Final Exam Flashcards
Type 1 Diabetes
loss of insulin production by pancreas
Type 2 Diabetes
Resistance to the actions of insulin
5 abnormalities due to insulin deficiency
- hyperglycemia
- increased lipolysis
- acidosis
- increased LDL; decreased HDL
- osmotic diuresis (increased urination)
Insulin replacement therapy
insulin associates as hexamer
rate limiting step for capillary absorption is the dissociation of hexamers into dimer and then monomers
5 different types of insulin
- ultra fast/ short acting: lispro
- short acting: regular
- intermediate acting: NPH
- long acting: lente /ultra lente
- ultra long acting: glargine
2 insulin treatment regimes
- Intensive insulin treatment (frequent monitoring of blood glucose, 3 or more daily injections of insulin)
- Continuous subcutaneous insulin infusion (insulin pump with lispro or regular insulin, allows control of dawn phenomenon, patient triggered bolus before meals)
4 adverse effects of insulin therapy
- hypoglycemia (especially dangerous in Type 1 diabetes)
- allergy and resistance to insulin
- lipohypertrophy
- lipoatrophy (due to impurities: switch to highly purified insulin)
Insulin resistance is due to?
decrease insulin receptor number
decrease insulin receptor kinase activity
post receptor defects
decrease GLUT4 translocation from impaired signalling (less glucose can be transported into cell)
Impaired islet function is due to?
loss of first phase insulin secretion
increase secretion of proinsulin
Treatment of type 2 diabetes
- diet and exercise: most effective, increase insulin sensitivity
- monotherapy with oral agent
Sulfonylureas (Glyburide)
Most effective when B cell function has not been severely compromised
Increased insulin secretion favors lipogenesis
inhibit voltage gated K channel -> activates voltage gated Ca channel -> more intracellular calcium -> cause insulin secretion
Repaglinide and Nateglinide
decrease ATP-sensitive K+ conductance
similar to sulfonylureas
maybe more specific for B-cell sulfonylurea receptor (fewer off targets effects)
action maybe glucose dependent
insulin release is rapid and brief
taken with meals for postprandial hyperglycemia
Repaglinide and Nateglinide
decrease ATP-sensitive K+ conductance
similar to sulfonylureas
maybe more specific for B-cell sulfonylurea receptor (fewer off targets effects)
action maybe glucose dependent
insulin release is rapid and brief
taken with meals for postprandial hyperglycemia
Biguanides (Metformin)
antihyperglycemic
inhibit gluconeogenesis
inhibit glucose-6-phosphatase activity -> glycogen sparing
decrease insulin resistance
mediated by activation of 5’AMP-activated protein kinase (AMPK) in hepatocytes and muscle
DO NOT INCREASE INSULIN SECRETION
NOT HYPOGLYCEMIC EVEN AT HIGH DOSES
Thiazolidinedione (Glitazones)
Activates peroxisome proliferator-activated receptor Y
increase adipose tissue -> weight gain
decrease TNFa
decrease leptin
increase lipoprotein lipase
increase GLUT4 and GLUT 1
a glucosidase inhibitors (Acarbose)
competitive and reversible inhibitors of a glucosidase
delay carbohydrate digestion and absorption
smaller rise in postprandial glucose
taken with first bit of meal
DO NOT PRODUCE HYPOGLYCEMIA, LACTIC ACIDOSIS or WEIGHT GAIN
effective regardless of age, genetic factor, body weight, duration or severity of the disease
PDGF receptors (platelet-derived growth factor)
activation: open c terminal loop, phosphorylation
involved in wound healing
released from activated platelets by degranulation
stimulates fibroblast migration, chemotactic and angiogenic
plays a role in arteriosclerosis (overactivity of PDGF)
blocking antibodies have been developed (problem: too much blockade will end up with bleeding disorder, no healing)
3 drugs that bind covalently to enzymes
- Acetylsalicylic acid (ASA, aspirin)
- Penicillin
- Phenelzine
Aspirin
irreversibly inactivates COX, inhibiting prostaglandin production
inflammation: due to prostaglandin E and F
ASA acetylates both COX1 and COX2, but COX2 is more important because it is inducible by inflammatory cytokines
antithrombotic: inhibition of COX1 leads to antithrombotic effect (prolonged bleeding)
analgesic: inhibition of prostaglandin synthesis decrease perception of pain
antipyretic: decrease prostaglandin synthesis in hypothalamus induce vasodilation and sweating, leads to decrease body temperature
COX2 selectivity for ASA
structural difference between the substrate binding channels in COX1 and 2
VAL434, ARG513, VAL532 side pocket absent in COX1
Penicillin
inhibit cross wall formation in bacteria -> abnormally elongated cells -> rupture and cell death
Transpeptidase cleaves terminal D-ala and connects it to m-dap, which is inhibited by penicillin
B-lactamase (decoy) give penicillin resistance to pathogenic bacteria
Phenelzine (Nardil)
antidepressant agent
mediates by 5-hydroxytryptamine (5-HT) and catecholamines (norepinephrine and dopamine)
inhibits monoamine oxidase (MAO) MAO has 2 isoforms A and B MAO A: 5-HT and norepinephrine MAO B: phenylethylamine MAO-A is more important for antidepressant effects
contains a hydrazine moiety similar to substrates of MAO
inactivates enzyme when covalently binds
non-selective MAO inhibitor
requires several weeks for onset for activity
food restriction for tyramine containing (cheese, red wine, beer) -> leads to hypertension
3 drugs that bind reversibly to enzymes
- Ramipril
- Sulfonamide
- Neostigmine
Ramipril
inhibit ACE enzyme
blood pressure control and congestive heart failure
reduce formation of angiotensin II, decrease blood pressure
adverse effect inhibit bradykinin metabolism, dry cough, throat irritation, dizziness, itching
Sulfonamide (antibiotic)
Interfere microbial folic acid biosynthesis
competes with para-aminobenzoic acid (PABA) substrate for dihydropteroate synthase (DHPS)
use in treatment of bacterial infection
resistance developed by overproduction of PABA or structural change to DHP enzyme
Neostigmine
muscle stimulant
inhibit hydrolysis of acetylcholine so acetylcholine cannot be metabolized
will release eventually
3 drug that mimic enzyme substrate (pseudosubstrate)
Zidovudine (AZT)
Acycloguanosine
Cytosine Arabinoside
Zidovudine (Retrovir, Azidothymidine AZT)
first approved drug for HIV treatment
nucleotide reverse transcriptase inhibitors (NRTIs)
site of action at RNA-directed DNA polymerase (reverse transcriptase) enzyme
inhibits reverse transcriptase in virus
lacks 3’ oxygen, cause DNA chain termination when incorporated into a growing DNA strand
Highly active anti-viral therapy (HAAT)
combinations of two or three drugs of different classes
AZT or another nucleoside mimics & non-nucleoside reverse transcriptase inhibitors
entry inhibitors = prevent virion from attaching to host cell membrane
integrate inhibitors = stop DNA incorporation into host DNA
decrease viral load
not curable of HIV but can improve quality of life
Acycloguanosine (acyclovir)
topical antiviral drug
treat symptoms of herpes simplex virus infections of the skin, mucous membrane and genitals
mimics deoxy guanosine
viral and host kinase convert acyclovir into Acycloguanosine triphosphate and used by viral DNA polymerase.
no tertiary hydroxyl group prevent binding of next nucleotide
Cytosine Arabinoside (cytarabine, araC)
pyrimidine analogue
cytotoxic
incorporation of AraCTP into DNA
mimics deoxycytidine
inhibit DNA polymerase activity, block DNA synthesis
inhibit topoisomerase I results in DNA supercoiling during synthesis
OH group modifies DNA structure inhibition of transcription factor binding to DNA
used in treatment of leukemia
3 types of natriuretic peptide
A type: 28 amino acid, secreted by myocyte in atria
B type: 32 amino acid, secreted by myocyte in ventricle
C type: 22 amino acid, secreted by vascular cells
3 effects of increased cGMP
- increase natriuresis (urination)
- decrease peripheral vascular pressure (decrease blood pressure)
- suppress renin-angiotensin
Mechanism of natriuresis (ANP)
ANP increase glomerular filtration
ANP stimulate phosphorylation of ENac (epithelial sodium channel) blocking Na reuptake
net increase excretion of water and sodium
Mechanism of muscle relaxation by Nitric oxide on soluble guanylyl cyclase
NO binds -> cGMP production -> cGMP binds to PKG -> PKG phosphorylates IP3 and L-type Ca channel -> decrease [Ca]
-> decrease MLCK activity -> decrease muscle contraction
Half life of nitroglycerin, isosorbide dinitrate and isosorbide mononitrate
Nitroglycerin: acute treatment, 2min
Isosorbide dinitrate: prophylactic (long-lasting) treatment, 1 hour
Isosorbide mononitrate: prophylactic treatment, 5 hours
release of NO (rapid dilation of blood vessels)
PDE inhibitor Methylxanthines
increased cortical arousal, more alert and deferral of fatigue myocardial contraction relaxation of smooth muscle increase gastric secretion increase digestive enzymes BRONCHODILATION
Theophylline
treats asthma bronchodilator agonist, inhibit PDE from turning cAMP to AMP decrease Ca smooth muscle relaxation
Rolipram
PDE4 inhibitor (cAMP selective)
treats depression
nausea GI disturbance and emesis
Roflumilast
PDE4 inhibitor
used in chronic obstructive pulmonary disease (COPD)
still upsets GI
Sildenafil (Viagra) and Tadalafil (longer halftime)
PDE5 inhibitor (cGMP specific)
inhibit breakdown of cGMP to GMP
higher cGMP concentration leads to muscle relaxation
leads to increase blood flow to corpus cavernosum of penis
erection restore
HYPOTENSIVE SHOCK if used with NITROGLYCERINE
Ligand binding domain of nuclear receptors
11-13 a helices arrange into a three layer antiparallel a-helical sandwich
long helices 3,7 and 10 form two outer layers
4,5,8,9 create ligand binding pockets
Agonists function of nuclear receptors
stabilize nuclear receptor formation and maintaining AF-2 helix 12 in the active conformation
Ligand binding pocket specificity is determined by?
- shape
- size
- plasticity
Ligand binding pocket specificity is determined by?
- shape
- size
- plasticity
Ligand binding of nuclear receptor triggers ? (6 steps)
- conformational change in LBD
- dismissal of corepressor
- recruitment of ubiquitylation leads to corepressor degradation
- enhanced affinity for co-activators
- recruit co-activator complex
- activation of gene transcription
Zinc finger domain in DNA binding domain (DBD)
P-box (proximal) domain: DNA binding in major groove
D-box (distal) domain: NR dimerization
nuclear receptors can bind to DNA as monomer, homodimers and heterodimers
Estrogen receptors
Type 1
activates gene containing estrogen response element (ERE)
can function as homodimers (a-a, b-b) or heterodimers (a-b)
ERa: breast, endometrial, ovarian and hypothalamus tissue (sex organs)
ERb: brain, bone, endothelial, heart, intestine, kidney, lung and prostate tissue (non-sex organs)
have overlapping and non-overlapping function, can oppose each other
What is the natural ligand of estrogen receptor?
17B- estradiol (estrogen) agonist induce puberty derived from cholesterol primarily produced in ovaries
Estrogen deficiency
menopause
ovarian insufficiency
hyperprolactinemia (elevated prolactin to enhance breast development during pregnancy and lactation)
Elevated estrogen level
weight gain liver toxicity breast hypertrophy thrombosis increase cancer risk endometrial cancer breast cancer