Mechanisms Exam 2

what are ulcers?

abrasions in the stomach lining that have been met with stomach acid

where is gastric acid (H+) released from?

parietal cells

what is the mechanism for the release of gastric acid?

G cells release gastrin which stimulates ECL cells releasing histamine, histamine stimulates parietal cells which release H+, acetyl choline from the cholinergic nervous system/vagus nerve stimulates parietal cells directly

what allows for the release of H+ without dropping the stomach pH?

the bicarbonate buffer system

How is H+ in the parietal cell transported into the stomach lumen?

the hydrogen/potassium ATPase shuttles H+ out and K+ in, Cl- comes from the exchange of HCO3- into the cell and leaks into the stomach along the concentration gradient to get HCL in the stomach

What is the primary regulator of acid secretion and what pathway?

Acetyl choline, Gi or Gq which then uses calcium to stimulate the ATPase

How do covalent inhibitors raise pH of the stomach?

they attach to the ATPase stopping H+ release into the stomach, non reversible

Covalent inhibitors that raise stomach pH (drugs)

esomeprazole, omeprazole

H2 (histamine) receptor antagonists for raising stomach pH

competitively bind H2 receptor, leaves other receptors active for only partial H+ reduction

H2 receptor antagonists (drugs)

cimetidine, ranitidine, famotidine, nizatidine

antacids neutralize stomach acid (what are they?)

Al(OH)3, CaCO3, Mg(OH)2

peptic ulcers also coincide with what? and what can cause them?

bacterial infections, stress, NSAIDS, Helicobactor pylori

what is the main goal of the kidneys?

maintain extracellular volume, regulate electrolyte concentration in the blood

how do diuretics work in general?

they reduce extracellular volume maintenance and ion excretion, as salt concentration decreases in the blood, osmosis will lead to decreased water concentration in the blood

what are diuertics used to treat?

edema, congestive heart failure, renal failure, hypertension, and diabetes

what are the main sites of diuretic action within the nephron?

proximal convoluted tubule, proximal straight tubule, thin descending/ascending limb, thick ascending limb, distal convoluted tubule, cortical collecting tubule, medullary collecting tubule

where do osmotic diuretics work?

proximal convoluted tubule, proximal straight tubule, and thin descending limb

how do osmotic diuretics work? what is an example?

they extract water from intracellular compartments decreasing blood viscosity, cause an increase in osmotic pressure within the tubule inhibiting passive reasborption of water - mannitol

how do the thin descending and thick ascending loops work without the presence of loop diuretics?

a Na/K/Cl ion symporter moves these ions from the urine to the cell, and a Na/K ATPase maintains Na/K ion concentrations in cell and the blood

what are loop diuretics?

the Na/K/Cl symporter is inhibited, those ions remain in the urine

examples of loop diuretics/high ceiling diuertics

furosemide, ethacrynic acid, torsemide, bumetanide

how does the distal convoluted tubule work in the absence of thiazide diuretics?

Na/Cl transporter allowing for oppportunity to reabsorb Na/Cl into the blood - Na/Ca transporter on blood side

how do thiazide diuretics work?

increase Na and Cl excretion by inhibiting Na/Cl transporter, trapping them in the urine

interesting side effect of thiazide diuretics

activates Na/Ca transporters on the blood side allowing Ca to replace the Na lost, can treat kidney stones

collecting tubule/K-sparing diuretics

last opportunity for reabsorption, relatively weak, inhibits the Na channels but allows for K reabsorption - counter cramping effects of loop and thiazides

K-sparing diuretics examples

triamterene, amiloride

how do you treat hypertension?

reduce blood volume

describe the renin-angiotensin system

when blood pressure falls, renin is released, renin cleaved angiotensinogen into angiotensin 1, angiotensin 1 gets cleaved by angiotensin-converting enzyme into angiotensin 2, angiotensin 2 can either bind to receptors at the blood vessels causing them to constrict or stimulate adrenal glands to release aldosterone

describe how aldosterone increase blood pressure?

aldosterone (steroid hormone) enters the renal epithelial cell through the blood, binds to steroid hormone receptor (mineralocortocoid receptor) within the cell, and modulates gene transcription through increasing transcription of AIPs, these upregulate Na/Ca channels and Na/K ATPase, more salt from urine side to blood side leads to increase in blood volume

aldosterone antagonist, drug + action + result

spironolactone blocks binding of aldosterone to mineralocorticoid receptor, less salt and water are reabsorbed

describe congestive heart failure

heart fails to effectively pump blood, its too weak so the blood flows back into the heart and fluid builds up in the lungs, volume of the ventricles decreases

what are some causes of congestive heart failure?

hypertension, coronary artery disease, heart attack

digoxin

drug that treats congestive heart failure, increase intracellular Ca by inhibiting the Na/K ATPase, slowing down the Na/Ca transporter that moves Ca out

inamrinone and milrinone

phosphodiesterase inhibitors stop the cleavage of cyclic nucleotides (cAMP) promoting phosphorylation of Ca channels in the heart which improves the force of contraction and vasodilation

blood pressure, diastolic pressure, systolic pressure

pressure that the blood exerts on the inside walls of the blood vessel, pressure when the heart is not contracted, pressure while the heart is contracted

hypertension

chronic diastolic of 90 or more and systolic of 140 and more

cardiac output

the degree of which the blood is pumping through the system

peripheral vascular resistance

the strength at which the blood vessels resist blood flowing through them, if they loosen can lower blood pressure

how do diuretics treat hypertension

cause salt and water excretion through the urine, lowering the blood volume (reducing cardiac output)

nitroprusside and mechanism

direct vasodilator given in emergency situations - NO released and diffuses into cell binding soluble guanylyl cyclase which converts GTP to cGMP which then activates cGMPK, this can either phosphorylate MLCP which relaxes MLC or phosphorylates membrane Ca channel closing it and reducing Ca in the cell

minoxidil andn mechanism

direct vasodilator - activates ATP dependent K channels, K flows out of cell, blood vessels relax

verapamil, nifedipine, diltiazem

Ca channel blockers - relaxes the muscles

benazepril, captopril, enalapril, fosinopril

ACE inhibitors.- stops the conversion of angiotensin 1, prohibting downstream effects

iosartan, valsartan, candesartan, eprosartan

AT1 receptor antagonists (stops angiotensin 2 from binding)

metoprolol - B1AR antagonist

reduces heart rate and force of contraction, B1AR in the heart increase heart rate and contraction

prazosin - A1AR antagonist

reduces peripheral resistance, A1AR in the arteries cause contraction in the vascular smooth muscle

atherosclerosis

disease of blood vessels, aorta, peripheral arteries caused by injury to vascular endothelium - eventually leading to occlusion stopping blood from reaching target tissues

what does atherosclerotic plaque do to the body?

initiated due to body sensing injury to vessel wall, plaque binds to receptors allowing lipids to get into the vessel, macrophages invade the vessel wall and engulf the lipids becoming foam cells and just hang around and build with the plaque, buildup of fibrous tissue can stabalize the plaque making it hard, can break off and travel down the blood stream occluding smaller blood vessels

how are fat and cholesterols circulated? and what are those things?

chylomicrons, which are the largest lipid units and apolipoproteins which are proteins that surround the chylomicron allowing them to bind to specific receptors

what aspect of cholesterol allows it to embed itself in the membrane of the chylomicrons?

esters/OH group attached to it, makes it more lipophilic

why is LDL considered bad?

its apolipoprotein is ApoB100 which facilitates its entry into the artery wall

why is HDL good?

its a major transporter of lipids from peripheral tissues to the liver for excretion/metabolism and can even remove cholesterol from artieral walls

what is the rate limiting step and its components in the cholesterol synthesis pathway in the liver?

HMG CoA reductase (rate limiting enzyme) converts HMG CoA to mevalonate

what are statins? how do they work?

drugs that help reduce cholesterol levels, they inhibit the function of HMG CoA reductase via competitive inhibition as well as increase transcription of LDL receptors leading to enhanced removal of LDL

what are PPARas? what do they do?

peroxisomal proliferator activated receptors - steroid hormones that bind endogenous fatty acids, bind to RXR in the nucleus and targets genes that increase lipoprotein lipase activity, increase synthesis of HDL apos, decrease apoC-III which inhibits LDL, and inhibits fatty acid synthesis/promotes fatty acide oxidation

gemfibrozil (fibric acid derivative)

PPARa ligand that works with fatty acids to increase translation PPARa translation targets to treat high cholesterol

what are the main cellular effects of insulin?

energy storage, gluconeogenesis inhibition, stimulation of glucose uptake by skeletal muscle/adiopocytes, stimulation of glycogen synthesis

describe the insulin pathway

insulin receptors belong to RTK family, once activated IRS (insulin receptor substrate) binds to the docking site, gets phosphorylated by the receptor, PI3K binds to IRS and becomes activates, PI3K cleaves PIP2 into PIP3, PIP3 acts as membrane site for PDK, PDK phosphorylates Akt/PKB which then has signaling effects on glucose uptake and glycogen synthesis

what happens with a short term increase in circulating glucose?

blood glucose heads to pancreas, pancreatic B cells secrete insulin, circulating insulin moves to muscle cells, and insulin receptors on GLUT4 bind insulin activating Akt/PKB

how does insulin effect glucose uptake?

glucose is moved into the muscle cells via GLUT4 transporters, when insulin is secreted and bound to its receptor on GLUT4 it activates Akt/PKB, this signals for the cell to release vesicles that contain trapped GLUT4 to fuse with the membrane, this allows more GLUT4 transporters to be available for glucose and either provide energy or be stored

how does insulin effect glycogen synthesis?

insulin activates Akt/PKB, Akt/PKB phosphorylates GSK inhibiting its ability to phosphorylate GS, this leaves GS in the active state allowing for storage of glucose as glycogen

what is type 1 diabetes?

the immune system attacks pancreatic B cells making them nonfunctional, they cannot release insulin

what is type 2 diabetes?

can produce insulin, but body does not respond properly to insulin binding its receptors, miscommunication between pancreatic B cells and uptake of glucose

in a normal patient what does the glucose tolerance test look like?

time 0 will have normal glucose/insulin ranges - circulating glucose/insulin will both intially go up and then fall back down as they regulate each other

what does a glucose tolerance test look like in someone with type 1 diabetes?

time 0 will have higher than normal glucose concentration - glucose concentration will go up but insulin will be flatline - lag in glucose coming down as it has to be filtered out in the urine

what does a glucose tolerance test look like in someone with type 2 diabetes?

time 0 will have higher than normal glucose concentration - glucose will go up as it normally does, insulin will either have a lag in coming up or can have a high constant insulin concentration

describe the mechanism of insulin secretion from pancreatic B cells

secretion of insulin is stimulated by elevation of circulating glucose, when glucose is low so is ATP, the K channel is open but the Ca channel is closed, K leaves and the Ca cannot enter - elevated ATP closes K channel and Ca enters, the Ca influx allows for vesicle docking and release of insulin

sulfonylureas and meglitinides

promote release of insulin by blocking the K channel in pancreatic B cells allowing for Ca to enter

DPP4 inhibitor - sitagliptin

DPP targets GIP and GLIP which effect pancreatic islet cells, the drug inhibits DPP and inhibits the cleavage of GIP and GLP increasing their circulation and their effects (decrease in circulating glucose/increase in insulin)

liraglutide and semiglutide

GLP1 analogues, stimulate their effects

metformin

antihyperglycemic agent, modulates effects of AMPK which causes increase in glucose-stimualted insulin secretion and glucose uptake, decrease in gluconeogenesis

acarbose, miglitol

a-glucosidase inhibitor - stops the enzyme from breaking down saccharides and raising blood glucose

SGLT inhhibitors

prevent glucose reasborption in the nephron

thiazolindinediones/PPARg agonists

increase insulin sensitivity - modulates expression of lipid and glucose metabolism decreasing leptin and increases adiponectin

graves disease

hyperthyroid condition characterized by enflamed, enlarged eyes due to contraction of the eye muscles and an overly active/overly secreted thyroid hormone

describe how T3 and T4 is released and regulated

the release is stimulated by thryoid stimulating hormone (TSH), TSH is released from the pituitary gland, thyrotropin releasing hormone (TRH) is released from the hypothalamus to stimulates TSH

what is the mechanism for the release of TSH

TSH has to enter nucleus and bind to TRE with binding partner RXR in order to have stimulatory effect, TSH is controlled by hypothalamus which releases TRH, TRH binds to GPCR activating PKC stimulating TSH release

what is the negative feedback mechanism for the release of TSH

thyroid gland tells pituitary to stop releasing TSH - T3 binds hormone receptor and heterodimerizes inhibiting PKC, in absence the homodimer sits there

mechanism for iodinating tyrosines to form T3 and T4

I- enters the cell via Na/I symporter, I- is oxidized by thyroperoxidase, thyroglobulin provides the Tyrs, lyosomes degrade the Tg so that only T3 and T4 are released

perchlorate ion (CIO4-)

antihyperthyroidism - completitively inhibits the Na/I transporter that allows for I- to enter the cell

propylthiouracil and methimazole

antihyperthyroidism - inhibits the peroxidase enzyme that oxidizes I-

radioactive iodine

destructive B radiation causes necrosis, colloid disappearance but can possibly destroy the thyroid gland itself

B1AR antagonists for antihyperthyroidism

thyroid hormone increases production of B1AR mRNA, can help with hypertension due to the disease

glucocorticoids for antihyperthyroidism

cortisol degradtion is increased, inhibits deiodinase of T3 and T4