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Pharmacology III > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

Endocrine system function

A
  • coordinate and integrate the activity of the cells and tissues of the body using signaling molecs (hormones) that are carried in circulation
  • influences many organ systems
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2
Q

Pancreas: Endocrine

A
  • regulates energy balance and control of fuel mobilization by hormone production into blood (hepatic portal vein)
  • 1% of pancreatic weight (islets)
  • 10-15% arterial blood flow of pancreas
  • richly vascularized
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3
Q

Pancreas: Exocrine

A
  • secretes bicarb and digestive enzymes
  • 99% of pancreatic weight
  • products go to SI (duodenum)
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4
Q

Alpha cells (secrete 4)

A
  • surround beta cells towards outside of islet

- secrete glucagon, proglucagon, GLP-1 and 2

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5
Q

Beta Cells (secrete 5)

A
  • concentrated in center of islet

- secrete insulin, amylin, proinsulin, C-peptide, GABA

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6
Q

Delta Cells

A
  • surround beta cells towards periphery of islet

- secrete somatostatin

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7
Q

somatostatin

A
  • inhibitory of glucagon and insulin
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8
Q

PP cells (F cells)

A
  • around beta cells towards periphery

- secrete pancreatic polypeptide (PP)

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9
Q

Blood flow of endocrine pancreas

A
  • from islet center TO periphery

- fenestrations help blood to get to capillaries from islet cells

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10
Q

Fenestration

A
  • holes in capillary walls
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11
Q

Insulin inhibits:

A
  • glucagon secretion

- somatostatin secretion

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12
Q

glucose levels should be between:

A
  • 70-120 mg/dL
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13
Q

how much insulin is stored in pancreas vs how much secreted/day?

A
  • 8 mg in pancreas

- 0.5-1mg secreted daily

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14
Q

Production of insulin in B cells

A
  • synthesized as preproinsulin
  • cleaved to proinsulin and packaged into vesicles
  • processed to insulin in vesicles
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15
Q

What receptor does insulin and insulin-based drugs activate?

A
  • tyrosine kinase receptor
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16
Q

most insulin drugs are ______ based

A
  • recombinant DNA based
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17
Q

glucose metabolism increases the ______ (sensed by B cell)

A
  • ATP/ADP ratio
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18
Q

glc entry into B cells occurs via ______

- what happens once in B cell?

A
  • GLUT2
  • phosphorylated to G6P by hexokinase
  • metabolized to generate ATP and increase ATP/ADP ratio
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19
Q

High ATP/ADP ratio

A
  • stims insulin secretion
  • closes ATP-sensitive K channel
  • activates voltage gated Ca channels
  • leads to influx of Ca
  • stims exocytosis of vesicles with insulin
  • also cAMP generated which activates pathways which lead to release of intracellular Ca
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20
Q

K/ATPase pump regulates _____

A
  • insulin secretion
  • target of diabetes drugs
  • bind to SUR1 subunits to inhibit
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21
Q

other activators of insulin secretion

A
  • nonglc sugars
  • AA
  • FA
  • parasymp activity
  • GLP-1 and GIP (glc-dependent insulinotropic polypeptide
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22
Q

where is insulin degraded and by what?

A
  • insulinase in the liver and kidney
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23
Q

half life of insulin

A
  • 6 mins
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24
Q

what happens at target tissues of insulin

A
  • insulin binds to receptors on target cells
  • all tissues express insulin receptors
  • activates intracellular tyrosine kinase
  • activates a GPCR to bring glc transporters (GLUT4) to cell surface
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25
Q

insulin receptor makeup

A
  • glycoprotein
  • 4 disulfide-linked subunits
  • two extracellular a subunits
  • two transmembrane b subunits
  • intracellular tyrosine kinase domain
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26
Q

Glycogenesis

A
  • synth of glycogen in muscle and liver from glc
  • insulin favors glycogenesis
  • built by glycogen synthase
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27
Q

Glycogenolysis

A
  • breakdown of glycogen in muscle and liver to glc
  • insulin negative regulator of glycogen phosphorylase
  • liver and kidney have G6-phosphatase which can export glc from these cells
  • muscles does not have this enzyme so glc remains intracellular
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28
Q

hexokinase

A
  • adds p to glc (glc import)

- in most tissues

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29
Q

glucokinase

A
  • adds p to glc (glc import)

- in liver

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30
Q

insulin (Stims/inhibits) glycolysis

A
  • STIMULATES

- turns glc to energy

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31
Q

Gluconeogenesis

A
  • antagonized by insulin
  • converting noncarb precursors to glc or glycogen
  • substrates are glucogenic AA, lactate, and glycerol
  • mostly done in liver and kidneys
  • done in states of starvation
  • also occurs to clear metabolites
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32
Q

Glc made from gluconeogenesis pathway to out of cells:

A
  • G6P converted to Glc by G6-phosphatase
  • in liver and kidney but not in muscle and adipose
  • need this to export Glc out of cells
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33
Q

Lipid storage in adipose

A
  • stores triglycerides synthed from 3 FA and glycerol
  • insulin favors net deposition of triglycerides by increasing translocation of GLUT4 transporters to cell membranes
  • activates lipogenic enzymes
  • FA synth also stimed in liver and other tissues and can be transported to adipose via circulation
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34
Q

Lipolysis

A
  • hydrolysis of triglycerides by hormone-sensitive lipase to be exported from adipose and used by the body
  • stimulated by glucagon and inhibited by insulin
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35
Q

Glucagon

A
  • secreted by A cells
  • proprotein is cleaved to make glucagon (among other hormones (GLP-1-2)
  • stims mobilization of glucose, fats, and protein for energy
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36
Q

other stimuli for glucagon secretion

A
  • sympathetic nervous system, stress, exercise, high plasma levels of AA
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37
Q

half life glucagon & what it is degraded by

A
  • 6 mins

- degraded by liver and kidneys

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38
Q

what does glucagon activate on plasma membrane?

A
  • GPCR which increases cAMP and PKA
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39
Q

glucagon (catabolic or anabolic)

A

catabolic

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40
Q

insulin (catabolic or anabolic)

A

anabolic

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41
Q

PFK-1 does what

A
  • Glycolysis (stimulated by insulin)
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42
Q

pyruvate kinase does what

A
  • gluconeogenesis (by liver)

- stimed by glucagon

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43
Q

somatostatin overview

A
  • secreted by d cells in pancreas, hypothalamus, and GI tract
  • decreases insulin AND glucagon secretion
  • inhibits GI tract motility
  • inhibits secretion of some non-pancreatic hormones
  • stimuli are high plasma levels of glc, AA, and FA
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44
Q

half-life of somatostatin

A
  • 2 mins
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45
Q

GLP-1

A
  • glucagon like peptide 1
  • produced in enteroendocrine cells (L cells) of ileum
  • different cleavage of proglucagon
  • released from L cells during nutrient absorption in the GI tract
46
Q

what does GLP-1 do? (pancreas, stomach, hypothalamus)

A
  • pancreas: increases insulin secretion, suppress glucagon
  • stomach: delay gastric emptying
  • hypothalamus: decrease appetite
  • appeal for type 2 diabetes drug target
47
Q

half life of GLP-1, what degraded by

A

1-2 mins, degraded by dipeptidyl peptidase-IV (DPP-IV)

48
Q

Leptin

A
  • secreted from fat cells
  • regulates long term energy balance
  • signals to CNS the amount of energy stored (fat)
  • decreases appetite
  • allows endocrine system to spend energy on growth, reproduction, and maintenance of high metabolic rate
49
Q

Leptin acts on 2 centers

A
  • orexigenic and anorexigenic centers

- need balance between the two

50
Q

orexigenic

A
  • eat more, metabolize less
51
Q

anorexigenic

A
  • eat less, metabolize more
52
Q

what organ sees highest concentration of insulin?

A
  • liver

- insulin dumped into hepatic portal vein by pancreatic b cells

53
Q

What happens with continued fasting?

A
  • catecholamine and glucocorticoid levels increase
  • promote release of FA from adipose
  • promote breakdown of protein to AA in muscle
  • type 1 and 2 diabetes mimic fasting state in hormone response
54
Q

FFA are precursors to what?

A
  • ketone body production in liver
  • high rate of fatty acid oxidation in diabetes
  • can lead to ketoacidosis (potentially fatal)
55
Q

Pathophys of Diabetes Mellitus

A
  • disease state with hyperglycemia
  • type 1: lack on insulin secretion b/c of autoimmune destruction of b cells
  • type 2: insulin resistance of cells, response of insulin inadequate to take in glc from bloodstream
56
Q

type 1 diabetes

A
  • autoimmune destruction of b cells
  • 5-10% US cases
  • starvation-like response when not treated
  • typical onset in childhood but can occur any age
  • onset of clinical disease sudden, but actual destruction of b cells occurs gradually
  • onset when 85% of cells are destroyed
  • brief honeymoon phase with intermittent periods of adequate insulin
57
Q

Type 1 diabetes: Liver effects

A
  • glycogenolysis and gluconeogenesis produce excess glc
  • excess conversion of FA to ketone bodies, b-hydroxybutyrate, and acetoacetate
  • high levels of these deplete bicarb and cause diabetic ketoacidosis (life threatening)
58
Q

Type 1 diabetes: Muscle effects

A
  • breaks down protein and releases AA
  • AA substrate for liver gluconeogenesis
  • lose muscle mass and contractile protein
59
Q

type 1 diabetes: adipose tissue

A
  • breaks down triglycerides to release FA and glycerol
  • glycerol substrate for liver gluconeogenesis
  • FA substrate for ketone body production
60
Q

type 1 diabetes: kidneys

A
  • blood glc levels exceed kidney’s ability to reabsorb gluc
  • glc excreted in urine, water follows glc
  • causes osmotic diuresis and polyuria and polydipsia
61
Q

type 1 diabetes affect on appetite and weight

A
  • appetite increased (excessive hunger/polyphagia)

- weight loss b/c nutrients cannot be stored

62
Q

type 1 diabetes possible onset triggers-

A
  • genetic predisposition
  • flu-like syndrome may occur few weeks before onset
  • may represent viral illness that is a trigger to the autoanitbodies to b cell proteins
  • may also be increased levels of inflammatory mediators of autoimmune rxn
  • enviro factors also influence development
63
Q

all synthetic insulin drugs tend to do what?

A
  • bind to insulin receptors on cells
64
Q

administrations of insulin

A
  • usually subcu
  • IV used in hospital setting
  • FDA approved inhaled forms as well
65
Q

why is insulin usually injected subcu?

A
  • can create a depot of insulin at injection site
66
Q

factors affecting rate of insulin absorption

A
  • solubility of insulin prep
  • local circulation site-to-site variability
  • person-to-person variability
  • faster absorption gives faster onset of action and also shorter duration of action
67
Q

hexamer vs monomer absorption

A
  • hexamer: least absorbable, slow onset, long-acting

- monomore: most absorbable, fast onset, short-acting

68
Q

regular insulin

A
  • short acting
  • structurally identical to endogenous insulin
  • aggregates into hexamers
  • dissassociation of hexamers to monomers is rate-limiting step for absorption
69
Q

Insulin Lispro, Aspart, and Glulisine

A
  • ultrarapid-acting insulins
  • keeps molec in monomeric to speed absorption
  • difference between the three (& regular insulin) is in AA substitutions
  • can be injected minutes before a meal
  • abministered subcu
  • same mech of action as regular insulin (bind to tyrosine kinase receptor once in circulation)
70
Q

in principle.. IV rate of absorption vs injection

A
  • IV, everyone should have same rate of absorption b/c directly into blood stream
  • injection, diff rate of absorption
71
Q

NPH insulin

A
  • neutral protamine Hagedorn insulin
  • intermediate-acting
  • insulin combined with protamine (fish sperm protein)
  • prolongs absorption time of insulin
72
Q

Insulin Glargine, Detemir, and Degludec

A
  • long acting preparations
  • steady absorption w/o peak
  • mimics basal insulin secretion
  • modifications of AA increase presence of hexamer form
73
Q

acute vs chronic measurement of glc in diabetic

A

acute: measure blood glc with glc meter
chronic: measure glycohemoglobin (HbA1c)

74
Q

Glycohemoglobin test (HbA1c)

A
  • glc in blood non-enzymatically glycosylates blood proteins
  • occurs at rate proportional to level of glc in blood
  • RBC cannot make new Hb and cannot break down Hb
  • gets rid of sampling bias wiht acute testing
75
Q

lifespan of RBC

A

120 days

- important for HbA1c test for chronic blood glc levels

76
Q

Type II diabetes info

A
  • 90% of US cases
  • obesity most important risk factor (also genetics play role)
  • commonly affects >40 yrs
  • develops gradually, usually found in routine screening
  • transporters are insulin resistant, need increased insulin to respond correctly to glc intake
  • initially resistance is compensated with increased insulin secretion, but eventually b cells cannot keep up with demand
77
Q

What % of type II diabetes cases are caused by rare variants?

A
  • 1-2%
78
Q

rare variants in type II diabetes

A
  • Maturity onset diabetes of the young (MODY)

- healthy, not obese children

79
Q

B cell failure in type II diabetes

A
  • MODY: mutations impair B cell function

- lean and insulin sensitive patients often reduced B cell function

80
Q

Sudden onset of type II diabetes sometimes caused by (2)

A
  • glucocorticoids

- pregnancy (typically goes away after pregnancy)

81
Q

Morbidity and Mortality with type I and type II diabetes

A
  • type 1: progress rapidly to ketoacidosis, coma, and death if left untreated (rare for type II)
  • type 2: if left untreated can lead to death in week to months, side effects typically kill
82
Q

Diabetic Hyperosmolar Syndrome

A
  • blood glc >600 mg/dL
  • kidney cannot recover all glc from filtrate
  • leads to excess urine and severe dehydration
  • causes mental status changes, other complications, and death
  • most commonly associated with other illnesses (like infections) in type II patients
83
Q

Long-term Vascular Pathology (4)

A
  • type 1 and type 2
  • premature atherosclerosis
  • retinopathy
  • nephropathy
  • neuropathy
84
Q

Long-term vascular pathology… what happens

A
  • sorbitol builds up causing osmotic problems in tissues that more readily take up glc than others
  • damages the microvasculature
  • buildup of sorbitol attracts water into the cells and causes damage
85
Q

Patient Strategy for type II diabetes

A
  • improve insulin sensitivity by reducing body weight, increasing exercise, and altering diet
  • alone or in combo with pharm treatments
86
Q

Pharm agent mechs for type II drugs

A
  • increase insulin secretion by b cells
  • sensitize target cells to actions of insulin
  • inhibit glc recovery from kidneys
  • use insulin therapy (not first choice in type II)
  • slow absorption of sugars from the GI tract
87
Q

Biguanides

A
  • used to treat type II diabetes
  • act by increasing insulin sensitivity
  • available agent: metformin
  • common choice for initial treatment
  • other biguanides withdrawn from US market because of toxic side effects
88
Q

Metformin general info

A
  • half life 1.5-3 hrs
  • not bound to plasma proteins or metabolized in humans
  • excreted unchanged by kidneys
  • oral delivery
89
Q

Metformin mechanism of action

A
  • activate AMP-dependent protein kinase (AMPPK)
  • increases AMP production
  • blocks breakdown of FA
  • inhibit hepatic gluconeogenesis and glycogenolysis
  • increased activity of insulin receptor
  • energy metabolism effects more indirect
90
Q

Metformin therapeutic effects

A
  • lowers blood glc and insulin levels
  • beneficial in treating insulin resistance with polycystic ovarian syndrome (PCOS)
  • does not induce hypoglycemia
  • lowers serum lipids and decreases weight
91
Q

Metformin adverse effects

A
  • mild GI distress common
  • usually transient and can be minimized by adjusting dose
  • lactic acidosis (cause of nausea and weakness)
  • patient to patient variability
92
Q

Lactic Acidosis

A
  • adverse effect of metformin
  • causes nausea and weakness
  • metformin decreases flux of metabolic acids through gluconeogenic pathway so lactic acid can accumulate
  • incidence low and predictable (not huge concern for type II population as a whole)
  • risk factors: hepatic disease, heart failure, resp disease, alcohol abuse
93
Q

Metformin caution and contraindications

A
  • renal disease can reduce clearance b/c drug not metabolized in body
  • patients over 65 may have renal impairment that reduces clearance as well
  • reduced clearance means it remains in system longer
94
Q

Beneficial features of metformin

A
  • high efficacy in type II diabetes
  • low risk of hypoglycemia
  • not associated with weight gain
  • low cost
  • can be combined with additional drugs that have diff mechs of action
95
Q

Sulfonylurea Drugs

A
  • treat type II diabetes by stim insulin RELEASE from pancreatic b cells
  • uses raising circulating insulin levels sufficiently to overcome insulin resistance
  • inhibit b cell K/ATP channel
96
Q

Sulfonylurea mechanism of action

A
  • bind to the SUR1 subunit of K/ATP channel
  • thought to displace Mg-ADP that activates channel
  • inhibiting channel leads to Ca influx and increased insulin secretion
97
Q

Glyburide, Glipizide, and Glimepiride

A
  • second-gen sulfonylureas (1st gen less potent)
  • lower blood glc and cause metabolic improvements through increased insulin action
  • oral delivery
  • metabolized by liver
  • vary in duration of action
98
Q

which sulfonylurea has longest duration of action?

A
  • Glyburide

- use in patient with low risk of hypoglycemia

99
Q

Sulfonylurea adverse effects

A
  • hypoglycemia resulting from too much insulin secretion
  • can be very problematic for patients with impaired clearance or reduced capacity to recognize signs of hypoglycemia (e.g. elderly, use short acting drugs)
  • weight gain due to increased insulin action at adipose tissues
100
Q

Tolbutamide, tolazamide, acetohexamide, chlorpropamide

A
  • 1st gen sulfonylurea drugs
  • same mech of action as second gen (bind to SUR1 subunit of K/ATP channel, causing Ca influx and increased insulin secretion)
  • may be chosen for unique pharmokinetic properties, i.e. shorter duration of action, less chance of hypoglycemia (more freq dosing)
101
Q

which of the 1st gen sulfonylurea drugs has short duration?

A
  • tolbutamide
102
Q

Meglitinides

A
  • type II diabetes treatment
  • similar to sulfonylureas in absorption, metabolism, and adverse effects
  • stims insulin release by binding to SUR in b cell K/ATP channel
  • bind at diff site on SUR1 than sulfonylureas
103
Q

Repaglinide and Nateglinide

A
  • meglitinide class
  • rapidly absorbed from SI
  • complete metabolism in liver in inactive metabolites (half life
104
Q

Exogenous Insulin Drugs

A
  • always used for type I diabetes
  • sometimes used in type II if diet and other therapies not effective
  • high efficacy at reducing blood glc levels
  • high risk of hypoglycemia
  • weight gain also adverse effect
105
Q

Thiazolidineodines (TZDs)

A
  • type II diabetes treatment.. also treats PCOS
  • Rosiglitazone and Pioglitazone
  • sensitize peripheral tissues to insulin
  • act as antagonist for nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARy)
  • changes in fat metabolism alter metabolic enviro and indirectly increase liver and muscle insulin sensitivity
  • oral delivery
106
Q

PPARy

A
  • peroxisome proliferator activated receptor-y
  • site of action for thiazolidinediones (TZDs)
  • forms a heterodimer with retinoid X receptor (RXR)
  • activates transcription of target genes in promoter regions involved in glucose and lipid metabolism
  • mainly expressed in adipose tissue
  • TZDs increase insulin sensitivity in adipose tissue
  • inhibits hormone-sensitive lipase in adipose
107
Q

TZD site of action

A
  • PPARy is expressed at quite low levels in liver and muscle
  • TZDs have little effect on insulin sensitivity in liver and muscle cells in vitro
  • liver and muscle are primary sites of insulin resistance in type II diabetes
108
Q

Thiazolidineodiones (TZD) adverse effects

A
  • weight gain common
  • edema
  • heart failure
  • hepatotoxicity
  • do not increase insulin secretion or cause hypoglycemia
109
Q

GLP-1 agonists and mimetics

A

actions mimic endogenous peptide hormones called incretins including GLP-1

  • GLP-1 is of the enteroendocrine cell class
  • released from SI following nutrient absorption
  • cause increased insulin release, decreased glucagon release, slow gastric emptying, and decrease in appetite
110
Q

GLP-1 agonists and mimetics differences between endogenous GLP-1

A
  • GLP-1 endogenous has a very short half-life (1-2 mins)
  • broken down by dipeptidyl-peptidase IV (DPP-IV)
  • drugs have been developed to increase bioactivity
  • these drugs are peptide based, cannot survive GI tract, given sub cu
  • DPP-IV inhibitors developed to increase hormone half life

Pharmacology III (18 decks)

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