Pharmacology Exam 2

Sulfonylureas

MOA (pancreas): Stimulates release of insulin from pancreatic beta-cells, reduces hepatic glucose output and increases insulin sensitivity

Glyburide, Glipizide, Glimepiride

Non-sulfonylurea Secretagogues (Meglitinides)

MOA (pancreas): blocks ATP-dependent calcium channels
-increases amounts of intracellular calcium increases insulin release from beta cells

Rapaglinide & Nateglinide

Alpha-Glucosidase Inhibitors

Alpha glucosidase breaks down carbs into simpler sugars to digest

Inhibitors inhibit that, leaving the carbohydrates more complex, meaning you don’t absorb them and your blood sugar doesn’t rise, preventing glucose from entering the system

MOA (intestines, absorption pathway): competes for the alpha-amylase and alpha-glucosidase resulting in delayed intestinal digestion of complex carbohydrates, little systemic absorption

Acarbose & Miglitol

Biguanides

MOA (liver): reduces glucose absorption, improves insulin receptor sensitivity, and reduces hepatic glucose production

At high doses, may induce high rates of lactic acid and metabolic acidosis

Metformin

Thiazolidinediones

MOA (liver): reduction of hepatic glucose production, enhanced cellular response to insulin (via activiation of peroxisome proliferator-activated receptors (PPARs))

*PPARs involved in fertility process also

Rosiglitazone & Pioglitazone

Glucose-dependent insulinotropic peptide (GIP) and Glucagon-like peptide-1 (GLP-1)

Both secrete insulin in a glucose-dependent manner

GLP-1 agonists directly stimulate effects, however, the body has a mechanism of regulating GLP-1 called DPP-4

Therefore, DPP inhibitors are used to prevent the breakdown or inactivation of GLP-1s, meaning there are more prolonged effects of GLP-1 effects in the body = more insulin (lower appetite/increased satiety/eat less, less gastric emptying/food stays in body for longer, regulation of insulin is more stable, down-regulation of gluconeogenesis of storing glycogen for later)

Analogs: Semaglutide (Ozempic, Wegovy), Dulaglutide, Liraglutide, Exenatide
Agonists: Tirzepatide (Monjaro)
Triple-acting: Retatrutide

Glucagon

Signals liver to release stored glucose and convert glycogen counteracting insulin

Triple-acting: Retatrutide

Islet amyloid polypeptide (IAPP, or Amylin)

Co-secreted with insulin, slows gastric emptying, inhibits insulin and glucagon secretion by slowing glucose appearance (down-regulating glucagon)

Amylin analog: Pramlintide

Dipeptidyl peptidase IV inhibitors (DPP-4 inhibitors)

GLP-1 agonists directly stimulate effects, however, the body has a mechanism of regulating GLP-1 called DPP-4

Therefore, DPP inhibitors are used to prevent the breakdown or inactivation of GLP-1s, meaning there are more prolonged effects of GLP-1 effects in the body = more insulin (lower appetite/increased satiety/eat less, less gastric emptying/food stays in body for longer, regulation of insulin is more stable, down-regulation of gluconeogenesis of storing glycogen for later)

MOA: inhibits DPP-4 enzymes from breaking down incretin hormones, GLP and GIP, which increase insulin release

Sodium-Glucose co-Transporter 2 (SGLT2) Inhibitors

MOA (kidneys): inhibits SGLT-2 (primary site of filtered glucose reabsorption) in proximal tubules, resulting in increased urinary excretion of glucose and subsequent reduction in plasma glucose concentrations (makes you pee out glucose-laden urine)

Canagliflozin, Dapagliflozin, Empagliflozin

Insulin

MOA: stimulates hepatic glycogen synthesis (regulates metabolism of carbs, proteins, and fat)

Thyroid Hormone

Maintains homeostasis, and is stored as thyroglobulin

Thyroid follicles produce T4 and T3 (parafollicule produces calcitonin)
-Primarily secreted as T4, a prohormone, that is hepatically converted to T3)
-Local activation of T4, and deactivation of T3, also occur in tissues as counter-regulatory effects

T3 Thyroid Hormone

-Most potent thyroid hormone
-Affects body temperature, growth, and heart rate
-Four times more potent than T4
-Primarily produced by conversion from T4

T4 Thyroid Hormone

-Major hormone secreted from thyroid
-Converted to T3 by deiodinases
-More abundant than T3 in the body, but less important

Hyperthyroidism

-Heat intolerance
-Weight loss despite increased appetite
-Increased activity, sweating, palpitations
-Insomnia and shortened sleep cycles
-Hair loss
-May present with a goiter

*Due to increased levels of T3 and T4

Therapeutic options:

Thiomidines:
-Propylthiouracil (PTU) or Methimazole (Tapazole)
-MOA; inhibits peroxidase enzymes (responsible for incorporation of iodine into thyroglobulin), blocking hormone synthesis
-PTU also partially blocks peripheral conversion of T4 to T3
-Typically utilized for long-term management as both are oral tablets

Iodines:
-Lugol’s solution or SSKI (Super saturated potassium iodide)
-MOA: Directly inhibits release of thyroid hormone
-Typically utilized in preparation for thyroidectomy

Hypothyroidism

-Cold intolerance
-Weight gain
-Lethargy/somnolence
-Fatigue
-Dry hair/skin

*Due to a lack of adequate T3 and T4 levels

Therapeutic options:
-Levothyroxine: L-isomer of thyroxine (T4)
-Amour thyroid: T3 and T4 synthetic hormones (4:1 ratio)
-Liothyronine: T3 hormone only

Blood testing (thyroid panel) can help determine which one(s) someone will need (whether they have low levels of T4, low levels of active T3)

Adrenal Gland Functions

Adrenal Medulla secretes
-Epinephrine and Norepinephrine

Adrenal Cortex secretes
-Glucocorticoid hormones (primarily cortisol)
-Rate of secretion is controlled via hypothalamic-pituitary-adrenal axis (regulated by adrenocorticotropin hormone)
-Mineralocorticoid hormones (primarily aldosterone)
-Circulates unbound and exerts effects primarily on Na and K regulation via distal renal tubules
-Androgenic Steroids

Adrenocorticosteroids

Two types: Glucocorticoids & Mineralocorticoids
-Glucocorticoids receptors are found throughout the body, whereas mineralo-receptors are found in excretory organs (colon, kidney, and saliva/sweat glands)

-Cortisol in the primary human glucocorticoid
-Synthetic versions also exist
-Promotes metabolism, combat stress, and decrease inflammation
-Release in inhibited by etomidate, among others, via catabolic enzymes

Mineralocorticoids regulate electrolyte concentrations and water volume (Fludrocortisone)

Hormones for Growth

Most often created via recombinant DNA technology (same as insulin development)

Somatropin (rhGH): growth hormone agonist
-Synthetic version of human growth hormone to stimulate cartilage and bone development, builds muscle, regulates fat/protein/carb metabolism

Pegvisomant: modified GH analog (antagonist)
-Binds but produces no activation at GH receptor blocking the above processes

Octreotide/lanreotide: somatostatin analogs
-Bind to receptors in pituitary gland and block release of GH

Dopamine agonists: inhibit release of GH indirectly

Anabolic hormones such as testosterone/estrogen also signal release of GH
-Anti-androgenic agents block these effects

X

Hypertension

Blood pressure = cardiac output (contraction, filling pressure, heart rate) x peripheral resistance (arteriolar volume)

Renin

Stored/secreted by juxtaglomerular cells in walls of afferent arteriole
-Cleaves angiotensinogen to angiotensin
-Adenosine and ATP inhibit release, Prostaglandins stimulate release

Direct Renin Inhibitors

Prevents renin from binding with target receptors and thus prevents cascade
-Theorized to provide a more complete blockage of the RAAS system

Bradykinin build-up:
-Dry cough: occurs through build up of bradykinin, which antagonizes the lungs, allergic reactions due to vasodilation, swelling

Aliskiren

ACE Inhibitors (angiotensinogen converting enzyme inhibitor)

Prevent conversion of angiotensin I to angiontensin II by inhibiting angiotensin converting enzyme
-Reduce peripheral resistance without increasing cardiac output, rate, or contraction
-ACE also responsible for breakdown of bradykinin
-Therefore, bradykinin can build up with ACE inhibitors (causing bronchoconstriction/inflammation)

Captopril, Enelapril, Lisinopril, Ramipril

ARBs (angiotensin receptor blockers)

Prevent angiotensin II from binding to receptors on the kidney
-Increase arteriolar/venous dilation, decrease blood pressure
-Does NOT alter the degradation of bradykini

Losartan, Irbesartan, Olmesartan, Valsartan

Diuretics

Block exchange of electrolytes to get you to pee them out

Differs based on their site of action
-Loops
-Thiazides
-Potassium sparing
-Osmotic/carbonic anhydrase inhibitors

Loop diuretics

Targets the loop of Henle in the kideny

Inhibits Na/K/Cl co-transporter decreased fluid reabsorption and promotes excretion
-Transporter typically reabsorbs 25% of all Na+

Furosemide, Torsemide, Bumetanide
-Bumetanide is less dependent on protein (albumin) for its effects making it more potent

Can cause hypokalemia, hyperureacemia (kidney stones) and dehydration

Thiazide diuretics

Targets the distal tubule of the kidney

Inhibits Na/Cl transporter, decrease fluid reabsorption and promotes excretion

Most commonly used diuretics

Hydrochlorthiazide & Chlorthalidone

Can cause hypokalemia, hyperureacemia (kidney stones) and dehydration

Aldosterone-sparing diuretics (Potassium sparing)

Also called mineralcorticoid receptor antagonists (oppose mineralcorticoid effects)

Targets the distal tubule of the kidney and do not impact aldosterone function from adrenal glands
-Inhibits K+ transporter, reducing cellular exchange with hydrogen increasing fluid excretion

Spironolactone, Eplerenone, Finerenone, Drospirenone

Can cause hyperkalemia

Osmotic/Carbonic diuretics

Osmotic Diuretic:
-Mannitol works via inhibition of tubular reabsorption of electrolytes/water
-Primarily used to decrease intracranial pressure by decreasing cerebral volume (since it can cross the blood-brain barrier)

Carbonic anhydrous inhibitor
-Acetazolamide, or other agents, work via reducing reabsorption of proximal tubule reabsorption of electrolytes/water
-Used for a variety of indications from glaucoma to altitude sickness to metabolic alkalosis

α-agonist

Decreases adrenergic outflow via α2 agonism
-Recall adrenergic outflow increases blood pressure via peripheral vascular resistance

Reduces sympathetic output, thus lowering blood pressure and heart rate, may also produce muscle relaxation

Clonidine & Dexmedetomidine

β-blockers

Blockade of beta receptors (β1: heart, β2: lungs)

Reduction in sympathetic output:
-Bradycardia, fatigue, lethargy, depression, and sexual dysfunction
-Non-selective agents reported to have higher rates, although this has been debated within the literature

Recall cardioselective vs. nonselective
-Propranolol/nadolol/esmolol are nonselective
-Atenolol & metoprolol are selective
-Carvedilol/labetalol are dual agents (α and β activity)

Calcium Channel Blockers

Action depends on class:
-Nondihydropyridines
-Dihydropyridines

Both agents inhibit calcium channels in the vasculature (smooth muscles), more vasodilation → lowering blood pressure

Only nondihydropyridines slow action potential through the atrioventricular (AV) node
-Thus, decreases heart rate

Due to alteration of calcium, can induce a variety of effects:
-Bradycardia (nondihydropyridines only)
-Constipation
-Fluid retention (avoid in patients with heart failure)

Nondihydropyridines

Verapamil & Diltiazem

Dihydropyridines

Amlodipine, Felodipine, Nifedipine, Nicardipine, Clevidipine

Nitrate

Decreases peripheral vascular constriction via nitric oxide
-Increases arterial vasodilation, reduces stiffness

By conversion to nitric oxide they produce venodilation
-Possibly increase mitochondrial efficiency in the lungs (increasing exercise capacity)
-Methemoglobinemia:
-Excess amount of nitric oxide, shifts oxygen-carrying capacity of hemoglobin secondary to ferric state (vs. ferrous), treated with methylene blue which converts methemoglobin back to hemoglobin

Isosorbide dinitrate, Isosorbide mononitrate, Nitroglycerin

Individual-acting agents

Promote direct relaxation of vasculature thus decreasing blood pressure

Hydralazine & Minoxidil