THIAZIDES uricosuric agents anesthetics amphotericin B sulfonylureas diazoxide corticosteroids insulin Digitalis spp. FATAL VENTRICULAR ARRHYTHMIA NSAIDs lithium quinidine COX-2 inhibitors loop diuretics dofetilide bile acid sequestrants vitamin D arsenic trioxide II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 4. Thiazide and Thiazide-Like Diuretics- Gitelman Syndrome II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 5. K+ - Sparing Diuretics - Triamterene - Amiloride (long t1/2) Site: collecting tubule directly interfere with Na+ entry through the epithelial Na+ channels (ENaC) in the apical membrane of the collecting tubule Uses: - Liddle syndrome - cystic fibrosis (amiloride) - lithium-induced nephrogenic DI (amiloride) A/E: hyperkalemia, N/V, photosensitization (triamterene) NSAIDs- increased likelihood of hyperkalemia II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 6. Aldosterone Antagonists *Steroidal (MR antagonists) - spironolactone - eplerenone *Non-Steroidal - finerenone Site: collecting tubule bind to mineralocorticoid receptors and blunt aldosterone activity II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 6. Aldosterone Antagonists Uses: - hyperaldosteronism - edema and hypertension (co-administered w/ loop or thiazide diuretics) - hepatic cirrhosis (diuretic of choice) - HFrEF - hirsutism and acne (spironolactone)- partial agonist of estrogen A/E: - hyperkalemia, metabolic acidosis - (spironolactone) gynecomastia, impotence, decreased libido, SJS (rare), TEN C/I: patients with CrCl of ≤ 30 mL/min (eplerenone) or ≤ 25 mL/min (finerenone) II. DRUGS ACTING IN THE RENAL SYSTEM A. DIURETICS 6. Aldosterone Antagonists Drug Interactions - salicylates- reduce efficacy of spironolactone - cardiac glycoside- altered clearance with spironolactone - strong CYP3A4 (-) (fluconazole, ketoconazole)- increased plasma conc. of eplerenone and finerenone II. DRUGS ACTING IN THE RENAL SYSTEM B. SGLT2 INHIBITORS - dapagliflozin - canagliflozin - empagliflozin - ipragliflozin (Japan) reduces glucose excretion from 90% to only 30-50%, also increases sodium excretion Use: - third-line therapy for diabetes mellitus A/E: urinary tract infections II. DRUGS ACTING IN THE RENAL SYSTEM C. NATRIURETIC PEPTIDES Four (4) NPs: - ANP - BNP (most important) - CNP - urodilatin (similar to ANP) Site: collecting duct degraded by neprilysyn II. DRUGS ACTING IN THE RENAL SYSTEM C. NATRIURETIC PEPTIDES - nesiritide (human recombinant BNP) - carperitide (human recombinant ANP) - ularitide (recombinant urodilatin -IV) inhibits Na+ transport in the collecting duct, and also in the proximal and distal nephron, increasing GFR Use: - acutely decompensated CHF - improves short-term symptoms of dyspnea A/E: hypotension II. DRUGS ACTING IN THE RENAL SYSTEM C. NATRIURETIC PEPTIDES - sacubitril selective neprilysyn antagonist combined with ARB valsartan (Entresto®) Use: treatment of heart failure with reduced ejection fraction (HFrEF) II. DRUGS ACTING IN THE RENAL SYSTEM D. ADENOSINE RECEPTOR ANTAGONISTS *methylxanthines - caffeine - theophylline - theobromine *pamabrom A1 receptor- is expressed in the proximal tubule and stimulates reabsorption of Na+. Blockade of renal A1 receptors causes diuresis. II. DRUGS ACTING IN THE RENAL SYSTEM III.WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM A. VASOPRESSIN PHYSIOLOGY vasopressin/arginine vasopressin (AVP) antidiuretic hormone (ADH) - released by posterior pituitary gland that regulates body fluid osmolality* *increase the permeability of the cell membrane to water - potent vasopressor/vasoconstrictor - neurotransmitter that acts in the regulation of CNS functions - promotes release of coagulation factors and increases platelet aggregability III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM  A. VASOPRESSIN PHYSIOLOGY DRUGS THAT STIMULATE DRUGS THAT INHIBITS VASOPRESSIN SECRETION VASOPRESSIN SECRETION ethanol vincristine phenytoin cyclophosphamide low doses of morphine glucocorticoids tricyclic antidepressants fluphenazine nicotine haloperidol epinephrine promethazine lithium oxilorphan high doses of morphine butorphanol carbamazepine III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM  A. VASOPRESSIN PHYSIOLOGY VASOPRESSIN RECEPTORS AVP LOCATION ACTION WITH AVP BINDING RECEPTOR vascular smooth muscle adrenal gland myometrium vasoconstriction bladder adipocytes glycogenolysis hepatocytes increase peristalsis V1a platelets platelet aggregation renal medullary interstitial cells growth responses in smooth muscle cells vasa recta in the renal microcirculation ACTH release epithelial cells in the renal cortical collecting duct spleen testis III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM  A. VASOPRESSIN PHYSIOLOGY VASOPRESSIN RECEPTORS AVP LOCATION ACTION WITH AVP BINDING RECEPTOR antidiuresis principal cells of the renal increased Na+ and urea transport in thick collecting duct system ascending limb and collecting duct V2 epithelial cells in TAL vasodilation vascular endothelial cells release of coagulation factor VIII and von Willebrand factor (vWF) III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM  A. VASOPRESSIN PHYSIOLOGY VASOPRESSIN RECEPTORS AVP LOCATION ACTION WITH AVP BINDING RECEPTOR anterior pituitary several brain regions V3/V1b ACTH, prolactin, and endorphin release pancreas adrenal medulla III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM B. VASOPRESSIN RECEPTOR AGONISTS III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM C. DISEASES AFFECTING THE VASOPRESSIN SYSTEM 1. Diabetes Insipidus (DI) disease of impaired renal water conservation owing either to inadequate vasopressin secretion from the neurohypophysis (central DI) or to insufficient renal vasopressin response (nephrogenic DI) - can be differentiated through administration of desmopressin Patients with DI have polyuria and polydipsia. III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM C. DISEASES AFFECTING THE VASOPRESSIN SYSTEM 1. Diabetes Insipidus (DI) Central/Neurogenic Diabetes Insipidus - caused by head injury (surgical or traumatic) in the hypothalamus or pituitary region - may also be caused by hypothalamic or pituitary tumors, cerebral aneurysms, CNS ischemia, brain infiltrations and infections - may also be idiopathic or familial - Treatment: *Antidiuretic peptides (Desmopressin) *Chlorpropamide 125-500 mg daily: for patients who cannot tolerate desmopressin due to allergic reactions or side-effects *Carbamazepine 800–1000 mg daily in divided doses (rare) III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM C. DISEASES AFFECTING THE VASOPRESSIN SYSTEM 1. Diabetes Insipidus (DI) Nephrogenic Diabetes Insipidus - may be congenital or acquired - Factors that induce nephrogenic DI: hypercalcemia, hypokalemia, post-obstructive renal failure, Li+, foscarnet, clozapine, demeclocycline - Treatment: *assurance of an adequate water intake (mainstay) *amiloride (blocks Li+ uptake by the Na+ channel) * thiazide diuretics (reduces polyuria) * indomethacin (may involve a decrease in GFR, an increase in medullary solute concentration, or enhanced proximal fluid reabsorption) III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM C. DISEASES AFFECTING THE VASOPRESSIN SYSTEM 1. Diabetes Insipidus (DI) III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM C. DISEASES AFFECTING THE VASOPRESSIN SYSTEM 2. Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) disease of impaired water excretion with accompanying hyponatremia and hypoosmolality caused by the inappropriate secretion of vasopressin Clinical Manifestations: lethargy, anorexia, nausea and vomiting, muscle cramps, coma, convulsions, and death Diseases that induce SIADH: - malignancies - pulmonary diseases - CNS injuries/diseases (e.g., head trauma, infections, and tumors) - general surgery III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM C. DISEASES AFFECTING THE VASOPRESSIN SYSTEM 2. Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) Drugs that induce SIADH: - psychotropic medications (e.g., selective serotonin reuptake inhibitor, haloperidol, and tricyclic antidepressants)* *drug classes that mainly cause drug-induced SIADH - sulfonylureas (e.g., chlorpropamide)* - vinca alkaloids (e.g., vincristine and vinblastine)* - clonidine - cyclophosphamide - enalapril - felbamate - ifosfamide - methyldopa - pentamidine - vinorelbine III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM C. DISEASES AFFECTING THE VASOPRESSIN SYSTEM 2. Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) Treatment: - water restriction - intravenous administration of hypertonic saline - loop diuretics (which interfere with kidney’s concentrating ability) - drugs that inhibit the effect of vasopressin to increase water permeability in collecting ducts (vasopressin antagonists) III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM C. DISEASES AFFECTING THE VASOPRESSIN SYSTEM 2. Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM D. CLINICAL USE OF VASOPRESSIN AGONISTS - vasopressin (IV/SQ/IM/IA/intranasal) - desmopressin (IV/SQ/PO/intranasal) Uses: a) V1 receptor-mediated - vasopressin - postoperative ileus and abdominal distension - abdominal roentgenography - emergency setting for endoscopy, to prevent bleeding esophageal varices - reduce bleeding during acute hemorrhagic gastritis, burn wound excision, cyclophosphamide- induced hemorrhagic cystitis, liver transplant, cesarean section, and uterine myoma resection - hypotension in patients with vasodilatory shock III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM D. CLINICAL USE OF VASOPRESSIN AGONISTS Uses: b) V2 receptor-mediated - desmopressin - central (but NOT nephrogenic) DI - alternative to desmopressin in the initial diagnostic evaluation of patients with suspected DI - bleeding disorders (hemophilia A and von Willebrand disease) - primary nocturnal enuresis - post–lumbar puncture headache A/E: headache, nausea, belching, cramps, urge to defecate, marked face pallor, agitation, allergic reaction, water intoxication C/I: patients with CAD III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM E. CLINICAL USE OF VASOPRESSIN ANTAGONISTS - conivaptan (IV) - tolvaptan (PO) - lithium (never used) - demeclocycline (formerly used) MOA: - conivaptan: V1a and V2 blocker - tolvaptan: V2 blocker, has little affinity for V1 - lithium and demeclocycline: (-) insertion of aquaporins Uses: - FDA- approved treatment for hyponatremia A/E: hepatotoxicity and black-box warning against too rapid correction of hyponatremia (tolvaptan), GI adverse effects, bone and teeth abnormalities (demeclocycline), nephrogenic DI (lithium) III. WATER HOMEOSTASIS AND THE VASOPRESSIN SYSTEM THANK YOU! BY: NOVOCHINO CASTILLO, RPh