Pharmacology: Cardiovascular and Diabetes Drugs

• Pharmacology Colloquium 2 covers SGLT2 inhibitors, ACE inhibitors, ARBs, Thiazides, Fibrinolysis/Thrombolytics, Tirzepatide, Acarbose, Milrinone, Sacubitril, Dipyridamole, Pleiotropic effects of statins, Potassium-sparing diuretics, Alpha glucosidase inhibitors, PPAR-y agonists, Digitalis/Cardiac glycosides, NOAC, Ezetimibe, Antifibrinolytic drugs, HIT type 1 vs. HIT type 2, DPP-4 inhibitors, Loop Diuretics, PCSK9 inhibitors, Dihydropyridines and Thiazide diuretics.

SGLT2 Inhibitors

• Drug names include Canagliflozin, Dapagliflozin, and Empagliflozin, ending in "-GLIFLOZIN".
• SGLT2 inhibitors increase urinary glucose excretion and decrease glucose reabsorption in the proximal convoluted tubule (PCT).
• Used for Type 2 Diabetes Mellitus (T2DM).
• Contraindications include renal failure/dialysis and diabetic ketoacidosis.
• Side effects include risk for UTIs, hyperkalemia, glucosuria, and dehydration.

ACE Inhibitors

• Drug names include Captopril, Perindopril, and Lisinopril, ending in "OPRIL".
• ACE Inhibitors mechanism no ANG2 production, increases bradykinin, and reduces dilation SVR.
• Indications include hypertension and heart failure.
• Pregnancy and hyperkalemia are contraindications.
• Side effects include dry cough, angioedema, and hyperkalemia.

ARBs

• Drug names include Telmisartan, Losartan, and Candesartan, ending in "SARTAN".
• ARBs block the AT1 receptor, which results in no aldosterone, decreases SVR, increases ANG2 and increases renal blood flow.
• ARBs decrease ANG1 (less) compared to ACE inhibitors and have no bradykinin impact.
• Indications include hypertension, congestive heart failure, and diabetic nephropathy.
• Contraindications include pregnancy and hyperkalemia.
• Side effects include hyperkalemia, leg swelling, dizziness, and headaches.

Thiazides - Diuretics

• Drug names are Hydrochlorothiazide and Chlorothiazide, ending in "THIAZIDE".
• Thiazides mechanism a weak diuretic action, decreases Na2+, Mg2+, K+, NaCl, increases Ca2+, inhibits NaCl cotransporter in the early part of the distal tubule, causes NaCl excretion and results in vasodilation with decreased SVR.
• Thiazides treat hypertension, heart failure, and diabetes insipidus.
• Contraindications are pregnancy and hypokalemia.
• Side effects include hypokalemia, hypercalcemia, diabetes, and hyperlipidemia.

Fibrinolysis/Thrombolytics

• Drug names include Streptokinase and Urokinase ending in "KINASE".
• Thrombolytics dissolve existing clots, activate plasminogen into plasmin, and break fibrin crosslinks.
• They are indicated for anticoagulant use, DVT, MI, and PE.
• Bleeding, intracranial neoplasm, and recent ischemic stroke are contraindications.
• Side effects include bleeding, kidney damage, hypotension, and allergic reaction.

Tirzepatide

• Tirzepatide is a GLP-1 agonist.
• It is administered once weekly via subcutaneous injection using an autoinjector (pen).
• It can be used as monotherapy or with other diabetic medications like Metformin and SGLT2 inhibitors.
• It increases GLP-1 which promotes glucose-dependent insulin secretion, slows gastric emptying, and increase satiety.
• Used for T2DM.
• Contraindicated in patients with a history of pancreatitis.
• Side effects include pancreatitis and weight loss.

Acarbose

• Acarbose belongs to the class of Alpha-glucosidase inhibitors.
• Acarbose delays glucose absorption from the intestine.
• Acarbose is indicated for T2DM.
• Acarbose is contraindicated in gastrointestinal conditions, IBD, and intestinal obstruction.

Milrinone

• Milrinone is a PDE-III inhibitor
• Milrinone inhibits PDE-III which increases cAMP, resulting in a positive inotropic and lusitropic effect and vasodilation.
• It is used for acute decompensated and congestive heart failure.
• Contraindications include hypersensitivity to milrinone and acute MI.
• Side effects include chest pain, palpitations, and headache.

Sacubitril

• Sacubitril is a Neprilysin inhibitor
• Sacubitril is combined with valsartan (ARBs)
• Sacubitril inhibits neprilysin, increasing the concentration of natriuretic peptides and angiotensin II.
• Given with Valsartan, blocks angiotensin II, decreasing vascular resistance and blood pressure.
• Treats heart failure and patients with chronic heart failure.
• Contraindications include a history of angioedema due to ACEi/ARBs, diabetic patients using renin inhibitors, and pregnancy.
• Side effects include hypotension, hyperkalemia, angioedema, and renal failure.

Dipyridamole

• Dipyridamole is a Phosphodiesterase inhibitor.
• Dipyridamole inhibits phosphodiesterase which converts cAMP to AMP
• Increases cAMP, decreases Ca2+, inhibits platelet activation, and decreases SVR.
• Indications include antiplatelet, COPD, BPH, and erectile dysfunction.
• Contraindications include hypotension, hypertension, MI, and stroke in <6 months.
• Side effects include bleeding and headache.

Pleiotropic Effects of Statins

• Statins improve coronary flow, inhibit platelet aggregation, act as antioxidants, anti-inflammatories, and improve endothelial function.

Potassium-Sparing Diuretics

• Drug names include Spironolactone and Amiloride.
• Spironolactone and Amiloride are generally weak diuretics and often used in combination with other diuretics.
• EC: increases K+, decreases NaCl and NaHCO3
• They act in the collecting tubule
• They inhibit Na+ reabsorption and K+ + excretion.
• Spironolactone antagonizes aldosterone and Amiloride blocks Na+ channels.
• Indications include congestive heart failure, liver failure, and hypokalemia prevention.
• Contraindications include hyperkalemia, pregnancy, and renal insufficiency.
• Side effects include hyperkalemia, metabolic acidosis, GI upset, and Spironolactone can cause gynecomastia.

Alpha-glucosidase Inhibitors

• Drug name is Acarbose
• Acarbose delays glucose absorption from the intestine.
• Used for T2DM.
• Contraindications include gastrointestinal conditions, IBD, and intestinal obstruction.

PPAR-y Agonists

• Drug names include Pioglitazone and Rosiglitazone.
• They activate PPAR-y = increase glucose uptake in muscle and fat, increase insulin sensitivity, and decrease liver glucose production
• Used for T2DM
• Contraindicated in symptomatic angina or heart failure
• Side effects include weight gain, heart failure, edema, and increased fracture risk

Digitalis/Cardiac Glycosides

• Drug name is Digoxin
• Digoxin inhibits the Na+/K+ ATPase subunit alpha 1 = increases Na+ and Ca2+
• This increases the contractile force of the heart
• Stimulates the PNS through the vagus nerve = decreases HR.
• Used for atrial arrhythmias and congestive heart failure when other medications fail.
• Contraindications include acute MI and ventricular fibrillation.
• Side effects include nausea, vomiting, arrhythmias, and visual disturbances.

NOAC

• Direct Thrombin Inhibitors medication names Bivalirudin and Dabigatran.
• These bind directly to the thrombin active site
• Used as 2nd line of medications for patients with a history of DVT or AF, if heparin causes heparin-induced thrombocytopenia, with aspirin, and with clopidogrel - prevents clot formation in patients undergoing coronary artery surgery.
• Bleeding when taken in excess and GI disturbances are side effects.
• Contraindications include bleeding and allergies.
• Direct Factor Xa Inhibitors medication names Apixaban, Edoxaban, and Rivaroxaban
• Direct Factor Xa Inhibitors bind directly to Factor Xa's active side.
• These treat deep vein thrombosis, pulmonary embolism, stroke, and coronary artery disease.
• Bleeding is a side effect.
• Contraindications include bleeding, liver dysfunction, atrial fibrillation, and prosthetic heart valves.

Ezetimibe

• Ezetimibe is a 2nd line pharmacotherapy agent used in combination with other lipid-lowering agents.
• It blocks Niemann-Pick C1 Like1 Protein (NPC1L1P), a critical mediator of cholesterol absorption in the GI tract.
• Lowers hepatic LDL, upregulates LDL receptors, and lowers LDL in the blood.
• Indications include Hyperlipidemia and primary hypercholesterolemia
• Contraindications include pregnancy, liver issues, and renal impairment.
• Side effects include darkened urine, GI upset, and liver damage.

Antifibrinolytic Drugs

• Medications include tranexamic Acid and aminocaproic Acid.
• Indications include Bleeding episodes and Haemophilia
• Inhibit fibrinolysis by inhibiting plasminogen activation
• Side effects include Thrombosis, Hypotension, myopathy, and Diarrhea
• Contraindications include DVT, Pulmonary embolism, and Seizures

HIT

• HIT Type 1 occurs within the first 2 days of heparin use, it is a non-immune disorder that does not require management, and the platelet count normalizes with continuous heparin therapy.
• HIT Type 2 is immune-mediated, occurring 4-10 days after exposure to Heparin, involves autoantibody formation against factor 4, and causes venous and arterial thrombosis.

DPP-4 Inhibitors

• Drug names include Sixagliptin, Sitagliptin, and Linagliptin
• DPP-4 Inhibitor mechanism inhibits GLP-1 being broken down, which increases insulin release, decreases glucagon release, increases gastric emptying, and increases feelings of satiety.
• Treats T2DM.
• Contraindications include hypoglycemia and a history of pancreatitis.
• Side effects include urinary tract infections, upper respiratory infections, and weight loss.

Loop Diuretics

• Drug names include Furosemide and Torsemide and have a greatest diuretic effect.
• Loop Diuretics act on the ascending loop of Henle
• Loop Diuretics involves Na/Ca2+/K+ co-transporter and removes water, reducing peripheral resistance.
• Indications include Hypertension, Liver cirrhosis, Congestive Heart Failure and Renal disease
• Contraindications include: hypocalcemia, hypokalemia, anuria, pregnancy and hepatic coma
• Side Effects: Hypokalemia/ K+ wasting, Hyperuricemia, Hypovolemia and Hypocalcemia

PCSK9 Inhibitors

• Drug names EROLOCUMAB and ALIROCUMAB
• Act as antibodies that target PCSK9 protein
• PCSK9 functions as transporter of LDL receptor
• Inhibits breakdown and function of LDL receptors and increased LDL receptors and decreased blood LDL
• Indication: Primary hypercholesterolemia and Mixed dyslipidemia
• Contraindications: Hypocholesterolemia, Lowered liver and kidney function and Pregnancy
• Side Effects: Neurocognitive problems and Upper respiratory tract infections

Dihydropyridines

• Drug names AMLODIPINE and FELODIPINE, in hypertension treatment
• Mechanism: Inhibit L-type Ca2+ channels in vascular smooth muscle, Vasodilation and decreased systemic vascular resistance
• Indications: Hypetension, Arrythmias and Stable Angina
• Contraindications: Heart Failure and Hypotension
• Side Effects: Peripheral Edema, Headache, Dizziness, Flushing