UNIT 5 DRUG LECTURES
DYSLIPIDEMIA AND ANTILIPEMIC AGENTS
Hinds
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QUESTIONS BEFORE CLASS
o Which lipoprotein contain Apo B100? LDL and VLDL
o Which apolipoprotein is required to deliver triglycerides to adipose tissue?
o Which apolipoprotein is required for transport back to the liver?
o Know endogenous and exogenous pathways for lipid metabolism.
o What are the major targets of niacin, fibrates, and statins?
o What is the major function of LPL?
o Which combo of lipid lower drugs can cause gallstones?
Dyslipidemia
o Abnormal amount of lipids in the blood
o Two primary forms of lipids in the blood
 Triglycerides (TGs)
 Cholesterol
o Water-insoluble fats that must be bound to apolipoproteins (specialized lipid-carrying proteins)
o Lipoproteins are the combination of triglycerides or cholesterol with apolipoprotein
Cholesterol
o Serves as a component of cellular and intracellular organelle membranes
 provides fluidity in the lipid bilayer
o Is involved in the synthesis of certain steroid hormones including estrogen, progesterone, testosterone, adrenal
corticosteroids
o Needed for the synthesis of bile salts which are needed for digestion and absorption of fats.
o Is deposited in the stratum corneum of the skin to help ↓ evaporation of water and create impermeability to
water soluble compounds (helps keep moisture in skin)
o Absorbed from the diet (eggs, lobster, shrimp, etc), as well as, synthesized in the liver from saturated fats.
 saturated fats increase acetyl coA which is part of the first step in synthesis of cholesterol in the liver.
o HDL helps get rid of the LDL.
o HDL picks up cholesterol from tissues and LDL delivers it to the tissues.
Causes of Dyslipidemia
o When you exercise, your body produces catecholamines, growth hormone, glucagon, and for long enough
glucocorticoids.You start breaking down the fat. When you break down that fat, HSL (hormone sensitive lipase)
breaks it down. Catecholamines signal via PKA for HSL to break down perilipids to break down triglycerides into
free fatty acids and glycerol into the serum. When that happens it's either taken up by muscle and oxidized (beta
oxidation AKA fatty acid oxidation is burning of the fat to use it for ATP) or it goes to the liver where you get amino
acids from working out and nonhexogsubstrates which can be made to make glucose (gluconeogenesis) .
o Abnormal lipid levels are most commonly caused by eating a diet that is high in fat (MOSTLY SATURATED FATS (NO
DOUBLE BONDS)
 Your body breaks down the fat using hormone sensitive lipase (HSL). The catecholamines can signal
through PKA to HSL to break down perilipans? to release TG's, free FA, and glycerol into the serum. When
that happens its either taken up by muscles for beta-oxidation/fatty acid oxidation (burning of fat to make
ATP) or those things can go back to the liver.
o Risk factors:
 Being overweight
 Heavy alcohol use
 b/c increases oxidative stress on the liver.
 Lack of exercise and sedentary lifestyle
 Gluconeogenesis--producing new sugars.
o Other factors:
 Diabetes (type II mellitus)
 insulin resistant state (problem with insulin receptors)
 Polycystic ovary syndrome (PCOS)-- can also lead to insulin resistance as well
 Kidney disease
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UNIT 5 DRUG LECTURES
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 Underactive thyroid gland
 Pregnancy
Lipid Metabolism
o Chylomicrons—Are Huge
o IF THE EXOGENOUS PATHWAY IS ON THE ENDOGENOUS IF OFF AND VICE VERSA
o Exogenous pathway-- cholesterol from food
 Intestinal mucosal cells convert dietary fatty acids to triacylglycerols and package them, along with dietary
cholesterol, into lipoproteins called chylomicrons. Lipids are delivered to tissues via the diet.
o Endogenous pathway-- cholesterol synthesis from liver
 Very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins
(LDL) are synthesized by the liver to transport triacylglycerols and cholesterol from the liver to the
peripheral tissues.
Absorption of Lipids
o EXOGENOUS PATHWAY
 Absorption of TGs and cholesterol from diet get packaged into chylomicrons and secreted into blood.
 Chylomicrons deliver dietary triacylglycerols to muscle and adipose tissue and dietary cholesterol to the
liver.
 After a fatty meal, the blood is full of chylomicrons, which makes it appear milky.
 The word "chylomicron" is made up of "chylo-", milky + "micron", small. = small milky (globules).
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 Non-lipemic: if your hungry this is what your serum would look like
 Lipemic: after a meal this is what you serum looks like b/c it is full of chylomicrons
Lipoprotein Metabolism
o Exogenous Pathway
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Small intestines absorbs the lipids and then they are packaged w/ apolipoprotein B-48 into nascant
chylomicrons. They then go into the lymph --> liver to deliver TG and cholesterol. This schematic is not
entirely correct it doesnt always go to the liver first.
 Remnant chylomicron-- w/ APO E
 can be reabs back into the liver
 Apo C-II is on the surface of the chylomicron
 LPL is on the surface of the adipocyte
EXOGENOUS PATHWAY--liver makes cholesterol
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UNIT 5 DRUG LECTURES
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The signaling from the body to the peripheral tissues. If the exogenous pathway is turned on, the
endogenous pathway is turned off. But the exogenous pathway is always on.
 VDLD has lots of TG’s
 Fat cells store TG’s (get it from VLDLs)
 Muscle cells burn TG (gets rid of more TG’s from IDL)
 LDL molecule (lots of cholesterol)
EXOGENOUS PATHWAY—
o B100 is important for secretion of VLDL from the hepatocyte
o Liver synthesizes cholesterol via the HMG- CoA reductase
pathway
o Then packages TGs and cholesterol into lipoproteins
o Lipoproteins are then secreted into blood.
o HMG-CoA Reductase pathway
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Class of drugs that inhibit HMG-CoA Reductase
are the STATINS
LIPOPROTEINS
 Serve as carriers for transporting lipids (cholesterol and triglycerides) in the blood.
 Apolipoproteins
o Embedded in the lipoprotein shell
 work as signaling molecules to bind to surfaces of tissues to deliver their goods.
 Three functions
o Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the
lipoprotein.
o Activate enzymes that will metabolize the lipoprotein
o Increase structural stability of the lipoprotein
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 Apolipoproteins
o All lipoproteins that deliver lipids to peripheral tissues (nonhepatic tissues) contain apolipoprotein B-100 (apoB100) (Ex: VLDL, LDL)
o All lipoproteins that transport lipids from peripheral tissues back to the liver contain apolipoprotein A-I (apoA-I)
(Ex: HDL)
 this is delivery not recycling (apo E is important in recycling)
 VLDL (very low density lipoprotein)
o Produced in liver and secreted (endogenous pathway)
 must have apo B100
o Contain triglycerides (TGs) and some cholesterol
o Account for nearly all TGs in the blood
o Contain apoB-100
o Deliver triglycerides from the liver to adipose tissues and muscles.
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o Remnants of hydrolysis are IDL (intermediate density lipoproteins), which can be transported to liver or converted
to LDL
 LDL (low density lipoprotein)
o “Bad cholesterol”
o Contain cholesterol
o Account for 60-70% of cholesterol in the blood
o Contains apoB-100
o Delivers cholesterol to peripheral tissues
o Formed from IDL, the remnants of VLDL
o Makes the greatest contribution to coronary atherosclerosis
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Oxidized LDL contributes to atherosclerotic plaque
form oxidized cholesterols= oxysterols which combine to liver X receptor in the endothelial cells which
contribute to plaque formation and forms "foam cells"
o Removed from plasma via endocytosis by liver converting it to bile acids excreted in GI
HDL (high density lipoprotein)
o “Good cholesterol”
 normal levels are at about 200 if your 30-40 y/o
o Contain cholesterol
o Account for 20-30% of cholesterol in the blood
o Some contain ApoA-I and ApoA-II
o ApoA-I is cardioprotective
 b/c ApoA-1 is important for transport of cholesterol/HDL from peripheral tissue (muscle and adipose)
back to the liver so it promotes cholesterol removal--> anti-atherogenic
o Transports cholesterol from the peripheral tissues back to the liver – promotes cholesterol removal
o Anti-atherogenic
Intravascular VLDL Metabolism
o Triacylglycerol and cholesterol are assembled with apoB100 to form VLDL particles (large fluffy molecules)
o Nascent VLDL particles are released into the bloodstream
via a process that depends upon apoB-100.
o HDL donates apoC-II and apoE to develop the ‘mature’
VLDL
 HDL donated:
 apo C II and apo C III
 apo E
o VLDL requires apoC-II to bind to adipocytes
o Upon binding lipoprotein lipase (LPL-on adipose molecules) releases TGs in adipose and muscle tissues
 exercise increases LPL and HDL
o VLDL is hydrolyzed to LDL and VLDL remnant (has apoE on it)
o The presence of apoE allows the recycling back into liver
o HDL have essentially the opposite function of LDL: They remove cholesterol from the tissues.
o HDL functions as cholesterol scavenger
o Intravascular VLDL Metabolism
TREATMENT OF HYPERLIPIDEMIA
 1st line Treatment of hyperlipidemia
o Non-Pharmacological Therapy
 Diet modification
 Decrease intake of total fat (especially saturated fat)
 Increase fiber intake
o pushes the fat out of the body
 Increase Omega-3-fatty acids (found in fish and in nuts) and omega 6
o oleic acid- helps you oxidize fats of the heart
 ↑ fruits and vegetables (antioxidants)
o green tea and chocolates inhibits LXR
 ↓ simple sugars (sucrose)
 Exercise (will ↑ HDL levels)
 also increases HSL and LPL
 Reduce risk factors if possible--excess alcohol, etc.
 What are antilipemic agents?
o Cholesterol Absorption Inhibitor
o Niacin (nicotinic acid)-- a vitamin
o Fibrates (fibric acid)
o HMG CoA Reductase inhibitors --STATINS
o Bile Acid Resins
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UNIT 5 DRUG LECTURES
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Bile acids bind to fats to absorb them into your intestines. Some of these actually can increase your VLDL
from liver and triglycerides
CHOLESTEROL ABSORPTION INHIBITOR
o Ezetimibe (Zetia)
 Inhibits absorption of cholesterol and related sterols from the small intestine
 MOA: Targets a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein
on the GI tract epithelial cells as well as in hepatocytes.
 NPC1L1 is on the surface of the GIT
 In addition to this direct effect, decreased cholesterol absorption leads to an upregulation of LDLreceptors on the surface of cells and an increased LDL-cholesterol uptake into cells, thus decreasing levels
of LDL in the blood plasma
 Administered alone or in combination with an HMG-CoA reductase inhibitor (statin)
 Patient has normal triglycerides and HDL but HIGH LDL. What would you give them? THIS! (Get
rid of their LDLs!)
NIACIN (NICOTINIC ACID)
o Among the oldest antilipemic drugs, favorably affecting virtually all lipid parameters.
o Vitamin B3: Nicotinic acid but not its amide form
o Reduces VLDL, LDL, and increases HDL
 reduces both bad ones & increases the good one!
o HSL, as its name indicates, is sensitive to certain hormones. It is stimulated by catecholamines, glucagon, and
growth hormone.
 exercise also increases HSL activity and also glucocorticoids if you work out long enough
o Blocking HSL activity by niacin inhibits adipocytes from releasing FFA (thus reducing TG's ) and glycerol into the
blood, thus reducing triglyceride levels.
o Exercise increases HSL activity - releasing FFA and glycerol into blood to produce sugars from liver
(gluconeogenesis).
o By inhibiting HSL in adipose tissue using niacin, triglycerides in adipocytes are not released in high amounts even
during exercise.
o This leads to a significant decrease in fatty acid oxidation during exercise, which may affect endurance
performance.
o If you take too much B3, it might affect your performance. Cuz you need that fatty acid oxidation to produce ATP.
You won't release as many triglycerides if you need them.
INHIBITS FAT OXIDATION
LESS FFA RELEASE IN THE BLOOD
 GLYCEROL RELEASE IN BLOOD
o SIDE EFFECTS OF NIACIN
 Niacin universally causes significant facial flushing which has been shown to be prostaglandin and
histamine mediated.
 You actually give them a dose until they flush and then you dose down.
 Taking aspirin 30 minutes before taking niacin has been shown to significantly reduce the amount of facial
flushing.
 Niacin has also been shown to cause liver function test abnormalities, although not as commonly as
statins.
 ALT & AST tests can go up
 FIBRATES
o benzafibrate
o clofibrate
o fenofibrate (Trichor or the new TriLipix)
o gemfibrozil (Lopid)
o MECHANISM OF ACTION OF FIBRATES
 Activate the nuclear transcription receptor PPARa (peroxisome proliferator-activated receptor–alpha)
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UNIT 5 DRUG LECTURES
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Expressed mainly in liver, muscle, intestine and adipose tissue
Induces fatty acid oxidation.
Avantia targets PPARγ . Causes fat tissue in your heart, etc. Stores fat. Close to being banned.
PPAR increases mitochondrial proteins that activate it so they burn fat. Fibrates are ligands that bind to
PPAR to activate it.
increase fatty acid uptake
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Reduce VLDL production.
 Increase hepatic fatty acid uptake and conversion to acyl-CoA. (not HMG-CoA)
 Stimulate fatty acid oxidation and reduce de novo fatty acid synthesis.
o regulated by fatty acid synthase (FAS)
o PPAR inhibits FAS
 Inhibit hormone-sensitive lipase (HSL) in adipose tissue.
Increase VLDL clearance.
 Transcriptionally up-regulate LPL.
o LPL is on the surface of the muscle and adipose to bring in the VLDL to increase the
triglycerides in the blood
 Increase intrinsic activity of LPL.
Increase HDL and reverse cholesterol transport by upregulating apoA-I (anti-arthrogenic) and apoA-II.
Enhance the removal of LDL particles by increasing its affinity for LDL-R.
 Binding and holding & taking it in!
Stimulating LPL acts to decrease the amount of free fatty acids (FFA) in the circulation. These FFA can be
utilized by the muscles for energy.
The FFAs and glycerol produced by triglyceride breakdown is transported to the liver and participates in
gluconeogenesis to produce glucose via gluconeogenesis
Fibrates act to primarily reduce triglyceride levels and have only minimal lowering affects on LDL
cholesterol.
Significantly raise HDL.-- so look for this in the target patient!
Exercise itself has been shown to nearly double LPL activity in many studies, thus allowing muscles to use
more FFA which would be beneficial in theory.
So it would make sense that stimulating LPL with fibrates would lead to increased FFA utilization by
muscles during exercise thus enhancing endurance performance, however this is NOT the case
Fibrates most likely actually inhibit the exercised induced stimulation of LPL leading to overall lower LPL
activity during exercise.
Thus without fibrates, exercise is able to increase LPL activity, however with fibrates, exercise is not able
to stimulate LPL activity as much.
This has been verified metabolically in many studies and leads to a moderate decrease in fatty acid
oxidation during exercise.-- does not increase your endurance
FIBRATES AND EXERCISE
INHIBITS FAT OXIDATION
LESS FFA RELEASE IN THE BLOOD
--Reduced by reduced HSL. HSL increases
the FFA in the blood and the glycerol.
 GLYCEROL RELEASE IN BLOOD
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UNIT 5 DRUG LECTURES
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Side Effects of Fibrates
 Fibrates, like statins, can cause significant myalgias and even rhabdomyolysis (breakdown of muscle).
 Thus, the use of statins and fibrates in combination must be used with great caution.
 Fibrates have also been shown to cause diarrhea.
 bc PPAR is also in the intestines so you induce diarrhea
Adipose tissue:
o Decreases lipolysis by reducing hormone-sensitive lipase (HSL) activity, reducing FFA transport to the liver.
Liver:
 Inhibits both the synthesis and esterification of fatty acids, lowering VLDL and LDL.
 Enhances LPL activity, promoting chyromicron and VLDL clearance.
 Raises HDL by decreasing fractional clearance of apoA-I.
HMG-COA REDUCTASE INHIBITORS
o lovastatin (Mevacor) – The first statin produced – weakest
 weaker inhibitor
o fluvastatin (Lescol)
o pravastatin (Pravachol)
o simvastatin (Zocor) – Slightly stronger than lovastatin
o atorvastatin (Lipitor) – Slightly stronger than simvastatin
 stronger inhibitor
o rosuvastatin (Crestor) – The strongest statin
o
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MOA:
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Inhibition of HMG-CoA Reductase
 They bind to the HMG-CoA and inhibit it
 Statins act by inhibiting the HMG-CoA reductase, the main enzyme in the
pathway that synthesizes cholesterol.
 Saturated fats also increase the de-novo synthesis (through FAS)
as well by increasing HMG-CoA via the endogenous pathway
 This results in the production of less cholesterol leading to lower LDL levels.
 PT has normal HDL but high LDL you give them STATINS!!!
 Statins are thought to have additional properties unrelated to their cholesterol lowering effects.
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Anti-inflammatory properties
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“Plaque stabilizing” properties
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Bone density stimulating properties
o Osteoporosis is when the bone cells actually change to adipocytes and the statins
actually inhibit that
o Extremely important b/c a lot of the anti-diabetic meds actually increase the fat
property of bones.
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Anti-dementia properties
Statins have become the most prescribed medication in all of medicine producing over $20,000,000,000 in sales
last year in the U.S. alone! If you have a history of the risk factors, you should probably prescribe a statin to reduce
risk even if the person hasn't had symptoms
 RED SEA RICE-- potent STATIN that's in FOOD!!!! Works as well as a drug
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UNIT 5 DRUG LECTURES
o
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Statins and inflammation
 Statins have been shown to decrease CRP (C-reactive protein) levels.
 Lots of fatty foods causes NAFLD (non alcoholic fatty liver disease) can actually give you NASH
(nonalcoholic steatohepatitis) and cirrhosis and fatty liver issues
 CRP is a well known marker of inflammation.
 secreted from the liver w/ inflammation
 High CRP levels have been linked to higher amounts of atherosclerosis, heart attacks, and strokes.
 Lower CRP levels would indicate less atherosclerosis and a lower risk of heart attacks and strokes.
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If you decrease the amount of inflammation you'll end up decreasing the inflammation in the
vascular system and the appearance of Coronary Artery Disease
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Statins and Plaque Stabilization
 Statins have been shown to “stabilize” plaques, making them less prone to plaque rupture and thrombosis.
 Plaque rupture and thrombosis is the principle cause of heart attacks and strokes.
 This phenomenon may be related to the anti-inflammatory properties of statins.
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Statins and Exercise
 Fat oxidation is crucial to endurance exercise since triglycerides and free fatty acids are the most import
energy substrate in long duration endurance events.
 The mechanism of statins (unlike that of fibrates and niacin), in theory should not affect fat oxidation.
 Studies have confirmed no affect of statins on fat oxidation.
Fat oxidation
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FFA release in blood
Glycerol release in blood--No effect on glycerol
Niacins and Fibrates inhibit HSL and increase the LPLs And when you exercise you increase the
HSL but statins work differently so they shouldn't affect this
It won't affect indurance training.
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Thus, metabolically, statins have no affect on fat oxidation or utilization, so there should be no
affect on exercise performance.
 They found that there was no effect.
o Side effects of statins
 Statins are well known to cause myalgias (muscle aches).
 This can result in significant muscle damage and muscle cell death (rhabdomyolysis).
 Myalgias occur in 1-10% of people taking statins.
 On a smaller level, myalgias from statins can be mild and result only in discomfort.
 Myalgias are dose and potency dependent, thus the higher the dose of the statin or the more potent the
statin, the higher the risk of myalgias.
 Myalgias may not occur immediately after starting a statin and may only be evident after a person begins
an exercise program.
 In general, if a person experiences significant myalgias, the statin is discontinued or the dose reduced.
 Statins are also well known to cause abnormalities in liver function tests, more specifically AST and ALT
elevations.
 In general, these liver function test abnormalities are mild and reversible after statin cessation. There has
never been a report of liver failure caused by statin drugs.
BILE ACID-BINDING RESINS
o
o
o
o
o
o
o
o
o
 pretty large structures
 cholestyramine (Questran)
 colestipol hydrochloride (Colestid)
 colesevelam (tablet form only
Prevent resorption of bile acids from small intestine
 prevent reabsorption of the bile acids from the small intestine
Bile acids are necessary for absorption of lipids
Bile acid resins bind bile acids in the intestine, which reduces the enterohepatic recirculation of bile acids.
This promotes the conversion of cholesterol in the hepatocyte into bile acids.
This decreases the cholesterol content in the hepatocyte, which enhances LDL-receptor expression, which in turn
increases the removal of LDL and VLDL remnant particles from the circulation.
 Increase amount into the liver
Will decrease LDL, and may increase hepatic VLDL production and thereby raise serum TGs
 Bad thing actually but not seen as often
(elevated TGs prior to treatment require niacin combo)
MECHANISM OF ACTION
 Bile acids, the metabolites of cholesterol, are normally reabsorbed in the jejunum and ileum.
 When resins are given, they bind to bile acids in the intestinal lumen, preventing their reabsorption and
increase their excretion.
 ↑ excretion creates a demand for ↑ synthesis of bile acid. Liver cells must have an ↑ cholesterol supply
(provided by LDL) to synthesize bile acid. Liver cells will ↑ their LDL receptors, ↑ing uptake of LDL from
plasma.
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o
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INDICATION
 Used alone to ↓ LDL (by 15-20%)
 STATINS got up to 60% in some pts
 Normally used as adjuncts to the statins to ↓ LDL (by 50%)
 (Not all patients are the same so you may need an adjunct)
 Large doses may impair absorption of fats or fat soluble vitamins (A, D, E, and K)
 might not be getting as much nutrients are you should
COMBOS THAT REDUCE BOTH CHOLESTEROL AND TGS
o Niacin and statin
 Statin dose needs to be reduced to avoid myopathy
 ADVICOR: lovastatin plus extended-release niacin in a fixed-dose preparation
o Niacin and resin
 Niacin does not bind resins, can be taken together
o Fibrate and statin--avoid normally because can cause rhabdomyolysis
 TriLipix (fenofibrate) plus statin
^^but this is good
o Fibrate and resin
 Increased risk for cholelithiasis
 INCREASE GALLSTONES!!!
o Statin and resin
 Synergistic for familial hypercholesterolemia
 Less control for VLDL with familial combined hyperlipoproteinemia
 statins given 1 hr before or 4 hr after resins
o Niacin-resin-statin triple complex-- for SEVERE elevation!!!!
 Patients with severe elevation of LDL.
 Little compound toxicity as effective doses of individual drugs may be lowered.
o Statins and ezetimibe -- inhibitor for absorption
 Complementary and synergistic for primary hypercholesterolemia
 Has some effect in homozygous familial hypercholesterolemia.
 Not as good as the niacin resin statin triple complex though
 VYTORIN: Zocor (simvastatin) and Zetia (ezetimibe)
AGAIN THE QUESTIONS AT THE BEGINNING OF THE LECTURE
o Which lipoprotein contain Apo B100? LDL and VLDL
o Which apolipoprotein is required to deliver triglycerides to adipose tissue? ApoC
o Which apolipoprotein is required for transport back to the liver? ApoE
o Know endogenous and exogenous pathways for lipid metabolism.
o What are the major targets of niacin, fibrates, and statins? Niacin and fibrates HSL; HMG-CoA Reductase
statins
o What is the major function of LPL?
o Which combo of lipid lower drugs can cause gallstones? Fibrate and resin
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ANTIULCER DRUGS INTRODUCTION
I.
PEPTIC ULCERS
a.
b.
c.
d.
The exact cause of peptic ulcers is not known; however, there is a close association between infection by the spiral
bacterium Helicobacter pylori, ulcers, and stomach cancer. H. pylori is a spiral bacterium which is able to bore
through the mucus and to attach itself to epithelial cells. The following diseases are associated with H. pylori
infection (50% of the population is infected)
i. Gastritis (100% of those infected)  atrophic gastritis
ii. Gastric and duodenal ulcers (10% of those infected)
1. 90% of ppl w/ulcers are infected
iii. Cancer
1. Gastric adenocarcinoma (3-12 x increase in probability)
2. low-grade B cell lymphomas of gastric mucosa-associated lymphoid tissue (MALT) The mechanism of pathogenesis is uncertain; however, there appears to be a correlation between strains that
produce a potent cytotoxin VacA and pathogenesis. In cultured gastric cells, VacA induces the formation of
vacuoles that may destroy the integrity of the gastric epithelium. Cytotoxin VacA targets mitochondria and induces
apoptosis (releases cytochrome c) and cell dealth and vacuole formation. H. pylori attaches to epithelial cells via
Lewisb antigen
i. Lewisb antigen is on our epithelial cells maybe some of us are more sensitive than others
Acid pH, pepsin and NSAIDs appear to promote the process and, consequently, protection against these remains
an important element in the treatment of ulcers.
i. Gastric acid-- aggravates the situation by decreasing the rate they can heal and increasing the pain
ii. Pepsin-- causes the protease release from the chief cells and breaks down the mucous
QUESTION—How does H. pylori survive in the acidic stomach?
i. They have protective UREASE!
1. Hydrolyzes urease into CO2 and ammonia (weak base) which will bind protons and become
ammonium
2. Process is regulated by a channel that allows the urea to enter the bacterium and that channel is
activated by protons and acidic pH
3. So to diagnose give C13 labeled urea and the bacterium will produce C13 labeled CO2 which can
be detected by a breath test urea breath test
4.
II.
𝑈𝑅𝐸𝐴𝑆𝐸
CO(NH2)2 + H2O + 2H+ →
CO2 + 2NH4+
PHYSIOLOGICAL CONTROL OF GASTRIC ACID SECRETION (Fig. 1) a.
b.
c.
d.
e.
A basic understanding of this process is central to understanding the diverse mechanisms of action of several
important drugs. The figure shows the major steps involved in controlling gastric acid secretion in the parietal cell.
Mechanism of HCl secretion: Mediated by the combined actions of an H+/K+- ATPase pump, a K+ channel and a
Cl- channel located in the membrane of secretory caniculus and is regulated by modulating the number of pumps
in the membrane.
Stimulation of Acid Secretion: Histamine, acetylcholine and gastrin stimulate acid secretion. Acetylcholine and
gastrin not only mediate their effects via an IP3 dependent elevation of cell Ca2+, and consequent activation of
protein kinases, but also by inducing histamine release from enterochromaffin like (ECL) cells. Histamine mediates
its effect via H2-receptors and elevation of cAMP. Acetylcholine also stimulates secretion of HCO3- and mucus that
protect the gastric mucosa.
Inhibition of Acid Secretion: Parietal cells also have receptors for prostaglandin E2 (see notes on Eicosanoids and
NSAIDs). These receptors are coupled to Gi proteins that inhibit adenylate kinase and hence limit the effect of
histamine. Prostaglandins also stimulate HCO3- and mucus secretion by mucous cells and promote blood flow
within the stomach wall and are classified as “cytoprotective” agents.
Integration of concepts: Note that in the GI tract, both cAMP and Ca2+ promote acid secretion. This is similar to
the synergistic effect they have on promotion of neurotransmitter release and contraction of cardiac muscle and is
in contrast to their mutually antagonistic roles in activation of platelets and mast cells and control of smooth
muscle tone.
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f.
III.
This represents a parietal cells in contact w/ the lumen of the stomach. Acid secretion is dependent on the proton
pump (protons in exchange for K in an electroneutral fashion). There is also a K channel to recycle the K lost to that
exchanger and to keep everything neutral there is also a Cl- channel. So net result of those 3 channels is net
secretion of HCl. Regulation of this isn’t really shown on the picture but it depends on the fushion of vescicles in
the parietal cells which contain the proton pumps with the parietal cell membrane and increase the number of
pumps on the cell membrane. This is regulated by Ca ( stimulates it) and cAMP, which amplifies it.
g. ECL Cells—in the adrenal medulla release epinephrine. EC cells in the gut release serotonin. ECL
(enterochromaffin-like) cells in the stomach release histamine
DRUGS THAT INHIBIT ACID SECRETION—control of acid secretion by the parietal cells
a. ANTIMUSCARINIC DRUGS, E.G., PIRENZEPINE (SEE “ANTICHOLINERGICS”)
i. Atropine was used before introduction of H2-blockers and can inhibit basal secretion 40-50% but is less
effective in blocking stimulated secretion.
1. Atropine blocks the muscarinic receptors
2. Use is limited by classical “antimuscarinic” side effects
a. dry eyes, dry nose, dry mouth, blurred vision,  HR
b.  GI function 
i.  which will lead to mucous & bicarb secretion
ii.   gastric motility delayed gastric emptying will allow more acidic to
accumulate, constipation
c.  LES is controlled by the PSNS so if you block this it will cause it to dilate and cause
heart burn and reflux—contraindicated in GERD
ii. Pirenzepine and telenzepine have a higher affinity for M1 than M2 and M3 receptors, which helps
minimize side effects, and although they are available in other parts of the world, they are not approved
for use in the U.S.A.
b. H2 BLOCKERS
i. Most of gastrin's effects are focused on stimulating the histamine response so H2 is very important in
acid secretion
ii. The existence of H2 receptors was not established until 1972, when Black identified a drug that could
block the effect of histamine on gastric acid secretion. Four are available:
1. Cimetidine (Tagamet®, 1977)--PROTOTYPE
2. Ranitidine (Zantac®, 1983)
a. the most frequently prescribed one
3. Famotidine (Pepcid®, 1986)
4. Nizatidine (Axid®, 1988)
5. Fig. 2 Structures of the H2 antagonists. Unlike older H1 blockers, H2 blockers have a hydrophilic
ring and a polar “tail” which make it difficult for them to enter the CNS
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UNIT 5 DRUG LECTURES
iii. MECHANISM/EFFECTS OF H2 BLOCKERS
1. Competitive antagonist of H2 histamine receptors
2. H2-BLOCKERS DECREASE GASTRIC SECRETION of
a. H+ (from parietal cells)
b. Pepsin (Chief cells)
c. “Intrinsic Factor of Castle” (from Parietal Cells) induced by: histamine, gastrin, and
acetylcholine
i. Intrinsic factor is important for binding B12 and having it absorbed in the
terminal ileum (doesn't cause a deficiency in B12 so its okay)
d.  volume of acid secretion too
iv. SECRETION IS BLOCKED IRRESPECTIVE OF THE STIMULUS (Acid secretion will be inhibited by Histamine,
Gastrin or Acetycholine)
1. Basal (Fasting) Secretion
2. Food Induced
3. Caffeine Induced
4. Fundic Distention Induced
5. Nocturnal Secretion is also inhibited
6. Insulin Induced
v. ABSORPTION, FATE, AND EXCRETION
1. These drugs are taken orally, metabolized in the liver and excreted in urine.
2. Half-lives are all about 2 hr, all except nizatidine have bioavailabilities between 40-60%, due to
hepatic “first pass” effect.
vi. THERAPEUTIC USES - TO LOWER GASTRIC ACID SECRETION
1. DUODENAL ULCER & GASTRIC ULCER - usually heal within 4-6 weeks, but 50% reoccur w/in 1 yr
2. Gastro-esophageal reflux disease (GERD), esophagitis, pyrosis (heartburn)
3. Hypersecretory diseases
a. Zollinger-Ellison syndrome—tumor in the pancreas that secretes gastrin
b. Systemic mastocytosis—skin, GI tract— produce way too many mast cells in the skin and
GI tract producing vasodilation, itching, stimulating acid secretion, producing ulcers
i. These patients are treated w/ H1 blockers, H2 blockers, inhibitors of acid
secretion (PPI’s), chromalin sodium (to inhibit mast cell activation), inhibitors of
PG’s (mast cells produce PGD)
c. MEN I (i.e. multiple endocrine neoplasms, type 1 – the “P” lesions: pituitary, parathyroid,
pancreas (produces excess gastrin))
4. Treatment of severe angioedema and urticaria in combination w/ H1 blockers
vii. ADVERSE REACTIONS AND SIDE EFFECTS
1. These drugs have relatively few side effects.
The most important are associated with cimetidine
which is the prototype.
a. Side effects are usually minor and their incidence is low—Why?—b/c there aren’t that
many physiological functions of H2 receptors in the body besides acid secretion.
2. DRUG INTERACTIONS
a. IMPORTANT: Cimetidine is a very important example of a drug that has a large
number of drug interactions
i. When you get a question w/ cimetidine its either going to deal with the fact
that it inhibits acid secretion or that it has lots of drug interactions
ii. Its OTC so you don't know if the patient is taking it or not
b. The most important side effect of cimetidine is inhibition of P450 - mediated (CYP1A2,
CYP2C9, CYP3A4, CYP2D6) metabolism of drugs such as warfarin, phenytoin,
theophylline, phenobarbital, diazepam, propranolol, and imipramine. Hence, if
coadministered with cimetidine, the doses of these drugs may have to be decreased.
c. Remember: 60% of all drugs are metabolized via CYP 3A4.
d. **This does not occur w/ Ranitidine
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UNIT 5 DRUG LECTURES
3.
4.
IV.
ENDOCRINE EFFECTS
a. Cimetidine blocks androgen receptors (ANTI-ANDROGENIC) and when taken in high
doses for long periods, e.g., for treatment of Zollinger-Ellison Syndrome, can lead to
i. Gynecomastia
ii. Impotence in men
iii. Galactorrhea in women.
CNS EFFECTS
a. These are rare but slurred speech, delirium, confusional states have been reported esp.
in elderly patients.
PROTON PUMP INHIBITORS
a.
b.
Examples of PPI’s:
i. Omeprazole (Prilosec®, 1989)
1. Zegerid ® is another formulation of omeprazole w/ NaHCO3 which avoids getting activated in the
stomach
a. To preserve bioavailability
b. Can be a capsule or powder (can be injected in patients that cant take pills orally—
patients w/ NG tube or OG feeding tubes)
c. Other alternatives is mix the granules of Nexium w/ apple sauce
ii. Lansoprazole (Prevacid®, 1995)
iii. Rabeprazole (AcipHex®, 1999)
iv. Pantoprazole (Protonix®, 2000)
v. Esomeprazole (Nexium®, 2001)
1. Newer purple pill—was released after omeprazole was up to become generic. So they released
omeprazole as OTC and Nexium as prescription
vi. Dexlansoprazole (Dexilant®, 2009)
vii. QUESTION: Is the new purple pill better than the old purple pill?
1. Omeprazole (R & S omeprazole)--> undergoes a rxn to form the active drug and both generate
the same intermediates
2. Nexium (just S omeprazole)--> just the S and might act a bit more slowly
3. Comparing the two
a. In the acidic pH they both get converted into the same active intermediate
b. Duration of Action longer?
i. Both metabolized by CYP2C19 and 3A4 to inactive products so same drug
interactions
ii. S-form may be metabolized more slowly—but duration of action is similar b/c
they both are irreversible inhibitors
c. Side effects different or fewer?
i. Very few—HA and diarrhea are most common but no difference between R
and S forms
d. Efficacious?
i. At the equal amounts of the drug there isn't a difference between.
e. So old drug or new drug? Same thing just different prices
MECHANISM (see fig. 3)
i. The low pH of the secretory canaliculus converts these drugs to a form that reacts with and irreversibly
inhibits the H+/K+ proton pump.
1. This is a covalent reaction
2. Irreversibly inhibit the pump so they last a long time
3. Drug is a weak base and accumulates in secretory vesicles, where it is activated by the low pH
a. Weak bases get protonated and get trapped in acidic places (in the secretory canaliculi
of the stomach) --> perfect b/c the proton pumps are here!
b. Once it gets protonated it changes the structure (conformational change) which forms
the active drug—so the active drug is only made in an acidic environment so it is specific
4. Active form of the drug irreversible inhibits the proton pump—need to synthesize new pumps to
reactivate—effect has a long duration
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UNIT 5 DRUG LECTURES
a.
Active form of the drug has the potential to go all over the body EXCEPT the t1/2 is only
1.5 minutes so it only works in the stomach by binding covalently on the pump in the
stomach.
i. No effect on other secretion or GI motility because it doesn't reach other cells
b. Irreversible inhibition blocks H+ secretion by > 90% and it takes 2-4 days to return to
normal (need to synthesize new pumps)
ii. For a single dose, the maximum effect seen in two hours
For repeated doses, plateau reached after 4
days (90% inhibition 40mg/day)
iii. Upon cessation of treatment, acid secretion returns to normal in 3-5 days.
1. Has potential to block acid secretion completely
iv.
c.
d.
Fig. 3 Mechanism of action of the proton pump inhibitors.
PHARMACOKINETICS
i. Administered orally, but the pellets in the capsule are enteric-coated to protect from gastric acid
(prevented from activation in the stomach b/c must go into blood). They should not be chewed, but may
be mixed with apple sauce if capsules cannot be swallowed. Also available for IV administration.
1. Absorbed from small intestine
a. NOT FROM THE STOMACH!!!!
2. Saturable first pass effect
3. Plasma t 1⁄2 = <1hr
4. Bioavailability is 30-50% for omeprazole (b/c of 1st pass metabolism)
a. Lansoprazole 80%
b. Rabeprazole 52%
c. Pantoprazole 77%
USES
i. SHORT TERM (4-8 weeks)—to healed gastric mucosa
1. Gastro-esophageal reflux disease - GERD
2. Erosive esophagitis and maintenance of remission
3. Gastric and duodenal ulcers (4-8 weeks)
ii. LONG TERM (1-5 years)
1. Hypersecretory diseases
a. Zollinger-Ellison syndrome-- pancreatic tumor that secretes a ton of gastrin
b. Systemic mastocytosis,
2. MEN I (i.e. multiple endocrine neoplasms, type 1 – the “P” lesions: pituitary, parathyroid,
pancreas (produces excess gastrin))
3.  risk of NSAID-associated gastric ulcer
a. naproxen + esomeprazole = Vimovo ®
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UNIT 5 DRUG LECTURES
V.
4. Healed erosive esophagitis
iii. PPI’s are currently some of the worlds most frequently prescribed drugs. In 2009, about 91 million
prescriptions were written for these drugs in the U.S.
e. SIDE EFFECTS AND CONCERNS
i. Few side effects are associated with these drugs and omeprazole (Prilosec OTC®) is now available overthe-counter.
1. No effect on volume of secretion, levels of pepsin, or intrinsic factor
2. Gastric motility unaffected
ii.  gastric pH  stimulates antral G cells to produce gastrin   serum gastrin levels  inducinECL cell
hyperplasia
1. was seen as a concern since ECL tumors develop in rats treated with the drug for > 2 years, but
no tumors in humans found yet
iii.  gastric pH leads to  in intragastric viable bacteria growth
1. This is a concern since it has been suggested that nitroso (NO2-)-compounds synthesized from
nitrites may lead to gastric cancer
2. May  risk of Clostridium difficile–associated diarrhea (CDAD) (FDA 2/2012)
iv. Bone Fracture: Warning/Precaution (2010):
1. After > 20 years of use, no tumors attributable to PPI’s have been reported in man; however
long-term and multiple daily dose PPI therapy may  risk for osteoporosis-related fractures of
the hip, wrist or spine.
v. HYPOmagnesemia: Warning/Precaution (2011, 38 AE reports) tetany, dysrhythmias seizures
1. Long-term (> 1 yr) use PPI therapy may cause hypomagnesemia leading to nerves and muscle
problems because magnesium competes w/ Ca
2. Consider monitoring Mg2+ especially in patients taking digoxin or loop or thiazide diuretics
f. DRUG INTERACTIONS
i. INHIBITION of CYP450 SYSTEM
1. Omeprazole and esomeprazole
a. Significant INHIBITION OF CYP 2C19 and weak 3A4 inhibition
i. Interaction w/ Diazepam, phenytoin, warfarin, cilostazol elimination prolonged.
ii. Avoid use with clopidogrel (Plavix®) due to inhibition of clopidogrel activation
1. Clopidogrel (Plavix) blocks the ADP receptor to prevent activation of
platelets; it's a PRODRUG that gets activated by CYP2C19 so it doesn't
work as well --> heart attack risk!
2. Other drugs in class: CYP450 inhibition less significant
ii. Interactions due to INCREASED GASTRIC pH e.g. Decreased bioavailability of
1. **Changes of the drug pH can change the amounts of drugs absorbed
2. Ketoconazole, itraconazole
3. Fe2+ salts
a. When you take Fe supplements iron gets absorbed as Fe2+ from the gut and if the pH
goes up the Fe2+ interacts w/ OH- and is more easily oxidized to Fe3+ which doesn't get
absorbed so you need to reduce it back to Fe2+
4. Ampicillin esters
5. Digoxin ( bioavailability)
6.
a. Protease inhibitor
CYTOPROTECTIVE DRUGS a. Drugs that protect the gastric mucosa. b. MISOPROSTOL (Cytotec®, 1988)—(PGE1 analog)
i. Derivative of prostaglandin—b/c patients on NSAIDs don't
produce many PG’s that protect the gastric mucosa ( acid
secretion and promoting mucus and bicarb secretion)—so these
patients are at high risk for gastritis and ulcers
ii. More slowly metabolized than PGE2 so longer half life (see
notes on Eicosanoids). As an analog of prostaglandin E1,
misoprostol has the following effects:
16
UNIT 5 DRUG LECTURES
c.
d.
e.
iii. ACTIONS/MECHANISM
1. Inhibits acid secretion
2. Stimulates HCO3- and mucus secretion
3. Promotes gastric blood flow
iv. SIDE EFFECTS
1. Diarrhea due to increased intestinal motility and secretion
2. Abdominal cramping
3. Uterine contraction can cause abortion of pregnancy
a. Contraindicated unless you're using it to induce abortion in the 1st 49 days of pregnancy
v. USES
1. Misoprostol is approved for use by patients taking nonsteroidal anti- inflammatory drugs
(NSAIDS), which block synthesis of endogenous PGE2 and thereby increase risk of ulcer formation.
Arthrotec® (1997) is a combination drug that combines misoprostol (0.2mg) with the NSAID
diclofenac (50 or 75mg) in a single tablet.
2. Pregnancy termination in combination with mifepristone (RU486, Mifeprex®) or methotrexate SUCRALFATE (Carafate®)-- like a SUCROSE molecule w/ a lot of OH molecules that have been sulfated (hydrophilic)
i. Protects existing ulcers and promotes healing by forming a protective layer across the ulcer crater.
ii. MECHANISM
1. If pH < 4 (acidic), sucralfate polymerizes to form a thick, sticky gel which adheres to proteins in
the ulcer crater—forming a simple protective barrier to prevent acidic from getting to the ulcer
2. Consequently, should not be administered < 30 min before or after antacids b/c needs acidic pH
to become active. Is effective for up to 6 hr.
iii. USES
1. Treatment of duodenal and gastric ulcer - about as effective as H2-blockers.
iv. SIDE EFFECTS
1. Very few b/c its doesn't get absorbed into the body
v. DRUG INTERACTIONS
1.  Absorption of cimetidine, omeprazole and tetracyclines
a. b/c these three drugs are used for treating ulcers so they are more likely to be
accidently given together
2. As stated above antacids are contraindicated 30 min after sucralfate administration
BISMUTH COMPOUNDS (e.g., Bismuth Subsalicylate (Pepto-Bismol®))
i. Act much like sucralfate by coating the surface of the ulcer, but may also kill H. pylori which is responsible
for ulcer formation
ii. Often used in conjunction with antibiotics and H2-blockers or proton pump inhibitors.
ANTACIDS—base that can neutralize an acid
i. Antacids were more important for ulcer treatment before H2-antagonists became available.
ii. Antacids promote ulcer healing not by blocking acid secretion but by neutralizing acid after secretion.
Although antacids can work as effectively as H2-blockers in treating ulcers, patient compliance is a
problem, because large quantities have to be taken frequently and when the pain goes away the patient
usually stops taking the medication. Their current importance arises more from the frequency with which
they are “self-prescribed”, although OTC H2-blockers are now more frequently used. Their major selling
point is the speed with which they can raise gastric pH and alleviate symptoms.
iii. IMPORTANT: When considering properties of antacids both the nature of the base (i.e., the anionic
component such as OH-, HCO3-, CO3=, citrate3- which binds H+) and the cation (e.g., Na+, Mg2+, Al3+,
Ca2+) must be considered.
iv. Most Common Antacids:
1. NONSYSTEMIC—stay in the gut and neutralizes the gut pH which will cause the gut to take that
bicarb and form carbonate and get rid of the base
a. Mg(OH)2
reacts quickly  pH 8-9
i. Rapid relief
b. Al(OH)3
reacts slowly pH ~ 4.5
i. Sustained relief
ii. **lots are mixtures of Mg and Al to get both the quick and sustained effects
c. MgCO3 & CaCO3 reacts slowly  CO2
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UNIT 5 DRUG LECTURES
SYSTEMIC—absorbed in the body and  blood and urine pH
a. NaHCO3
b. Na3citrate
“ACID NEUTRALIZING CAPACITY” (ANC)
1. Antacids can be compared using their ANC defined as “The mmol of HCl (1 M) that can be
brought to pH 3.5 in 15 min”.
EFFECTS AND USES OF ANTACIDS
1. Raise gastric pH - effect is prolonged by food (30 min 2 hr), which delays stomach emptying.
2. Pepsin is inactivated at pH 5-7.
3. Acid Rebound:  in gastric pH stimulates gastrin secretion. Gastrin stimulates acid secretion
leading to “Acid Rebound”, which is especially prominent in patients with duodenal ulcers and
when CaCO3 (tums) is used. The latter effect may be a consequence of the direct stimulation of
gastrin & acid secretion by Ca2+.
a. Prominent w/ Ca2+ antacids
i. Ca2+  or pH   gastrin    H+ secretion
4. Alkalosis/Alkaline Urine: Antacids can be divided into systemic and non- systemic antacids.
a. Systemic Antacids: e.g., NaHCO3, Na citrate (b/c Na+ gets absorbed into the body)
These neutralize stomach acid and are absorbed. Hence, ingested “alkali” must be
excreted by kidneys. Increase in blood pH which causes the urine pH to  which can
affect rate of excretion of acidic and basic drugs.
i. Alkalinization of the urine is useful for accelerating the excretion of toxic
overdoses of acidic drugs, e.g., salicylate, phenobarbital.
1. Alkalinazation of the urine is useful for trapping acids!
2. Used IV to promote excretion of acidic drugs—can be combined w/
diuretic acetazolamide!
ii. Adverse effect is the increased potential for the disposition of insoluble salts
(Ca phosphate) in the kidney. This is most likely so when NaHCO3, CaCO3, and
milk are taken together = “Milk Alkali Syndrome”. This can cause renal
problems
b. Non-Systemic Antacids (Ca2+, Mg2+, Al3+): Ca2+, Mg2+ and Al3+ are poorly absorbed
from the GI tract; consequently, are excreted as insoluble carbonates in the feces and
therefore produce little alkalosis. Small amounts of the cations are absorbed, but usually
present no problem unless patient’s renal function is impaired.
5. Gastric Motility (diarrhea/constipation):
a. Gastrin increases motor activity.
b. Mg2+  motor activity, accelerates gastric emptying  diarrhea.
c. Al3+  motor activity, slows gastric emptying constipation.
d. Hence, Mg(OH)2 and Al(OH)3 - are frequently mixed to minimize effect (e.g., Maalox®,
Mylanta®). Mg(OH)2 (Milk of Magnesia) is used as laxative.
i. In Milanta this is beneficial bc these MgOH and AlOH3 are mixed so together
more normal
DRUG INTERACTIONS:
1. Mg2+ and Al3+ (multivalent ions!) containing antacids can decrease absorption of certain drugs,
a. tetracycline and quinolone/fluoroquinolone antibiotics are the most important
examples.
i. Common fluoroquinolone is Ciprofloxacin
2.  in gastric pH inhibits absorption of the antifungals ketoconazole, itraconazole, also Fe2+ (as
discussed for PPIs)
TOXICITY of CATIONS (Al3+ Mg2+)
1. Not really seen when renal function is normal
IMPORTANT:
1. Mg2+ induces diarrhea
2. Al3+ induces constipation
3. Systemic antacids alkalinize blood/urine
4. Drug Interactions Al3+ and Mg2+ e.g., tetracycline
2.
v.
vi.
vii.
viii.
ix.
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UNIT 5 DRUG LECTURES
VI.
TREATMENT OF ULCERS WITH ANTIBIOTICS
a.
b.
It is now widely accepted that Helicobacter pylori plays a role in ulcer formation. Consequently, antibiotics have
become very important in the treatment of ulcers. About 50% of the world’s population is believed to be infected.
TREATMENT
i. Short courses (2 weeks) of multi-drug therapies are used to eradicate the bacteria and promote ulcer
healing.
ii. MAIN ADVANTAGE
1. The main advantage of eradicating H. pylori is the very low rate of recurrence of the ulcer after
cessation of treatment, e.g., in one study, recurrence = 1/46 of patients in which H. pylori had
been eradicated vs. 45/53 patients in whom it had not (H2-blocker used alone).
a. 2% vs. 85% recurrence after 1 year
iii. PROBLEMS
1. H. pylori rapidly becomes resistant to the antibiotics metronidazole and clarithromycin, therefore,
these drugs are not used alone, but in combination with other antibiotics.
iv. TYPICAL TREATMENTS (10-14 days)—don't need to memorize specific combinations
1. “Quadruple Therapy” -- Combination of:
a. tetracycline (or Amoxicillin)
b. bismuth subsalicylate
c. metronidazole and
d. H2-blocker or PPI
taken for 14 days has proved effective. Another “Triple Therapy” uses
a combination of metronidazole, clarithromycin and omeprazole.
MOST IMPORTANT DRUG NAMES TO REMEMBER
I.
The following is a minimum list of the drug names to remember.
a. Cimetidine
b. Omeprazole
c. Misoprostol
d. Sucralfate
e. Bismuth Subsalicylate
f. Magnesium and Aluminum Hydroxide
g. Tetracycline, metronidazole DRUGS THAT AFFECT GI MOTILITY
I.
INTRODUCTION
a. MOST COMMON INDICATIONS
i. IRRITABLE BOWEL SYNDROME (IBS)—not the same as IBD (UC/CD)
1. Symptoms – chronic abnormal motility of large intestine
a. Abdominal pain/cramping– relieved by defecation
b. Constipation, diarrhea or both
2. Cause unknown – disturbance of sensory (sensing more pain than you should be) and/or motor
function (motility dysfunction)?
3. Afflicts ~15% of U.S. population
4. More frequent in women – 3:1 women:men
ii. Gastroesophageal Reflux Disease (GERD)
iii. Prevention of vomiting
b. MODEL FOR CONTROL OF GI MOTILITY
i. Bolus of food via mechanical or chemical stimuli causes release of serotonin from enterochromaffin (EC)
cell
ii. Serotonin (5-HT3) activates the network of primary afferent sensory neurons via HT3 receptors, which are
ligand gated ion channels like the nicotinic receptor
iii. The sensory neuron activates proximal excitatory motor neurons, which release acetylcholine and
substance P and contract the circular smooth muscle in the direction of the mouth
iv. The sensory neuron also activates distal inhibitory motor neurons (in the anus direction), which release
NO and VIP and relax the circular smooth muscle – net effect is peristalsis movement of the bolus toward
the anus
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UNIT 5 DRUG LECTURES
v. The sensory neuron also activates a network of ascending (toward mouth) excitatory interneurons,
which conducts the excitatory contracting signal towards the mouth
vi. The sensory neuron also activates a network of descending (toward anus) inhibitory interneurons, which
propagates an inhibitory relaxing signal toward the anus
vii. Presynaptic serotonin 5-HT4 receptors, (elevate cAMP) on the sensory neurons promote
neurotransmitter release (may also be on ascending and descending interneurons) to promote motility
1.  cAMP in the neuron will promote opening of Ca2+ channels and promote the release of NT’s so
it accelerates the signal
a.
II.
LAXATIVES AND CATHARTICS (heavy duty laxative) a.
PHYSIOLOGY BACKGROUND
i. Laxatives are important drugs not so much for their clinical application, but because of their overuse and
abuse by a self-prescribing public. ii. Laxatives promote defecation by increasing the amount of water in the feces. Cathartics do a little more!
1. Depend on how much water gets into the feces and how much water intake you have iii. FLOW OF FLUID THROUGH THE INTESTINE 1. 7 liters of secretions plus 2 L from the diet
enter the GI tract each day so total is 9 L of
fluid enter the GI tract daily. About 7.5 L and
1.4 L are absorbed by the small and large
intestines, respectively. Only 1L reaches the
colon and only about 100-200 ml exits with
the feces. Increasing this to 300 ml producing
diarrhea. Most of the absorption of H2O by
the colon accompanies the reabsorption of
Na+, and Cl-. This flux is driven by the
gradient generated by Na/K+-ATPase pumps
that drive Na+ from the mucosal cell to the
blood. Cl-/HCO3- exchange, Na+/H+ exchange, and NaCl cotransport and Na+ channels mediate
influx from the lumen into mucosal cells. Cl- and K+ channels also exist and permit these ions to
pass from the mucosal cell into the lumen and be secreted. The colon cannot concentrate or
dilute the feces—it must be isotonic w/ the blood.
a. The villous cells reabsorb NaCl
b. Crypt cells between the villi these tend to secrete salts (especially K) and fluids these
utilize the NKCC2 that we saw in the kidney (this one is also sensitive to furosemide!)
but this channel is brining NaCl back into the cells of the gut
c. Cholera causes the G proteins to permanently be activated and secrete the fluids
2. The net flux is controlled by the enteric nervous system and a large number of neurotransmitters,
hormones and autacoids. As with gastric acid secretion, cAMP stimulates salt/fluid secretion and
inhibits absorption - choleratoxin is the most dramatic example of an agent that induces diarrhea
by elevating mucosal cAMP. Factors that lower cAMP or inhibit acetylcholine release increase
reabsorption - e.g., opioids.
iv. MODULATION OF AMOUNT OF FLUID REACHING THE RECTUM
1. These are controlled by the PSNS, SNS, ENS , autacoids (histamine, serotonin, PG’s) via processes
using messengers that include cAMP, cGMP, Ca2+ and NO
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UNIT 5 DRUG LECTURES
a.
b.
2.
b.
Intrinsic ion transport activities (water follows Na)
Presence of non-absorbed solutes
i. Osmotic laxatives—things that don't get absorbed from the gut lumen and
produce an osmotic effect which drives water into the lumen
c. Intestinal motility (Smooth muscle) transit time—faster it moves through the GI tract,
the less likely to be reabsorbed
d. Blood flow (vascular smooth muscle) – blood flow = better reabsorption of the things
from the interstitium
Laxatives increase the amount of fluid reaching the rectum by one or more of the following
mechanisms:
a. They provide a hydrophilic substances (that have osmotic pressure) that are not
absorbed.
b. They inhibit solute uptake or activate solute secretion.-- of salt uptake will inhibit the
reabsorption of fluids
c. They decrease the “transit time” by increasing motility of the gut.—less time for fluid
reabsorption
FIBER
i. Fiber is non-digested material from plant cell walls.
1. Includes: Cellulose, hemicelluloses, lignins, cutins, waxes, and some glycoproteins.
2. These are found in whole grains, bran, vegetables, and fruit.
ii.
1.
Fig. 2 The top half of the figure shows some of the ion fluxes that take place in villous cells and
are involved in net salt absorption driven by the “Na+- pump” on the basolateral membrane. The
lower half shows transport pathways located in crypt cells that enable the gradients generated by
“Na+-pumps” to drive secretion of salts.
iii. EFFECTS ON GI TRACT
1. Fiber helps to relieve constipation of “irritable bowel syndrome”
a. Binds water and ions - increase mass of feces
b. Through GI distention increases GI motility
i. So basically Fibers bind water and ions which  bulk of the feces which  the
stretch of the GI tract which will  gastric motility and  free water in the stools
so it prevents watery stools
2. Fiber helps prevent watery stools by binding water
3. Fiber binds bile acids –helps lower plasma cholesterol
iv. ADVERSE EFFECTS OF FIBER THERE ARE VERY FEW AND MOST ARE MINOR
1. Possible allergic reactions
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UNIT 5 DRUG LECTURES
2.
3.
4.
c.
Flatulence
Borborygmi---noises you hear in the stomach which are 
Binds other drugs
a. Cellulose – binds cardiac glycosides (digoxin), salicylates, nitrofurantoin.
b. Psyllium- coumarin (warfarin)
c. **warfarin and digoxin have narrow therapeutic windows—you don't have to change
their concentration by a lot to go below minimum effective conc or go above minimum
toxic concentration so they are more susceptible to  fiber in the diet
5. Intestinal obstruction may occur if stenosis, ulceration, or adhesions are present
v. DIETARY FIBER CAN BE SUPPLEMENTED
1. Psyllium (Metamucil®) - from plantago seed
2. Methylcellulose (Cologel®)
3. Polycarbophil (e.g., Fibercon®) – an acrylic resin 4. ALL should be taken with water (250 ml/gram) to prevent constipation b/c these bind water
SALINE OR OSMOTIC LAXATIVES i. Saline/osmotic laxatives act in small intestine and colon and can induce laxation in 1-3 hours (pretty
quickly).
ii. MECHANISM
1. They are non-absorbed molecules, which retain water in the GI tract by virtue of the osmotic
pressure they generate.
2. If they are administered in hypertonic solutions, they will draw water from the blood and  the
water content of the GI tract.
3. They act in both the small intestine and the colon.
4. Note: Unlike urine in the kidney tubules, the contents of the GI tract tend to remain isotonic with
blood.
iii. Examples:
1. Mg2+ salts: MgSO4 - Epsom Salt
2. Mg(OH)2 - Milk of Magnesia
3. K+ or Na+ salts of phosphate, tartrate, sulfate
4. Lactulose (Chronolac®, Cephulac®) - can  blood NH3 in patients with chronic liver disease so
used to treat hepatic encephalopathy (brain damage due to  NH3 in the blood)
5. Sorbitol or glycerin—doesn't bind to charcoal so can be combined w/ it to treat drug OD
6. **Only osmotic laxatives are recommended for treatment of drug overdose (sorbitol 70%)
iv. ADVERSE EFFECTS
1. Hypertonic solutions  net loss of water (dehydration)
2. Mg2+ may produce toxicity if renal function impaired
3. Phosphate nephropathy—rare but serious acute renal failure (ex: Fleet Phospho-soda)
a. Risk  by renal function , age , blood volume , diuretics, ACEI, ARB’s, NSAIDS
i. Especially when people are concentrating these things in the urine
4. Lactulose can lead to cramps and flatulence
5. Na+ --will get  Na so should be avoided in patients with congestive heart failure 6. IMPORTANT: Osmotic laxatives are used in conjunction with charcoal to minimize absorption
and accelerate elimination of drugs in cases of overdose. Important properties are rapid action,
act in both small intestine and colon and most important they are not adsorbed by charcoal.
v. WHOLE BOWEL IRRIGATION (CoLyte®, GoLYTELY®, 1984)
1. Special isotonic formula (so you don't lose water) designed to be administered orally in large
volumes to flush out the GI tract without net absorption or loss of salts or water
a. The fluid is not absorbed nor does it promote secretion
b. Administration orally or through NG tube in adults
c. Infusion continued until rectal effluent is clear
d. Cleanses/decontaminates the entire GI tract
2. Composition: In 4L (1 gal) bottle
22
UNIT 5 DRUG LECTURES
a.
d.
Polyethylene glycol 3350 (240g), Na2SO4 (22.72g) NaCl (5.84 g), NaHCO3 (6.72g), KCl
(2.98g)
Flavor (1.852g) optional
Composition ensures virtually no net absorption or loss of salts or water
b.
c.
3. USES
a. Catharsis: Bowel cleansing prior to colonoscopy, barium enema X-ray exam, surgery, etc
b. Adults 240ml rapidly, every 10 min, first bowel movement in 1hr
“STIMULANT” LAXATIVES—most common self prescribed laxatives
i. At normal doses, most act in colon and produce laxation is in 6-8 hr
1. POPULAR & Frequently abused OTC drugs that act in the COLON w/ effects seen in 6-8 hours by
inhibiting absorption and stimulating secretion and motility
ii. MECHANISM
1. These drugs increase salt (and water) secretion and decrease the transit time. The mechanism
appears to involve generation of NO, PGE2 and activation of protein kinase C.
2. Excessive use can lead to fluid and electrolyte deficits
iii. PHENOLPHTHALEIN (FDA approval withdrawn)
1. 1906 - marketed as Ex-Lax®
2. 1997 - Withdrawn from market due to risk of cancer. Found to induce tumors in laboratory rats
and mice.
3. Some excreted in urine which turns red if pH > 9
iv. BISACODYL (Dulcolax® (1957), Feen-A-Mint®, Correctol®) and Sennoside A (Senokot ®)
1. Structurally related to phenolphthalein
a. The acetyl groups are removed in the small intestine and the drug is absorbed
conjugated to glucuronate and secreted in the bile. The glucuronate derivative is not
reabsorbed, but passes to the colon where bacteria remove the glucuronate groups and
release the active drug.
b. These act in the colon due to enterohepatic cycling of glucuronides—producing laxation
in 6-8 hours
2. IMPORTANT: Bisacodyl tablets are enteric-coated (comfort coated) to prevent the active drug
(and its action) from being released in the upper small intestine (duodenum) and stomach, which
can induce vomiting and retrograde peristalsis. Tablets should not be chewed or crushed or
administered with antacids or other drugs that raise gastric pH as this can cause premature loss
of the enteric coating.
v. ANTHRAQUINONES AND RELATED COMPOUNDS (e.g., Ex-Lax®, Sennoside--Senokot®, Nature’s
Remedy®)
1. Glycosides of danthron and other related substances such as dianthrones (sugar residues added
to the -OH moieties) are found in Senna, Cascara sagrada, rhubarb and aloe.
a. These are acted upon in the colon by bacteria to release the active drug. Danthron itself
is not used due to reports of hepatic and intestinal tumors in lab animals (this was also
seen w/ phenolphthalein—both have been withdrawn from the market)
2. IMPORTANT POINTS
a. The actions of phenolphthalein and bisacodyl are prolonged by enterohepatic cycling.
Glucuronidation in the liver prevents effect being produced until the drug reaches the
colon where bacteria remove the glucuronate.
b. These drugs are absorbed  saliva, milk, urine
3. ADVERSE REACTIONS OF STIMULANT LAXATIVES
a. Fluid and electrolyte deficits—loosing fluids from the body in diarrhea, which can lead
to hypovolemia.
i. In the small intestines most of the ions absorbed are Na
ii. In the colon (net secretor of K and bicarb) K gets secreted into feces and Na
gets reabs so if  feces (w/  levels of K) then patient can become hypokalemia
especially if they have low K in their diet
b. Absorbed milk, urine, saliva
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UNIT 5 DRUG LECTURES
c.
e.
f.
Note: In 1996, the FDA reclassified these laxatives as category III laxatives, and
requested studies be done demonstrating safety and efficacy. Only data for bisacodyl
and senna were received. The other drugs were removed from market.
d. Chronic use of these agents is NOT recommended
vi. CASTOR OIL (Purge®, 1939)
1. Castor oil is a triglyceride of ricinoleic acid from castor bean plant Ricinus communis.
a. Note the castor bean is also the source of ricin, a cytotoxin that is an enzyme, which
inactivates ribosomes. As little as 1mg may be sufficient to kill an adult.
2. Ricinoleic acid is released by pancreatic lipases in small intestine. Ricinoleate acts on small
intestine and the colon stimulating peristalsis and fluid secretion producing complete emptying
in 1-6 hr.
3. NOT RECOMMENDED FOR COMMON CONSTIPATION.
a. Can induce uterine contraction in pregnant women.
4. Question: Could this drug work by binding to PGE2 receptors?
a. Maybe, but no one has shown it, because stimulates GI peristalsis and fluid secretion
and induces uterine contraction in pregnant women
vii. LUBIPROSTONE (Amitiza®, 2006)
1. Keto form of a prostaglandin
2. MECHANISM: laxation
a. Directly activates Cl- channels promoting secretion and thereby motility
i. Effect is not mediated via PG receptors and cAMP elevation
3. INDICATIONS
a. Chronic idiopathic constipation
b. IBS with constipation in women
4. SIDE EFFECTS
a. Nausea, diarrhea
b. Effect on pregnancy unknown, category C
i. Need to have a pregnancy test, contraception before use
viii. LINACLOTIDE (Linzess®, 8/30/2012)
1. A new drug that is a 14 amino acid peptide (has 3 S-S bonds/disulfide bridges) no absorption
a. Stimulates fluid secretion in GI tract
2. MECHANISM: laxation
a. Activates guanylate cyclase type C in luminal membrane of intestinal epithelium
elevating intra- and extra-cellular cGMP
b. Result: CFTR HCO3- and Cl- channels activating salt secretion and thereby motility
3. INDICATIONS
a. Chronic idiopathic constipation (CIC) and IBS with constipation in adults.
b. Contraindicated in children <6 y.o.; avoid use in patients 6-17 y.o.
4. SIDE EFFECTS
a. Nausea, diarrhea
STOOL SOFTENERS
i. DOCUSATE (Colace®, Surfak®)
1. Mild laxation produced with 1 - 3 day latency.
2. Lubricant, emulsifier and detergent (“WD40 for the GI Tract)
3. Mechanism of action uncertain, but probably the same as stimulant laxatives.
4. Absorption is minimal, it's a strong acid (poor partition coefficient)
USES OF LAXATIVES
i. CONSTIPATION
1. Note “Laxatives have NO role in treatment of constipation that results from intestinal pathology”
(Goodman and Gilman).
2. Before Drugs are Used Try:
a. If cause is an underlying disease, correct any underlying disease
b. If constipation is induced by another drug (side effect), adjust dose or change drug
24
UNIT 5 DRUG LECTURES
c. Modify habits: Fiber rich diet, bowel-training, increase fluid intake, exercise
Then: Bulk forming agents
(Metamucil, etc)
Finally: stimulant laxatives at LOWEST effective dose, as INFREQUENTLY as possible and
DISCONTINUE promptly and COMPLETELY
ii. TO PREVENT STRAINING AT STOOL (BOWEL MOVEMENTS MORE EASY)
1. In patients with:
a. Hernia
b. Cardiovascular disease
c. Hemorrhoids -- before and after surgery, etc.
iii. EVACUATION OF COLON Stimulant or saline laxatives are used to evacuate the colon
1. Prior to RADIOLOGICAL EXAMINATION of abdomen, GI tract, etc.
2. Prior to ELECTIVE BOWEL SURGERY
3. Prior to PROCTOLOGICAL EXAMINATION, COLONOSCOPY
4. Following DRUG OVERDOSE (Osmotic laxatives only!  sorbitol (70%) or MgSO4 (30 g)—usually
with charcoal)
3.
4.
MOST IMPORTANT DRUG NAMES TO REMEMBER
I.
The following is a minimum list of the drug names to remember.
a. Magnesium Hydroxide
b. MgSO4
c. Sorbitol
d. Psyllium
e. Phenolphthalein
f. Bisacodyl
g. Senna
h. Docusate
i. Castor Oil PROKINETICS I.
II.
III.
Drugs that  GI motility
a. For conditions like
i. acid reflux (get the acid moving down not up in the esophagus), Vomitting, Diabetic gastroparesis—
neuropathy of the vagus nerve controlling the emptying of the stomach, & IBS associated w/ constipation
Laxatives increase motility of the colon indirectly, whereas prokinetics have a direct effect and can increase motility of both
the small intestine and the large intestine. This can be used to reduce acid reflux, treat diabetic gastroparesis, reduce risk of
vomiting and also treat chronic constipation. In the GI tract, the PNS promotes motility and controls sphincters.
CHOLINERGICS
a.
BETHANECHOL (Urecholine®, 1948)
i. Bethanechol is a quaternary (poor partition coeff)
muscarinic agonist, carbamate ester resistant to
hydrolysis by acetylcholinesterase
ii. USES
1. Promotion of GI motility, but produces more
of a generalized contraction of the smooth
muscle all over rather than effective
propulsive movements - can be used to
promote GI motility after surgery under
general anesthesia. May increase tone of
lower esophageal sphincter
2.  LES pressure (on oral administration) so  reflux
3. More frequently used to promote bladder emptying in patients with non- obstructive urinary
retention and neurogenic bladder
iii. SIDE EFFECTS
1. Poorly absorbed from GI tract (poor partition coeff) - Supposedly has negligible muscarinic
cardiovascular effects
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UNIT 5 DRUG LECTURES
2.
3.
IV.
Increases acid secretion
Muscarinic agonist—said to have minimal CV effects though
SELECTIVE SEROTONIN 5HT4 AGONISTS
a.
b.
c.
CISAPRIDE (Propulsid®, 1993-2000)—PROTOTYPE
i. MECHANISM
1. Cisapride is a serotonin agonist selective for 5-HT4 receptors found in the myenteric plexus of the
GI tract which  cAMP on the ascending excitatory cholinergic interneurons in the myenteric
plexus and afferent neurons which lead to stimulation of the descending inhibitory network
which induces relaxation.
2. In contrast to the action of opioids, activation
of these receptors stimulates acetylcholine
release and hence increases motility.
a. Stimulates contraction the ascending
excitatory network to contract
3. These drugs have three important effects:
a. Hasten esophageal clearance and
gastric emptying
b. Increase motility of small (and large)
intestine
c. Increase tone of the lower
esophageal sphincter (LES)-- acid
from coming up into the esophagus
4. All of these contribute to decreased acid reflux.
5. Unlike a direct cholinergic agonist, such as bethanechol, it does not increase gastric secretion.
ii. USES
1. Treatment of gastro-esophageal reflux disease (GERD), especially nocturnal heartburn.
2. Diabetic gastroparesis
3. Chronic constipation
iii. DRUG INTERACTIONS
1. Bioavailability is normally 40-50% due to metabolism to an inactive metabolite by cytochrome
CYP 3A4; however, it is increased by inhibition of this enzyme by erythromycin, ketoconazole,
grapefruit juice etc.
2. IMPORTANT PROBLEM: The parent drug can prolong the cardiac QT interval and lead to cardiac
arrhythmias and possibly death. In 2000, analysis of 341 adverse event reports, which included
80 deaths, revealed that ~85% of them occurred in patients with identifiable cardiac risks.
Because of these problems, Janssen withdrew cisapride from market in 2000.
TEGASEROD (Zelnorm®, 2002-2007)
i. MECHANISM
1. Partial 5-HT4 agonist in the myenteric plexus of the GI tract
ii. USES
1. Treatment of irritable bowel syndrome (IBS) in women when it is associated with abdominal pain,
bloating and constipation, when primary symptom is constipation
2. Chronic constipation in men and women
iii. ADVERSE EFFECTS
1. Diarrhea leading to hypovolemia, hypotension and syncope can occur
2. After approval, cases of ischemic colitis, mesenteric ischemia, gangrenous bowel, rectal bleeding,
syncope, suspected sphincter of Oddi spasm, bile duct stone, and cholecystitis with elevated
transaminases were reported
3. Increased incidence of serious CV events, e.g. unstable angina, heart attacks, stroke and death
compared with placebo was revealed by a reanalysis of 29 clinical studies of Zelnorm® leading to
removal from market in 2007
METOCLOPRAMIDE (Reglan®, 1979)—still on the market only one in this class!
i. MECHANISM OF ACTION 1. Metoclopramide has several actions
a. Like cisapride and tegaserod, it is an agonist at 5-HT4 receptors;
26
UNIT 5 DRUG LECTURES
b.
It is also a weak 5-HT3 antagonist and a dopamine D2 receptor antagonist in the CTZ
(chemoreceptor trigger zone),(see antiemetics below)
ii. USES
1. Treatment of GERD
2. Diabetic gastroparesis
3. Nausea and vomiting associated with chemotherapy and surgery
iii. SIDE EFFECTS (DISCUSSED UNDER ANTIEMETICS/dopamine antagonists)
I.
II.
III.
IV.
ANTIDIARRHEALS Drugs that  intestinal motility
a. Remember that PSNS promotes GI motility so antimuscarinic drugs and opioids would  GI motility
Motility of the GI tract is regulated by the autonomic and enteric nervous systems.
Activation of the parasympathetic system increases GI motility and relaxes sphincters promoting defecation. Thus, agents
such as cholinesterase inhibitors that promote action of acetylcholine often result in diarrhea, while antimuscarinic drugs
decrease GI motility.
i.
ANTIMUSCARINIC DRUGS - ANTISPASMODICS
a.
b.
c.
d.
e.
MECHANISM
i. Relax GI smooth muscle - decrease motility
ii. Not for patients with GERD or glaucoma (CAG) -Why?
L-HYOSCYAMINE (Levsin®, Anaspaz®)
i. Active isomer of atropine, remember “atropine” is a racemic mixture
ii. May produce all the standard antimuscarinic side effects, e.g. dry mouth
DICYCLOMINE (Bentyl®, 1950)
i. Compared with atropine supposed to have relatively smaller effect on secretion (salivary glands, sweat
glands) and cardiovascular system (heart rate)
GLYCOPYRROLATE (Robinul®, 1961)
i. Quaternary antimuscarinic (must give IV or orally to get to GI tract) local effect - poor GI absorption and
will not cross blood-brain barrier
USE
i. Oral administration to treat irritable bowel syndrome
1. Not for patients w/ GERD or glaucoma (CAG), or UC
a. GERD b/c ur relaxing the LES somewhat so  risk of reflux
b. Glaucoma—b/c this is dilate the pupil which  likelihood that the iris will block the
trabeculated meshwork and induce an acute attack of closed angle glaucoma
i. It will also relax the ciliary muscle which will  rate of drainage through
uveolsclero route so also bad for CAG
c. Ulcerative colitis is an inflammatory dz of the colon—your losing colonic epithelium
which is reabs water. So if you use a drug that is  motility (which normally would give it
more time to reabs water) when you cant absorb the fluid b/c of the damaged
epithelium you will just get a toxic megacolon
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UNIT 5 DRUG LECTURES
ii. IV administration as antisialogogue for surgery
V.
OPIOID AGONISTS
(DIPHENOXYLATE AND LOPERAMIDE)
a.
VI.
MECHANISM
i. Inhibit acetylcholine release in the myenteric plexus
1. Decrease motility, peristalsis, but  tone of GI smooth muscle and anal sphincter
ii. Also inhibits fluid/chloride secretion
iii. As with morphine, NO tolerance to this effect develops
b. DIPHENOXYLATE (Lomotil®, 1960)
i. At “recommended” doses, no analgesia or euphoria, etc.
ii. At high doses, physical dependence and euphoria (CNS effects) can be produced
iii. Marketed as mixture with atropine to limit abuse potential
iv. USE
1. Onset of action 1hr
2. Duration of action 3 - 4 hr
3. Active metabolite
4. Used for treating constipation specifically
c. LOPERAMIDE (Imodium®, 1976)
i. Does NOT enter the CNS due to P-gp/MDR1 activity in the BBB (this is an active process) – hence no
analgesia, euphoria, etc.
ii. No physical dependence—available OTC
iii. No abuse potential
iv. USE
1. Treatment of diarrhea, and IBS
a. available OTC
2. t1/2 = 10.8 hr, duration of action 24 hr
a. undergoes enterohepatic cycling (P-gp)
v. SIDE EFFECTS – minimal
vi. CONTRAINDICATION
1. Ulcerative colitis - may precipitate toxic
megacolon
ALOSETRON (Lotronex®, 2000)
a. MECHANISM
i. Serotonin antagonist at 5-HT3 receptors
1. Blocks receptors in sensory neurons of
myenteric plexus to decrease motility
2. Blocks receptors on vagal afferent pain fibers
3. **so effects pain and motility (so good for IBS
associated w/ DIARRHEA not CONSTIPATION!)
b. INDICATION
i. Treatment of severe, diarrhea-predominant irritable bowel syndrome in women, e.g. those with frequent
and severe abdominal pain and fecal incontinence
c. ADVERSE EFFECTS
i. Ischemic colitis, has lead to deaths – use strictly controlled
ii. Severe constipation
DRUGS THAT AFFECT VOMITING
I.
DRUGS THAT INDUCE VOMITING (EMESIS) a. Vomiting or emesis is a coordinated process controlled by the emetic center in the brain (medulla) which induces
vomiting
b. Certain drugs and other agents (emetics) can act as irritants in the small intestine, stimulating secretion of
serotonin by enterochromaffin cells.
28
UNIT 5 DRUG LECTURES
c.
d.
e.
f.
g.
h.
II.
Signals initiated by serotonin are mediated via 5-HT3
receptors, which are ligand-gated cation channels on vagal
afferents, lead to stimulation of the emetic center.
Emetics carried by the blood can stimulate the
chemoreceptor trigger zone (CTZ) located in the brain
(medulla) outside the blood-brain barrier in the floor of the
4th ventricle.
Signal transduction to the emetic center is mediated by
serotonin (5-HT3), dopamine, acetylcholine and possibly
histamine receptors. Summary
i. Emetics induce vomiting by 2 mech:
1. Action on EC cells in the gut releasing 5-HT
which stimulates
a. 5-HT3 receptors on vagal nerves to the emetic center and 5-HT3 receptors on pain
sensing (nociceptive) nerves
b. Also stimulates colon motility via 5-HT3 and 5-HT4
2. Emetics entering blood can act on the CTZ which is in the brain but outside the BBB
a. Signals from the CTZ are sent to the emetic center and signal is dependent on 5-HT, D2,
M, and maybe H receptors
SYRUP OF IPECAC (1938) i. Extract of the root of the rhizome Cephaelis ipecacuanha and contains alkaloids such as emetine (Fig. 1)
that act on GI tract and directly on CTZ. 1.  protein synthesis by binding to ribosomes so it can cause damage to the liver, kidney, skeletal
muscle so should not be used for more than 10 days
ii. USE
1. Induction of vomiting following drug overdose or ingestion of poison
iii. ABUSE
1. Has been abused by bulimic and anorexic patients
iv. ADVERSE EFFECTS related to chronic abuse/use
1. Cardiotoxicity – abuse can lead to congestive heart failure
2. Myopathy – weakness, tenderness, stiffness
3. Use for > 10 days is contraindicated
4.
APOMORPHINE
i. Apomorphine is a dopamine 2 receptor agonist in the CTZ and therefore an emetic.
ii. It is not currently approved for emetic use in the U.S., but as Apokyn® it has been approved for
intermittent treatment of “off” episodes in Parkinson’s disease (administered SC (2-6 mg)), it is also under
investigation for treatment of erectile dysfunction (Uprima®).
iii. Administered SC to induce vomiting
iv. Side effect: Respiratory depression
1. Emetic effect and respiratory depression can be reversed by naloxone
ANTI-EMETICSDRUGS USED for PROPHYLAXIS of VOMITING RESULTING from CHEMOTHERAPY or
ANESTHESIA ( VOMITING)
a. SEROTONIN HT3 ANTAGONISTS
i. Examples
1. ONDANSETRON (Zofran®, 1991)
2. Granisetron (Kytril®, 1995)
3. Dolasetron (Anzemet®, 1997)
29
UNIT 5 DRUG LECTURES
a.
4. Palonosetron (Aloxi®, 2003)
v. MECHANISM OF ACTION
5. Antagonist at serotonin (5-hydroxytryptamine) 5-HT3 receptors which are ligand-gated channel
on nerves.
a. Serotonin is involved in signal transduction between the GI tract (e.g. released from
enterochromaffin cells) and the chemoreceptor trigger zone (CTZ) in the brain.
b. These are especially used to treat acute vomiting
ii. USE
1. It is extremely useful in preventing ACUTE VOMITING associated with chemotherapy or radiation
therapy of cancer.
2. For maximum effect, used with glucocorticoids such as dexamethasone or methylprednisolone to
maximize the anti-emetic effects.
3. Preventing post-operative nausea and vomiting.
4. Can be administered orally or by IV route
iii. SIDE EFFECTS
1. Has relatively few, and until recently limited to constipation experienced by 11% of
chemotherapy patients on multiday therapy.
2.  QT interval in a dose-dependent manner (when given IV), which can lead to potentially fatal
dysrhythmias, e.g. torsades de pointes
a. Avoid use in patients with additional risk factors for prolonged QT interval
b. Should not give single IV dose > 16 mg. (12/2012 32 mg IV dose removed from market)
DOPAMINE (D2), MUSCARINE (M) AND HISTAMINE (H1) ANTAGONISTS
i. These are used to treat delayed vomiting along w/ glucocorticoid (dexamethasone)
ii. D2 receptors in the CNS AGONISTS CAUSE:
1. CTZ-vomiting
2. Anterior pituitary—inhibits prolactin
a. So blocking those  prolactin  infertility in women and impotence in men
3. Substantia nigra-corpus striatum—movement
a. So blocking D2 receptors will cause you to have trouble controlling your movement
4. Euphoria/psychosis
a. These are antipsychotic drugs
iii. CHLORPROMAZINE (Thorazine®, 1957)
1. Chlorpromazine is the prototypical dopamine antagonist antipsychotic drug (see Antipsychotics
lecture for detailed discussion).
2. In addition to blocking dopamine receptors it also blocks, muscarinic, histamine H1 and 1adreneric receptors
3. USES
a. Indications include
i. Schizophrenia
ii. Nausea and vomiting
iii. Relief of restlessness and apprehension prior to surgery
4. ANTIEMETIC MECHANISM
a. Blocks dopamine D2 receptors in CTZ
b. Blocks muscarinic receptors
c. Blocks histamine receptors
5. SIDE EFFECTS
a. Dopamine antagonism leads to
i. extrapyramidal symptoms, including acute dystonia within hours of therapy,
and parkinsonism, akathisia and tardive dyskinesia with prolonged treatment.
1. Tardative dyskinesia is an irreversible condition where you cant
control your movement—patients w/ diabetic gastroparesis take these
long term so be careful of tardative dyskinesia
ii. It also leads to elevation of plasma prolactin
b. H1 (and dopamine) antagonism in CNS leads to sedation
c. M antagonism leads to classical antimuscarinic effects
30
UNIT 5 DRUG LECTURES
d. 1 adrenergic blockade leads to orthostatic hypotension
iv. METOCLOPRAMIDE (Reglan®, 1979)
1. MECHANISM OF ACTION
a. Metoclopramide has two independent actions
i. As a dopamine D2 receptor antagonist in the chemoreceptor trigger zone (CTZ),
it inhibits nausea, and vomiting mediated by the CTZ.
ii. Like cisapride and tegaserod, it is an agonist at 5-HT4 receptors and therefore
increases upper GI tract motility, stomach emptying and tone of the lower
esophageal sphincter; also a weak 5-HT3 antagonist
2. USES
a. Nausea and vomiting associated with chemotherapy and surgery
b. Treatment of GERD
c. Diabetic gastroparesis 3. SIDE EFFECTS
a. Parkinsonism – predicted from dopamine antagonism in nigrostriatal system; tardive
dyskinesia after prolonged use especially elderly women
i. Tardative dyskinesia is an irreversible condition where you cant control your
movement—patients w/ diabetic gastroparesis take these long term so be
careful of tardative dyskinesia
b. Hyperprolactinemia – predicted from dopamine antagonism in the anterior pituitary
a. Drowsiness
ii. PROMETHAZINE (Phenergan®, 1951)
1. MECHANISM
a. A phenothiazine, like chlorpromazine, but major sites of action are H1 receptors and
muscarinic receptors. Little effect at dopamine receptors
b. Administered orally, rectally, IM and IV
2. USES/ EFFECTS:
a. Antiemesis (prevention and control of nausea/vomiting motion sickness) associated
with anesthesia and surgery and motion sickness
b. Preoperative, postoperative and obstetric sedation
c. Postoperative pain with meperidine
d. Allergic reactions and anaphylaxis (after epinephrine administration)
3. ADVERSE EFFECTS
a. Adverse effects associated with of H1 and M and D antagonists can be seen, sedation
most prominent side effect
b. Cases of respiratory depression and sleep apnea, some of which have been fatal have
been reported in children
i. Contraindicated in children < 2 y.o.
ii. For children > 2 y.o. lowest effective dose should be used and it should not be
used with other drugs that induce respiratory depression
iii. Should be avoided if there is a family history of respiratory depression, sleep
apnea
iv. Contraindicated in patients with lower respiratory tract symptoms including
asthma and COPD
c. Potential Limb Loss—Should not be given SC due to irritation of tissue, intraatrial
administration is contraindicated as it can cause intense vasoconstriction gangrene in
extremities limb loss
iii. PROCHLORPERAZINE (Compazine®, 1956)
1. A phenothiazine that can be administered orally and parenterally (oral, rectal, IM or IV). This is
not a very selective drug.
2. MECHANISM: ANTAGONISM AT MANY RECEPTORS GIVES ANTIEMETIC PROPERTIES
a. Dopamine (D2)
b. Muscarinic (M)
c. Histamine (H1)
d. Serotonin (5-HT)
31
UNIT 5 DRUG LECTURES
3.
4.
III.
e.
USES
a.
1-adrenergic
Antiemetic and antipsychotic (see “antipsychotics”)
i. It is usually reserved for nausea and vomiting resistant to other agents
SIDE EFFECTS DUE TO DOPAMINE ANTAGONISM
a. Extrapyramidal Effects – dystonias, parkinsonism
b. Hyperprolactinemia, drowsiness
OTHER ANTIEMETICS FOR CHEMOTHERAPY, RADIATION THERAPY, AND SURGERY
a.
b.
d.
APREPITANT (Emend®, 2003)
i. MECHANISM
1. Antagonist at substance P/neurokinin (NK1) receptors in vagal afferent/sensory fibers in the CNS
ii. USE
1. Augments effects of ondansetron and dexamethasone on acute and delayed emesis induced by
cisplatin
2. Acute phase: No emesis - 90% vs 79%
3. Delayed phase: No emesis - 81% vs 59%
iii. ADMINISTRATION
1. Oral – 1 hr before therapy and 1 per day with dexamethasone for 2 days FOSAPREPITANT (Emend®, 2008)
vi. Water soluble phosphate derivative of aprepitant administered by IV route
vii. Prodrug rapidly converted to aprepitant.
viii. Administered 30 min before chemo-therapy
DRONABINOL ( -9-Tetrahydrocannabinol, Marinol®, 1985) & NABILONE (Cesamet®, 1985)
i. Synthetic THC, active agent in Cannabis sativa
-20%
1. Active compound of marijuana
ii. USES
1. Useful antiemetic in chemotherapy when other agents are not effective
a. Agonist at CB1 cannabinoid receptors in vomit center
2. Appetite stimulant in cancer and AIDS patients
3. Potential for abuse - schedule III and II controlled substances respectively
DRUGS FOR PROPHYLAXIS OF MOTION SICKNESS
I.
II.
III.
IV.
Vomiting associated with motion sickness results from input to the emetic
center from the motion detector in the vestibule of the inner ear. This
signaling pathway appears to involve muscarinic and histamine receptors.
Thus, muscarinic antagonists and the older antihistamines that antagonize
both H1 and muscarinic receptors are useful for prophylaxis of motion
sickness.
a. Thought to be because of a descrepency between what you eyes
and your ears are telling you—on a boat your eyes are telling you
nothing is moving but your ears are going crazy feeling the boat
move in the water. That leads to vomiting.
SCOPOLAMINE (Trans Derm Scop®, 1979) a. Most efficacious drug for prophylaxis of motion sickness
i. Very similar to atropine
b. Has also been approved for prophylaxis of nausea and vomiting associated with surgery (1997)
c. Available as patch for topical absorption
d. Antiemetic effects seen after 4 hours and may last for 72 hours
i. So start the treatment prior to beginning vomiting (prophylactically)
e. PROBLEM: Has pronounced antimuscarinic side effects (see Cholinergics)
DIPHENHYDRAMINE, DIMENHYDRINATE (Dramamine®) AND PROMETHAZINE
a. Antihistamines with pronounced antimuscarinic effects are useful in prevention of motion sickness, but both have
pronounced sedative and other antimuscarinic effects, but less so than scopolamine.
b. Note, dimenhydrinate is simply the 8-Cl-theophyllinate salt of diphenhydramine
MECLIZINE (Antivert®) AND CYCLIZINE
32
UNIT 5 DRUG LECTURES
a.
b.
c.
Not used for allergies at all
Useful for prophylaxis of milder cases of motion sickness
ADVANTAGE: produce less sedation than diphenhydramine, and promethazine, etc.
d.
MOST IMPORTANT DRUG NAMES TO REMEMBER
I.
Diphenoxylate and Loperamide
II.
Dicyclomine
III.
Cisapride
IV.
Metoclopramide
V.
Prochlorperazine
VI.
Syrup of Ipecac
VII.
Ondansetron
VIII.
Scopolamine
IX.
Diphenhydramine and Dimenhydrinate
X.
Promethazine and meclizine
33
UNIT 5 DRUG LECTURES
DRUGS FOR INFLAMMATORY BOWEL DISEASES
I.
Many of these drugs are also discussed elsewhere. They are used to treat inflammatory bowel diseases (IBD), which
include ulcerative colitis, and Crohn’s Disease and used to treat chronic recurrent disease.
II.
GLUCOCORTICOIDS (BUDESONIDE, Entocort ®, 2001)
a.
b.
c.
d.
e.
f.
Glucocorticoids are some of the most important drugs for treating inflammatory diseases. Prolonged treatment is
avoided if possible due to severe adverse side effects.
i. Systemic glucocorticoids are used to treat acute CD exacerbations—induction of remission
1. PREDNISONE
2. PRENISOLONE
3. Methylprednisolone
4. Dexamethasone
BUDESONIDE is practically insoluble in water and has high topical activity. Its formulation and properties minimize
systemic effects.
i. Because it is inhaled it has low bioavailability (~10%). When the drug is absorbed from the GI tract t is
rapidly inactived in the liver (high first pass metabolism by CYP3A4) and the metabolites have ~ 1%
activity of budesonide so this drug has minimal systemic side effects
ii. Topical activity (inhaled) for mild-moderate Crohn’s Disease (also used for long term (prophylactic)
treatment asthma—usually along w/ long acting 2 agonist)
1. These diseases affect the colon & the terminal ilieum so these drugs are modified for delayed
release so they can reach the inflammation.
ABSORPTION
i. The granules in the capsule are enteric coated to prevent dissolution at pH < 5.5 (so wont dissolve in the
stomach)
ii. Formulation was designed to delay absorption until drug reaches ileum and ascending colon, but only
appears to work in small percentage of patients, time to peak plasma concentration varied among
patients between 30 and 600 min, therefore FDA has not allowed it to be promoted on this basis.
iii. Due to high first pass metabolism by CYP 3A4, bioavailability is about 9% after repeated dosing.
iv. The metabolites have < 1% the activity of the parent budesonide. Thus as in the treatment of asthma, this
low bioavailability reduces some of the systemic side effects associated with treatment with
glucocorticoids. (see below).
v. Problem: Much variability in “delay”
1. some patients absorbed very quickly and some did not
DRUG INTERACTIONS VIA CYP 3A4
i. Grapefruit juice – doubles systemic exposure to budesonide
ii. Ketoconazole increases AUC 8-fold
SIDE EFFECTS When compared with prednisolone:
i. Incidence of acne was decreased (15% versus 23%)
ii. Incidence of moon face was decreased (11% versus 37%)
SULFASALAZINE AND 5-AMINO-SALICYLIC ACID (5-ASA)
i. MECHANISM
1. Sulfasalazine is a prodrug, which is taken orally, and 90% passes to the colon where it is cleaved
by bacteria to release, 5-aminosalicylate (5-ASA or mesalamine) and sulfapyridine.
a. So the bacteria will activate the drug
2. 5-ASA is believed to be the active anti-inflammatory agent, 60-75% of which remains in the
colon.
a. Salicylic acid with an amino group on it probably blocks COX and 5’-Lipogenase
i. Probably inhibits COX-2, but exact mechanism is uncertain.
3. Poor partition coeff so it not absorbed by the gut (stays in the lumen) and it is activated by
bacteria so its selective in where it works
4. If it is absorbed Toxic effect: liver, pancreas, and kidney problems (10-45%)
a. One problem: The sulfapyridine part of the drug is toxic- liver, pancreas, and kidneys
ii. USES
1. Mild-moderate ulcerative colitis, maintenance of remission
2. Rheumatoid arthritis
34
UNIT 5 DRUG LECTURES
III.
IV.
V.
iii. NEWER DRUGS THAT RELEASE 5-ASA 1. Some patients do not tolerate sulfapyridine well and have hypersensitivity reactions. Newer
drugs have been designed to be better tolerated.
2. OLSALAZINE (Dipentum®, 1990) BALSALAZIDE (Colazal®, 2000)
a. Like sulfasalazine olsalazine and balsalazide are prodrugs taken orally and cleaved by
bacteria in the colon to release 5-ASA (selective in where it can be activated)
i. Olsalazine (Dipentum®, 1990) is split into two 5-ASA molecules
ii. Balsalazide (Colazal®, 2000) produces 5-ASA and 4-aminobenzoyl--alanine
which is “minimally absorbed and largely inert”—better tolerated & fewer side
effects
b. USES:
i. Mild-moderate UC
ii. Better than sulfasalazine for CD
3. MESALAMINE OR 5-AMINO-SALICYLIC ACID (5-ASA)
a. ORAL PREPARATIONS
i. (Asacol® (1992), Pentasa® (1993), Lialda® (2007), Apriso®, (2008))
ii. Delayed release preps deliver drug to terminal ileum and colon
1. Useful for maintenance therapy of UC and CD.
2. Or you can take the drug and formulate it or coat it so it has a slow
released & it doesn't release until you get further down the GI tract
iii. 28% absorbed –1.5-2 x more than with sulfasalazine
b. RECTAL SUPPOSITORIES/ENEMA
i. UC is a disease w/ inflammation that starts in the anus and works its way up; so
can administer this drug as suppository and bypass the absorption phase
ii. Rowasa®, (1987) enema for UC
iii. Canasa®, (2001) suppository for UC
INFLIXIMAB (Remicade®, 1998)
a. MECHANISM
i. Chimeric monoclonal antibody to tumor necrosis factor  (TNF).
1. Inflammatory diseases (IBD’s) and RA are very driven by this cytokine
2. Given every 8 weeks by IV and response is usually seen in 14 weeks
3. Messes w/ immune system so can have serious side effects
ii. Used in combo w/ methotrexate
b. GI USE
i. To reduce signs and symptoms and induce remission of active moderate- severe CD and UC, when
response to other treatments is inadequate
ii. Promotion of mucosal healing and closure of draining enterocutaneous (areas where the gut connects to
the outside world—like abdominal & perianal fistulas) and rectovaginal fistulas (rectum into vagina) and
maintaining fistula closure in patients with fistulizing Crohn’s disease
iii. Administered IV, at 0, 2 and 6 weeks then every 8 weeks. Response usually seen in 14 weeks or not at all.
iv. Effect diminishes upon repeat doses unless methotrexate is also used, due to generation of antibodies.
ADALIMUMAB (Humira®, 2002)
a. MECHANISM AND INDICATIONS
i. Human antibody against TNF
ii. Indications
1. Moderate-severe Crohn’s Disease and ulcerative colitis, when
response to other treatments is inadequate (also RA, AS,
psoriatic arthritis, psoriasis)
b. ADMINISTRATION AND USE
i. SC injection, 1x per 2 weeks (t1⁄2 = 2 wks)
ii. Used with or without methotrexate (MTX)
CERTOLIZUMAB, (Cimzia®, 2008)
a. MECHANISM AND INDICATIONS
i. Human Fab antibody fragment against TNF conjugated to pegol to prolong
half-life (14 d)
35
UNIT 5 DRUG LECTURES
ii. Crohn’s Disease (also RA)
b. ADMINISTRATION AND USE
i. SC injection, 2x 200 mg every 4 weeks (t1⁄2 = 2 wks)
ii. Used with or without methotrexate (MTX)
CROMOLYN SODIUM (Gastrocrom®)
a. MECHANISM
i. Prevents activation of mast cells (see notes on Asthma Drugs)
ii. Inhale it in the lungs and what gets in the gut doesn't get absorbed
b. USE
i. Treatment of ulcerative colitis, systemic mastocytosis
ii. Taken orally, very little is absorbed; has local effect on the colon
iii. 98% is excreted unchanged in the feces.
VI.
MOST IMPORTANT DRUG NAMES TO REMEMBER
I.
Sulfasalazine,
II.
Mesalamine,
III.
Balsalazide,
IV.
5-aminosalicylate (5-ASA)
V.
Cromolyn Sodium
VI.
VII.
VIII.
IX.
Infliximab
Prednisone
Prednisolone
Budesonide
DRUGS FOR DIABETES

Insulin is about dealing with the stuff we put down the GIT (protein, carb, fats)
o We use AA to make proteins which are important for muscle enzymes & energy (but we don’t store proteins for
energy) we either use them or oxidize them directly
o FA are important for structurally in membranes, in making steroidal hormones, PG, LK, and other signaling
molecules. When we esterify them to glycerol we have something that interacts w/ water and eliminates water?
They are very important store of energy--especially when fasting between meals. And we can store a lot of fats
o Carbs are very water soluble (lots of OH groups) so to store these is much more difficult. We store it as glycogen. It
is used as immediate energy b/c it doesn’t store well and we store the excess in liver and muscles.
DIABETES MELLITUS
 Diabetes mellitus results from failure of insulin to exert its normal metabolic effects
 FoodGlucoseInsulin Glucagon
o Glucose triggers release of insulin
o Insulin drives the uptakes of glucose, FA, AA into tissues from the blood
o Glucagon has the opposite effect of insulin
o  Insulin leads to…
 Rapid glucose FFA, AA uptake into tissues
 If these are not taken up into tissues they can be excreted in the urine and cause polyuria due to
osmotic diuresis. If this get severe enough it can cause death
o 180L of fluid (this is the GFR) are filtered through the kidney each day and from this we
must reabsorb all of the glucose. There is a limit to that ability so when you have 
insulin you have  glucose in the blood (and if you have >180mg/dl in the blood the
system gets saturated and you get glucose in the urine) in the urine it causes water to
come out in urine due to osmotic diuresis. Ketoacidosis is also caused by  insulin
o osmotic diuresis when too much glucose is in the blood b/c not all of it is taken up when
the levels reach a certain limit so it's osmotically active and draws water out of the
tissues
 Metabolic effects
 Glycolysis --stimulates its use as energy!
 FA oxidation --we don't need to use the fats as energy
 AA oxidation --we don't need to break these down for energy
 Glycogen synthesis --in order to store the glucose
 Glycogenolysis  --we have enough glucose so we don't need to break down glycogen for glucose
 Gluconeogenesis --don't to need to make glucose from other things because we have enough
36
UNIT 5 DRUG LECTURES




Two major classifications
o Type 1, (Insulin-dependent, IDDM, “juvenile onset”)
 Affects about 0.5% adults in USA
 Autoimmune destruction of insulin-secreting cells ( cells) in the Islets of Langerhans of the pancreas
(95% of cases)-- so they dont produce insulin
 Not associated with obesity - often below normal weight
 So think about the problem you have when you dont have this b/c it stores fats, carb, AA, etc so
you can become pretty thin.
o Type 2, (Non-insulin-dependent, NIDDM, “adult onset”)
 Patient is resistant to the effects of insulin. Tissues don't respond to the insulin there properly. This is
closely related by obesity
 Affects about 5% (24 million) adults in USA
 10x's more common than type 1
 Cause uncertain, but often associated with obesity
“Type 1” DIABETES
o Progressive loss of b cells leads to decrease in insulin secretion and elevation of blood glucose
 By 30 years of age, secretion essentially ceases-- they dont produce anymore insulin
 Insulin administration necessary for survival-- if they dont have it they will die
o Hyperglycemia leads to osmotic diuresis-- losing water in urine
o Ketoacidosis (DKA): v. low insulin + high glucagon leads to oxidation of fatty acids and amino acids
 They starts using the fats as an energy source so we oxidize them which generates acetyl co-A and we run
out of Co-A so we start making a lot of ketoacids (acetoacetate and  -hydroxybutarate)
 ketoacids smell like rotting apples
 Na, K salts of ketoacids leads to diuresis, K depletion
 Remember  agonists cause muscles to take up potassium
 Polyuria, polydipsia, vomiting, pH hyperventilation
 acidosis causes an increase in respiration to remove the CO2 from the lungs
o Hyperosmolar dehydration, shock, coma and death – but DKA symptoms provide early warning
“Type 2” DIABETES
o death rate from this is higher than in type 1
o Target cells become resistant to insulin
 Blood glucose rises
 Insulin secretion rises to compensate, but the concentration is less than would be found in a normal
individual with the same level of glucose. Why?

 cells become less sensitive to glucose
o Osmotic diuresis/Polyuria
 Dehydration “hyperglycemic hyperosmolar state”
 BP↓  HR↑, mental confusion, lethargy, coma  death in > 50% cases - few warning signs –Why?
 Insulin secretion↓, but not enough to cause ketoacidosis – so, NO vomiting, abdominal pain, or
hyperventilation
PROBLEMS ASSOCIATED with ELEVATED BLOOD GLUCOSE
o Osmotic diuresis - when glucose conc. > 10mM
 Na+/glucose cotransporters in kidney are saturated and kidney can no longer reabsorb it all
o Microangiopathy
 damage to the small BV that deliver blood to all the tissues
 narrowing of capillaries due to thickening of capillary basement membrane reduces blood flow to tissues
 Retina (blindness)
 kidney (kidney failure)
 nerves (neuropathy)
o diabetic gastroparesis--damage done to the vagas n.
 extremities (gangrene, amputations)
o Macrovascular disease
 Atherosclerosis (MI, stroke)
o Why? Non-enzymatic glycation of proteins?
37
UNIT 5 DRUG LECTURES



GLYCATION OF PROTEINS
o It isn’t very well understood. One thing glucose can do is glycate proteins
o Glucose is an 6C aldehyde and the OH can attack COH to produce a ring. Aldehyde and keto groups likes to react
w/ N-terminal -NH2 or epsilon-NH2 groups on lysine to produce a Schiff base that can be reversed by adding
water. Can undergo a rearrangement to make a diff 6 member ring called an Amadori product which is very stable
and this can get stuck in BV’s and can start causing all sorts of damage can react w/ Hemoglobin, LDL, collagen,
fibronectin, crystallins
 Linear form of glucose (aldehyde) can react with N-terminal a-NH2 groups or e-NH2 groups on lysine
o Glycation of HbA to HbA1c is irreversible - assayed every 3 months to monitor control of blood glucose
 The stable amadori product can accumulate in proteins that hang around a lot time (like Hemoglobin, LDL,
collagen, fibronectin, crystallins). When it reacts w/ Hb it forms HbA1c
 This measurement gives your average glucose level over the past couple weeks
o Control: HbA1c < 6.5% optimal, > 10% poor (means glucose isnt being well controlled)
INSULIN
o produce by  cells in pancreas
o most important drug to treat DM esp type 1
o Made as a single chain and stored in vesicles (waits to be secreted from the cell)
 before it gets secreted it gets cleaved at two sites by proteases which release and A chain, a B chain and a
C peptide
 Mature insulin has 51 amino acids
o 21 in A chain
o 30 in B chain
 The B chain is glycine, proline, prailine—this plays a key role in functioning
o “C-peptide” is removed to yield the active hormone
 net negative charge which keeps it in solution
o Insulin is stored as a hexameric complex containing 2 Zn2+ ions
 Zn forms a complex w/the insulin and when you take off the C chain it forms a hexomeric structure which
is not soluble. If you up the zinc a bit it's insoluble so easily stored in these vesicles
o Dissociates to active monomers upon release/dilution
SECRETION of INSULIN
o While fasting, insulin is normally secreted at a low basal rate
o Secretion is stimulated by glucose, gut hormones (also mannose, leucine, arginine, vagus)
 Glucose enters -cell  elevation of ATP, because glucokinase has high Km - sensitive to glucose conc.
 ATP blocks K+ channels  membrane depolarization  opening of voltage-dependent Ca2+ channels
 Elevation in cytosolic Ca2+ triggers secretion
o Compare to the mechanisms of neurotransmitter release and contraction of smooth muscle
o Glucose comes in (like after a meal) and the GLUT2 receptors on the pancreatic -cell allow glucose to get into the
cell (this is how it detects how much glucose is present) voltage gated Ca channel depolarization causes Ca channel
to open
o K channel allow K to flow out of the cell in order to maintain a negative resting membrane potential but when
glucose comes in it is converted by glucokinase into G-6-P which is fed into glycolysis in the mitochondria to
produce ATP. ATP blocks the K channels which creates a positive membrane potential (makes the inside of the cell
more positive so it is more equal to the positive extracellular environment) or in other works causes the
membrane to depolarize.
 Glucokinase has a high Km—so low affinity for glucose
 Only phosphorylates glucose if it is in high
amounts
 Found in liver & pancreas
 In  cells of pancreatic islets it serves as a
glucose sensor to control insulin release and
also controls the glucagon release by the 
cells
 In hepatocytes glucokinase responds to
changes of ambient glucose levels by
increasing or reducing glycogen synthesis
38
UNIT 5 DRUG LECTURES
 Only substrate is glucose
Hexokinase has a low Km b/c of a high affinity for glucose (and other hexoses) at low concentrations (they
are inhibited by their product G-6-P)
 This one is found in all tissues
o The depolarization of the cell membrane causes the Voltage gated calcium channel to open which allows the high
extracellular concentration of Ca to come into the cell.  intracellular calcium causes…
 Vesicles filled with insulin to fuse w/ membrane and release the insulin
 There are other ways to stimulate an  in intracellular calcium
 Stimulation of Muscarinic (M3) receptors by the vagas nerve will  intracellular calcium
  in calcium is amplified by an  in cAMP so things that  cAMP will  Cai
o G receptors on the  cell are activated glucagon like peptide 1 (GLP-1) and  cAMP
 An  in glucose causes release of GLP-1 by the gut
o SNS stimulation of 2 receptors (which  cAMP) and 2 receptors (which  cAMP) so
SNS doesnt play a huge role in insulin release b/c these two kind of cancel each other
out
o When glucose is absorbed it is taken up into the portal circulation
(along w/ GLP-1, etc) It travels in the blood going through the
pancreas which first sees the -cells. The  glucose signals the 
cells to secrete insulin and inhibits the  cells of the pancreas from
secreting glucagon (which is involved in raising blood glucose but we
have enough so we don't need this)
o After the pancreas the recently secreted insulin and remaining
glucose goes through the liver (this organ sees the most insulin than
any other organ). Half of insulin is metabolized after being taken up
by cells (like first pass metabolism) and half of it continues on into
the systemic circulation.
INSULIN: MECHANISM of ACTION in LIVER
o Insulin comes in and binds to the insulin receptor (which is a
tyrosine kinase receptor) and has many effects:
 stimulates the oxidation of glucose coming in from
the GLUT2 receptor (not rate limiting in the liver) to
produce glycogen (can store 100g)
 also causes storage of fats
 stimulates the uptake and transport of amino acids
as well as protein synthesis from the amino acids
coming into the cells (just ate a meal)
 inhibits
 gluconeogenesis
 FA oxidation and ketogenesis
 Amino acid oxidation
 Protein catabolism
 * b/c were in a building mode!--using glucose as the major source of energy while it is available
INSULIN: MECHANISM of ACTION
o External membrane receptor (a subunit) - linked to internal tyrosine kinase (b subunit)
o Phosphorylation of proteins including other kinases leads to activation of glucose metabolism – leads to immediate
effects
o Stimulates protein synthesis – delayed effects
o Insulin and receptors are internalized
o Excessive activation, e.g. in insulinoma, obesity, leads to down-regulation of receptors
EFFECTS of INSULIN
o LIVER
 Stimulates glycogen synthesis, glycolysis
 Inhibits glycogenolysis, gluconeogenesis
 Stimulates synthesis of fatty acids and fat from excess glucose




39
UNIT 5 DRUG LECTURES
 Inhibits oxidation of fatty acids and amino acids and hence inhibits ketogenesis
 Promotes amino acid transport and protein synthesis
 Inhibits protein catabolism, and urea synthesis
o Note: As in -cells, glucose metabolism in liver is not limited by entry of glucose into the cell. Contrast with muscle
and adipose tissue.
 INSULIN MECHANISM: MUSCLE AND FAT TISSUE
o Insulin comes into skeletal muscle and adipose tissues and binds to the
insulin receptor tyrosine kinase. W/o insulin glucose has no transporter
to get into these cells
o Insulin binding to its receptor stimulates
 GLUT4 (NOT GLUT2 like in the liver and pancreas) receptors to
 on the CM so the glucose can get into these cells
 This is the rate limiting step in muscle and adipose
tissue
 Insulin regulates the transport of glucose and FA
allowing them to go into cells and in the muscle
 The receptors are recycled and are taken up into vesicles once insulin stimulation is over
 Once glucose can get into the cell the insulin effects are oxidation of glucose into glycogen (can store up
to 400g in muscle)
 Also Storage of fats (they com in through the FATP)
o stimulates the enzymes on the outside to cause break down so the fats can get STORED
in the cell and stop the breakdown of the fats inside of the cell
 EFFECTS OF INSULIN IN MUSCLE AND FAT
o MUSCLE
 Promotes glucose transport by insertion of glucose transporters (GluT4) and glycogen synthesis
 Promotes amino acid transport and protein synthesis
o ADIPOSE TISSUE-- insulin tends to induce weight gain
 Insertion of glucose transporters (GluT4)
 Stimulates glycolysis for conversion of glucose to fat
 Increases rate of fatty acid import from blood (FATP)
 Increases rate of triglyceride (fat) synthesis
 Intracellular lipolysis; endothelial lipolysis
o Net effect is decreased plasma free fatty acids, increase in amounts of stored fat  weight gain
 INACTIVATION of INSULIN
o Insulin inactivated in liver and kidney, after internalization of insulin-receptor complex
 Disulfide bonds cleaved by glutathione followed by proteolysis of peptides
 b/c receptors are insulin bound and the receptors are metabolized so insulin gets broken down too
o Insulin secreted by pancreas enters hepatic portal vein
 Liver clears 60%, (50% removed in first pass)
 Kidney clears 35-40%, (filtered and then reabsorbed)
 Percentages are reversed for subcutaneous insulin
 b/c insulin isnt going through liver first because it isnt coming from the pancreas
 Half-life of circulating insulin 3-5 min
 short half life b/c its concentrations in the blood are controlled by glucose levels. You dont want
the muscles to suck up glucose when you dont have lot. You want insulin levels to parallel
glucose or you'll become hypoglycemic
HYPOGLYCEMICS
 INSULINS
o for type 1 and type 2 diabetes
 SULFONYLUREAS and MEGLITINIDES
o for type 2 diabetes only; stimulate release of insulin
 INSULINS
o For types 1 and 2 diabetes
 Insulin Lispro (Humalog®)
40
UNIT 5 DRUG LECTURES
o
o
o
 Regular Insulin (Humulin® R)
 Zinc (Lente) Insulin (Humulin® L)
 NPH Insulin (Humulin® N)
 Ultralente Insulin (Humulin® U)
 Insulin Glargine (Lantus®)
Many formulations are available with different
 Time of onset of action and duration of action
 Solubility
 Sources
 Purity—most insulins now are human so all are pretty pure and now this is a minor different between the
different types of insulin
Different formulations are used to mimic normal physiological fluctuations of plasma insulin
 Insulin normally follows changes in glucose
 Normally Insulin levels rise with a meal and insulin has a short half life
 Most prominent feature are “post-prandial” peaks
Short And Intermediate Acting Insulins

o

If you abs quickly it peaks quickly and you see a decay because of its half life
o This mimics rise in glucose that you see after a meal
o Short acting or ultra short acting insulin
 if you abs slowly then it will rise more slowly and the peak drops and it doesn't come down in the
same manner as the half life
o provide low levels of insulin during periods of fasting
o Intermediate acting
 Rapidly absorbed insulin administered shortly before a meal peaks at about the same time as
glucose and its decline follows glucose
 Slowly absorbed insulin has a delayed onset of action a lower peak and a longer duration of
action suitable for controlling fasting blood glucose
Long Acting Insulins





Rises until rate of infusion= rate of elimination (steady state)—poorly soluble, not in solution and
are absorbed at a pretty steady rate
SC administration of insulin that is not in solution can lead to a constant rate of absorption (zeroorder absorption), which mimics a continuous IV infusion
Under these conditions, plasma insulin reaches a steady state (absorption rate = elimination rate)
and no peak is seen
Provides control of fasting plasma glucose (generated by gluconeogenesis by liver)
41
UNIT 5 DRUG LECTURES


SHORT-ACTING INSULINS
o REGULAR INSULIN (Humulin® R)—available OTC
 Zn2+ insulin solution (hexamers, and dimers)
 Released moderately quickly from SC sites
 Onset of action:
30 min
 Peak plasma concentration:
1-2 hr
 Duration of action:
5-8 hours
 Must be administered 30-60 min before eating—because you want insulin concentration to
follow the glucose concentration (so the 30-60 min before meal allows for the lag period due to
absorption)
 ONLY TYPE that can be administered IV (or IM) in an emergency situation – e.g. diabetic coma
 Dissociates rapidly when diluted into blood stream to produce the active drug
o Make sure its in solution when you inject it!
 Onset < 15 min, duration 30-60 min, t1/2 = 9 min
ULTRA-SHORT-ACTING INSULINS
o INSULIN LISPRO (Humalog®, 1996)
 Sequence of 2 amino acids -B pro28-lys29 – switched
 The 3rd amino acid is threonine
 Inhibits formation of hexamers w/ Zn - no dissociation necessary
 Released very rapidly from subcutaneous sites
 Onset of action:
5-15 min
 Peak plasma concentration:
30-90 min
 Duration of action:
3-4 hours
 Should be administered 0-15 min before a meal versus about 30-60 min for regular insulin
 Lispro Versus Regular Insulin

o
Soluble, therefore may be administered IV, but works NO more rapidly than regular insulin,
which is cheaper
o It disappears quicker and that's an advantage b/c if the insulin is there longer than the
glucose then  risk for hypoglycemia
 Sequence of 2 amino acids -B pro28-lys29 - switched
 Inhibits formation of hexamers - no dissociation necessary
 Released very rapidly from subcutaneous sites
 Onset of action:
5-15 min
 Peak plasma concentration:
30-90 min
 Duration of action:
3-4 hours
 Should be administered 0-15 min before a meal versus about 30-60 min for regular insulin
 Soluble, therefore may be administered IV, but works no more rapidly than regular insulin, which is
cheaper
INSULIN ASPART (NovoLog®, 2000)
 Similar to lispro
 Amino acid – B-chain pro28 replaced by aspartate (net positive charge  net negative charge)
 Inhibits formation of hexamers - no dissociation necessary
 Released very rapidly from subcutaneous sites
 Onset of action:
5-15 min
42
UNIT 5 DRUG LECTURES
o
 Peak plasma concentration:
40-50 min
 Duration of action:
3-4 hours
 Should be administered immediately - 0-10 min before a meal versus about 30-60 min for regular insulin
INSULIN GLULISINE (Apidra®, 2004)
 Amino acid - lys29 replaced by glutamate and asn3 replaced by lysine
 Inhibits formation of hexamers - no dissociation necessary
 Released very rapidly from subcutaneous sites
 Onset of action:
5-15 min
 Peak plasma concentration:
55 min
 Duration of action:
3-5 hours




 Regular insulin is dropping glucose lower than the Apidra (seen in the graph to the left)
 Bigger peak seen in glucose on the graph to the right with regular insulin
 Should be administered from < 15 min before a meal to < 20 min after starting a meal
INTERMEDIATE-ACTING INSULINS
o NPH or Isophane INSULIN SUSPENSION (Humulin® N) – available OTC
 NPH = Neutral Protamine Hagedorn and contains 1 protamine () protamine is + charged protein that binds
to DNA but here it binds to the hexameric complex) per Zn2+ insulin hexamer  crystals
 So now you have a suspension and not a solution which causes slower absorption
 Released slowly from SC sites as the protamine is digested
 Onset of action:
2-4 hr
 Peak plasma concentration:
6-12 hr
 Duration of action:
16-24 hours
 Not useful for emergency situations
 Can be mixed with REGULAR INSULIN, etc, since it contains no free Zn2+, e.g. Humulin 70/30®
 1 protamine per hexamer so not a lot of protamine flying around and insulin is pretty well bound
so if you mix you wont have protamine ppt out the free insulin—pretty tight complex
o ZINC (LENTE) INSULIN (Humulin® L, OTC)
 Zn2+ insulin suspension –discontinued 2005
it is amorphous, due to higher level of Zn2+ than regular insulin - contains excess free Zn2+
 Essentially same kinetics as NPH insulin
 Should not be mixed with regular insulin, since extra zinc can slow absorption of regular insulin
INSULIN MIXES—always use NPH insulin as the longer acting insulin
o Humulin® 70/30 and 50/50 (1989)
 NPH insulin (suspension) and regular insulin (soluble) form a stable mixture – available OTC
o NPH insulin (suspension) and insulin lispro (soluble) can be mixed, but mixture is unstable (so not ideal) – it will
become “NPH lispro” suspension + regular (soluble)
 So mix and use right away!
o Humalog® Mix 50/50 and 75/25 (1999)
 A mixture of insulin lispro protamine suspension (NPL insulin) and soluble insulin lispro
o NovoLog® Mix 70/30 (2001)
 A mixture of insulin aspart protamine suspension (NPA insulin) and soluble insulin aspart
LONG-ACTING INSULINS
o INSULIN GLARGINE (lysine and arginine) (Lantus®, 2000)
 Modified human insulin: A21 (NG), B31,32 (-- RR)
 Makes it not soluble unless the pH <4
 N= asparagine
 Most frequently prescribed
43
UNIT 5 DRUG LECTURES
 Zero order absorption
Contains Zn2+ and is soluble at pH 4.0, but forms microprecipitates at pH 7 after SC injection
 And gives a very continuous absorption when it ppt (will be zero order)
 Released very slowly from SC site as it dissolves
 Onset of action:
2-3 hr
 Peak plasma concentration:
no peak - plateau
 Duration of action:
24+ hours
 Administered once daily at bedtime
 B/c you need low levels of insulin during the period of long fasting when you sleep
 Regular or lispro insulin given prior to meals
 Should not be mixed with other insulins
  rate of lispro absorption b/c the solution is at a pH <4 so DO NOT MIX
o INSULIN DETEMIR (Levemir®, 2005)
 Modified human insulin: B30 T removed, B29 lysine has 14 C fatty acid (myristic acid) amide-linked to
epsilon-NH2
 FA promotes self aggregation and albumin binding (98%)
 Insulin w/ FA attached—they aggregate and slow the absorption and when it gets into the tissue
it binds to albumin and provides a reservoir for this insulin
 Released very slowly from SC site due to low solubility
 Onset of action:
1-2 hr
 Duration of action:
24+ hours
 Most reproducible effect of intermediate and long-acting insulins
 Administered 1 or 2x daily, bedtime and before b’fast
 Should not be mixed with other insulins
CONTINUOUS SC INSULIN INFUSION
o Alternative to multiple injections of different insulin formulations
o Infusion pump
 Uses rapidly absorbed soluble (rapidly absorbed insulins) insulins, i.e. lispro, aspart and glulisine
 Basal infusion
 Bolus amounts can be infused prior to meal; amount is based on carbohydrate intake and
physical activity
 Provides most effective control of glucose and is best mimic of physiological insulin fluctuations
 Best way to control glucose levels in the blood
 Unit is replaced every 2-3 days
Summary: Types of Insulin
Prototype Onset hr Peak hr Duration hr #Perscriptions(class)
Lispro
0.1-0.25
1
3-4
7.6M
Regular
0.3-0.7
2-4
5-8
-NPH
1-2
6-12
18-24
2.1?
70/30 Mix
4.1
Glargine
4-6
plateau
20-36
14.4
o Administered by SC injection, abdomen for most rapid absorption
o ONLY REGULAR INSULIN can be administered IV (or IM) in emergency
INSULINS: SIDE EFFECTS
o Weight gain
o Hypoglycemia - most important
o Lipodystrophies at injection sites
 Effect lipid metabolism—atrophy of adipose tissue (correct w/ liposuction or changing the site of
injection)
 Lipohypertrophy - correct with liposuction
 Lipoatrophy - immune reaction to impurities? - rare with newer purified human insulin preps
o Allergic reaction, can be local or systemic but is less common with human insulin




44
UNIT 5 DRUG LECTURES
K+-CHANNEL BLOCKERS—stimulate insulin release
 SULFONYLUREAS
o For type 2 diabetes only
 1ST GENERATION
 TOLBUTAMIDE (Orinase®, 1957)
 CHLORPROPAMIDE (Diabinese®, 1958)
 ACETOHEXIMIDE (Dymelor®, 1964)
 TOLAZAMIDE (Tolinase®, 1965)
 2ND GENERATION (not many differences in their properties but diff in potency—need less of the newer
drug)
 GLYBURIDE (DiaBeta®, 1984)
 GLIPIZIDE (Glucotrol XL®, 1984)
 GLIMEPIRIDE (Amaryl®, 1995)
o MECHANISM: SULFONYLUREAS
These drugs block the K channel which causes
depolarization and Ca channel to open and
insulin gets released. You don't need glucose for
this drug to stimulate insulin release so this drug
can produce hypoglycemia (when no glucose is
around)

o
o

Stimulate insulin release from -cells in pancreas
o K+(ATP) channel blockade lowers cell membrane potential
o Opens voltage-gated Ca2+ channels
o Increase in cytosolic Ca2+ activates insulin secretion
 Remember: drugs that OPEN K+ channels in vascular s.m., such as
o Diazoxide (Proglycem®)
o Minoxidil
o and HCTZ
 ALL can lead to hyperglycemia
 Insulin  inhibition of glucagon secretion by  cells in Islets  serum glucagon
1st Generation Sulfonylureas
 CHLORPROPAMIDE
 Longest half-life 25-60 hr
o Effects wont go away quickly –take about 10 days to get it all out of the system
 DM and DI b/c Promotes action of ADH “SIADH” in the kidney, so tx of central DI
o Hyponatremia is a side effect b/c of the  water reabsorption
 TOLBUTAMIDE
 Shortest t1/2—5 hr
o Effects will go away quick
 Safest in elderly patients
2nd Generation Sulfonylureas
 Examples
 GLYBURIDE (DiaBeta®, 1984 Glucovance®) t1/2 = 10 hr
 GLIPIZIDE (Glucotrol XL®, 1984)
t1/2 = 2-4 hr
o XR formulation to compensate for its short half life
 GLIMEPIRIDE (Amaryl®, 1995)
t1/2 = 9 hr
 No more efficacious than chlorpropamide, but
 Much more potent – only major difference
 When first became available were associated with severe hypoglycemia and some deaths
45
UNIT 5 DRUG LECTURES



Administered once per day before breakfast
 All are available as generics
 Glucotrol® XL - compensates for short half-life
MEGLITINIDES
o REPAGLINIDE (Prandin®, 1997) & NATEGLINIDE (Starlix®, 2000)
 MECHANISM:- bind to sulfonylurea receptor—block K channel and stimulate release of insulin
 Rapid onset of action
 Short duration of action (t1/2 = 1 hr, 1.5 hr)
 Mimic physiological insulin profile
 Administered up to 4x or 3x per day before each meal
K+(ATP) CHANNEL BLOCKERS: Tachyphylaxis: “Secondary Failure”
o Resistance to the effect of sulfonylureas and repaglinide can develop
o POSSIBLE CAUSES
 Real tachyphylaxis due to sustained levels of drug?
 Failure to respond due to progression of disease
 Decreased number of  -cells—so  insulin can be released
 Decreased muscle mass-- ability to take up glucose
 Decreased physical activity—regulates insertion of glucose transporters in skeletal muscle
ADVERSE EFFECTS OF HYPOGLYCEMICS
 WEIGHT GAIN
 HYPOGLYCEMIA - most common
o Causes
 Too high dose - insulin, sulfonylureas, repaglinide
 Delay in eating
 Unusual physical exertion
o Symptoms- **if no “hypoglycemic unawareness”—normally people know when they are becoming hypoglycemic
because of these signs
 **SNS: Tachycardia, palpitations, sweating, tremors
 **PNS: Nausea, hunger (to help maintain blood glucose)
 CNS: Mental confusion, bizarre behavior, seizures, coma
 Hypoglycemic unawareness is caused by prolonged hypoglycemia (if your hypoglycemic for a day, the next
day the symptoms will lessen)
 Reversible if you maintain normal glucose levels for a while
o Treatment – may need to be prolonged
 If conscious:
Glucose, orange juice, etc.
 If unconscious: IV glucose if available (20-50ml 50%)
Glucagon (SC or IM)
 GLUCAGON (Glucagon®, 1960)
o Peptide hormone, pancreas a-cells, rDNA E.coli
o USE
 Indication: severe hypoglycemia
 Administration: SC, IM or IV, follow with carbs
o MECHANISM
 Effects are opposite of insulin – mobilizes glycogen
 Effects not blocked by b-blockers, cf. epinephrine
 Limitation: glycogen stores must be available…
 Not useful in starved patients, adrenal insufficiency
 Less effective in type 1 than type 2 diabetes
o Adverse Effects – few, nausea, vomiting (GI motility)
 “ANTIHYPERGLYCEMICS”
o For type 2 diabetes
 BIGUANIDES
 THIAZOLIDINEDIONES
46
UNIT 5 DRUG LECTURES
o
 GLUCOSIDASE INHIBITORS
BIGUANIDES
 For type 2 diabetes
 PHENFORMIN removed from market 1977
 METFORMIN (Glucophage®, 1994) 50M ps
 METFORMIN + Glyburide (Glucovance®, 2000)
 METFORMIN + Rosiglitazone (Avandamet®, 2002)
 METFORMIN + Sitagliptin (Janumet®, 2007)
 METFORMIN + Linagliptin (Jentadueto®, 2012)
 METFORMIN (Glucophage®, 1994)
 MECHANISM
 Promotes actions of insulin (especially in the liver—insulin in the liver inhibits gluconeogenesis) DOES NOT induce insulin release - most useful in insulin resistance
 Inhibits hepatic gluconeogenesis and enhances peripheral glucose uptake – exact mechanism
unclear
 Administered with (AM and) PM meals
o So need insulin and glucose for it to work
 ACTIONS
 Decreases fasting hyperglycemia
 Decreases post-prandial hyperglycemia
 Very rarely produces HYPOGLYCEMIA - Why?
 METFORMIN (Glucophage®, 1994)
 USE
o Treatment of obese, insulin resistant patients (just for type 2 diabetes)
o Can also be used with sulfonylureas (glyburide + metformin = Glucovance®), acarbose,
“glitazones” etc. if either drug alone provides inadequate control
 ELIMINATION - IMPORTANT
o Water soluble - not metabolized by liver
o Kidney eliminates it (99.9%, 90% active secretion by OCT2, MATEs)
 Diabetics and elderly are most common to have  renal function
o In patients with impaired kidney function, metformin may accumulate  risk of adverse
effects 
 SIDE EFFECTS
o Transient GI problems (NVD) in 20-30% patients, cause for discontinuation of treatment
in 3-5%
o  May cause some weight loss - drug-induced anorexia
 b/c normally type 2 diabetics are over weight
o Can impair vitamin B12 and folate absorption, very rarely leads to pernicious anemia
 ADVERSE EFFECTS - Lactic acidosis
o Medical emergency - frequently fatal (50% cases)
o Led to withdrawal of prototype phenformin in 1977
o Rare with metformin, 3 per 100,000 patient-years
o Renal function - needs to be monitored b/c of the potential fatal side effects
 Cr concentrations in the blood monitor renal function
 METFORMIN: Monitoring/Precautions
o Check renal function at least annually
 Serum creatinine must be < upper limit of normal
o Elderly patients
 Monitor kidney function more frequently
 Titrate dose to determine minimum effective dose
 Do not use maximum approved dose
o Drug interactions
 Cationic drugs compete for secretion in tubule
 IV iodinated contrast materials impair kidney function
47
UNIT 5 DRUG LECTURES


Used in Urograms, cholangiography, angiography, and computed
tomography (CT) scans
 So stop taking metformin when undergoing these procedures
o Surgical procedures ( renal function)
 Suspend metformin therapy
 Restart only when patient’s oral food and fluid intake has resumed and renal
function is normal
o Contraindications
 Congestive heart failure or MI - hypoxic states
 Also other hypoxic states that promote lactic acidosis
o NADH to reduce pyruvate to lactate so  lactate
 Liver disease
 Liver is important for lactate metabolism so you can get impaired
removal of lactate
 Excessive alcohol consumption
 Potentiates effect of metformin on lactate metabolism
THIAZOLIDINEDIONES “TZDs” or “glitazones”
o For type 2 diabetes
 TROGLITAZONE (Rezulin®, 1997-2000 RIP)
 ROSIGLITAZONE (Avandia®, 1999),
 rosiglitazone + metformin (Avandamet®, 2002)
 PIOGLITAZONE (Actos®, 1999)
pioglitazone + metformin (ActoPlus Met®, 2005)
o MECHANISM - requires insulin
 This is a long lipid soluble substance (metformin is a water soluble substance)
 Promote actions of insulin in adipose tissue and muscle (working at diff site than metformin so can
combine w/ metformin) - DO NOT induce insulin release
 Rarely produce hypoglycemia
 Agonists for the peroxisomal proliferator-activated receptor gamma (PPAR γ), which regulates
transcription (protein synthesis) of insulin-responsive genes, e.g. lipolysis, glucose transport,
utilization
 Takes hours to see effects just like glucocorticoids
 Administered 1 or 2/day independent of meals, Why? Because you don't need to tie in with meals
o ACTIONS
 Decrease post-prandial hyperglycemia
 Decrease fasting hyperglycemia
 Very rarely produce HYPOGLYCEMIA
o USE
 Can be used alone or in combination with metformin, sulfonylureas and insulin(?)
o SIDE EFFECTS
 Weight gain, e.g. 1.2-3.5 kg in 26 week period
 More weight gain than insulin or sulfonylureas
 With metformin (can counteract some of the weight gain) weight gain is decreased to 0.7-2.3 kg
 Edema (5%)
o PHARMACOKINETICS
 Administered orally and rapidly absorbed
 Undergo extensive metabolism in liver—b/c big and lipid soluble
o TOXICITY
 Severe liver toxicity: Troglitazone removed from market in 2000, due to 63 deaths and 90 reports of liver
failure
 Not seen with new drugs, but periodic monitoring of liver enzymes is recommended
 Risk of fractures increased in women (3/2007)
 Hand, wrist, forearm, feet, ankle, fibula, tibia
 1.9 versus 1.1 per 100 patient years—double the rate of bone fractures
48
UNIT 5 DRUG LECTURES
 Risk should be considered when women are treated with these drugs
Heart failure: All TZDs – BB warning (8/2007)
 Need to monitor patient for symptoms
 Contraindicated in class III and IV heart failure
 Cardiac ischemia, angina, MI: Only rosiglitazone– warning added to black box (11/2007)
 Analysis of 42 clinical trails indicated increased risk vs placebo
o Insulin, nitrates increase risk – use not recommended
 3 studies vs other drugs results inconclusive
 FDA reviewed data from new study 7/2010
o Label updated 2/2011…
 Rosiglitazone Cardiovascular Risks (2/3/2011)
 Labels now state that rosiglitazone and rosiglitazone-containing
medicines should only be used:
o In patients already being treated with these medicines
o In patients whose blood sugar cannot be controlled with
other anti-diabetic medicines and who, after consulting with
their healthcare professional, do not wish to use pioglitazonecontaining medicines (Actos®, Actoplus Met®, Actoplus Met
XR®, or Duetact®).
 Why not pick pioglitazone?
o FDA reviewing preliminary safety information on Actos (pioglitazone), 9/17/2010
 The FDA announced it had begun a safety review of the diabetes drug Actos
(pioglitazone), after receiving preliminary results from a long-term
observational study designed to evaluate the risk of bladder cancer associated
with use of this drug.
 “…5-year data from an ongoing, 10-year observational study … showed no
overall association between Actos exposure and risk of bladder cancer.
However, there was an increased risk of bladder cancer in patients with the
longest exposure to Actos and in those with the highest cumulative dose of the
drug.”
 -GLUCOSIDASE INHIBITORS
o For type 2 diabetes (type 1?)
 ACARBOSE (Precose®, 1995)
 MIGLITOL, (Glyset®, 1996/99)
o ACARBOSE and MIGLITOL
 ACTION
 Competitive inhibition of a-disaccharidases in proximal small intestine
 Hence, must be administered at start of each meal
 Slows down absorption of most carbohydrates
 Reduces post-prandial hyperglycemia by 45-60 mg/dl
 NO HYPOGLYCEMIA - when used alone
 Can be used alone or with sulfonylureas
Time (t)
 SIDE EFFECTS
 Flatulence (> 50%),
Diarrhea (30%) - decline with use
 Can lead to small weight loss 0.8-1.4 kg/yr
 CONTRAINDICATIONS
 Inflammatory bowel disease, due to gas/GI distention
 DIFFERENCES
 Acarbose is metabolized in GI tract, most metabolites are absorbed, conjugated and eliminated
in feces
 Miglitol is absorbed in SI and eliminated unchanged by kidneys hence, contraindicated if renal
impairment
NEWER DRUGS for TREATING DIABETES MELLITUS


100
Plasma Glucose
Concentration
90
80
70
60
50
40
30
20
10
0
0

1
2
3
4
5
6
49
UNIT 5 DRUG LECTURES

o Pramlintide (Symlin®, 2005)
o Exenatide (Byetta®, 2005)
o Sitagliptin (Januvia®, 2006)
o Canagliflozin (Invokana®, 3/29/2013)
SECRETION of INSULIN
Insulin and Amylin secretion (another
peptide/hormone that plays a role)—it
seems to slow down emptying of the
stomach, slow down rise in blood
glucose, inhibits release of glucagon,
acts in brain to  your appetite. Good
for patients w/ type II DM.


o
PRAMLINTIDE (Symlin®, 2005)
o Analog of amylin, a 37 amino acid peptide hormone released with insulin from b-cells
o MECHANISM
 Inhibits post-prandial glucagon secretion
 Slows gastric emptying (not for gastroparesis)
 Decreases appetite via action in CNS
 Net effect: glucose enters blood stream more slowly
o INDICATION – types 1 and 2 DM with insulin
 To improve glycemic control in patients, who have failed to achieve desired glucose control
o ADMINISTRATION
 SC injection prior to major meals with short acting insulin - but should not be mixed (pH4)
 pH is acidic so cant mix with regular insulin
o EFFECTS
 Decreases plasma glucose fluctuations
 Can produce severe hypoglycemia so don't use if unaware
 Decreases HbA1c 0.4% (6m)
 Decreases weight 1.7 kg/92.5 kg or 76 kg (6m)
 Decreases required dose of insulin (6m)
o ADVERSE EFFECTS
 Nausea, vomiting, severe hypoglycemia possible, —not for those with “hypoglycemia unawareness”
EXENATIDE (Byetta®, 2005)
o Incretin/GLP-1 mimetic
 Exenatide is synthetic exendin-4, a GLP-1-like peptide (39 aa) found in the venom of the Gila monster
(Heloderma suspectum)
 So you can treat patient w/ DM to stimulate insulin release
o SECRETION of INSULIN
50
UNIT 5 DRUG LECTURES
Stimulates inulin and amylin release. So now
glucose dependent action b/c need ATP from
glucose for this to function so much less
likely to have hypoglycemia.

USE – type 2 diabetes only –Why?
 If metformin or a sulfonylurea alone are inadequate
 SC injection 0-1 hr before breakfast and dinner
 Lowers postprandial and fasting plasma glucose
 Glucose-dependent promotion of insulin secretion (phase 1 and 2) and synthesis
 Inhibits glucagon release
 Slows stomach emptying
 Decreases appetite via action in CNS
o SIDE EFFECTS
 Nausea (44%), vomiting, diarrhea; increased hypoglycemia risk if used with sulfonylurea
o POTENTIAL PROBLEMS
 Acute pancreatitis
 Precaution added to label (10/2007, 8/2008)
o 30 postmarketing reports; 2 deaths
o Now 6 reports necrotizing pancreatitis
 Consequently: exenatide should be discontinued, if unexplained severe abdominal pain ±
vomiting,
 Note: It appears that exendin-4 was discovered following observation that venom from certain
snakes and lizards caused inflammation of the pancreas!!
 Decreased renal function (11/2009)
 78 cases (7M ps), exacerbated by NVD/hypovol?
LIRAGLUTIDE (Victoza®, 1/25/2010)
o Analog of human GLP-1 (res 7-37) linked to palmitic acid via glutamate spacer to lys 26
o Subcutaneous administration (1/day)
 Palmitoyl (16C) group results in self association, slow absorption and plasma protein binding (>98%)
 Result: Half-life 13hr, cf. 1.5-2 min for GLP-1 (DPP4)
 Long duration of action—only 1 injection per day
o Precautions – ongoing epidemiological studies…
 Pancreatitis
 Risk of thyroid C-cell tumors. Tumors were seen in rats and mice, hence contraindicated if family history
of medullary thyroid carcinoma, or MEN 2
SITAGLIPTIN (Januvia®, 2006) SAXAGLIPTIN (Onglyza, 2009) LINAGLIPTIN (Tradjenta®, 2011) ALOGLIPTIN (Oseni®,
1/25/2013
o Inhibitors of dipeptidyl peptidase-4 (DPP-4)
o SECRETION of INSULIN
o


o
o

Oral administration – 1 tablet per day
MECHANISM
51
UNIT 5 DRUG LECTURES


Inhibits inactivation of incretins GLP-1 and GIP
 Inhibitor of dipeptidyl peptidase-4 (DPP-4) enzyme
 Raises blood levels of GLP-1 and GIP 2-3 fold
 Effects of GLP-1 and GIP are increased:
 Glucose-dependent stimulation of insulin secretion
o USES – type 2 DM
 To improve glycemic control in type 2 diabetes
 Monotherapy as adjunct to diet and exercise
 In combination with metformin (Janumet®, 2007) ($0.46B) or a TZD
o ELIMINATION (cf. metformin)
 Kidney; water soluble drug, tubular secretion
 Dose adjusted according to kidney function
 25, 50 or 100 mg per day, for those with severe, moderate or mild-normal creatinine clearance
o POTENTIAL PROBLEMS
 ACUTE PANCREATITIS (9/25/2009)
 88 post-marketing cases (10/16/06 – 2/8/09)
 2 were hemorrhagic or necrotizing
 Patients should be monitored and drug withdrawn
if pancreatitis is suspected
CANAGLIFLOZIN (Invokana®, 3/29/2013)
o New Oral therapy for type 2 diabetes
o Administered 1 x/day prior to breakfast
o MECHANISM –Newer drug class in USA
 Inhibits renal reabsorption of glucose
 Increases urine glucose; decreases plasma glucose
o SIDE EFFECTS include
 Osmotic diuresis (b/c  glucose in the urine), hypovolemia, hypotension
 Hypoglycemia
 Female genital mycotic infections, urinary tract infection
ADRENAL STEROID PHARMACOLOGY
(Basic and Clinical Pharmacology, Katzung, 11th ed., Chapter 39; Chapter 20, pp347-348; Chapter 61, pp1058-1061)



ADRENAL STEROIDS
THREE MAJOR TYPES:
o Glucocorticoids (e.g. CORTISOL) - influence carbohydrate metabolism; suppress/moderate inflammatory response
o Mineralocorticoids (e.g. ALDOSTERONE)- regulate sodium retention by the kidneys so therefore helps control
blood volume
o Androgenic Steroids (PROGESTINS, ANDROGENS, ESTROGENS) - promote general growth of body tissues and
male sexual development
ENDOCRINE CONTROL OF GLUCOCORTICOID PRODUCTION
o Hypothalamus responds to stress (trauma—physical, anxiety, infection, surgery, etc) and sensory input by
secreting a peptide hormone, Corticotropin Releasing Hormone (CRH).
o CRH acts on the anterior pituitary to cause release of another peptide hormone, Adrenocorticotropic Hormone
(ACTH—aka Corticotropin).
o ACTH acts on the adrenal by binding to cell surface receptors. These receptors stimulate a cAMP second
messenger signal pathway which rapidly results in the synthesis and secretion of glucocorticoids (cortisol)
 There is also feedback regulation
o Stress events cause a HUGE release of cortisol!!
Cortisol FEEDS back on the hypothalamus to limit the release of
CRH
ENDOCRINE CONTROL OF MINERALOCORTICOID PRODUCTION
o Controled by the RAAS of the kidneys
o Low blood pressure ( BP) stimulates production of renin in the kidney by the JG cells of the macula densa
52
UNIT 5 DRUG LECTURES
o


Renin begins conversion of angiotensinogen (from the liver) to angiotensin I then to angiotensin II by ACE (in the
lungs)
o Angiotensin II acts on the adrenal to cause synthesis and secretion of aldosterone
o Aldosterone acts on the kidneys to increase retention of Na+, thereby increasing blood pressure
MECHANISM OF ACTION
o Mechanism is common to:
 Glucocorticoids - bind glucocorticoid receptor (GR)
 Mineralocorticoids - bind mineralocorticoid receptor
(MR)
 Androgens
 Estrogens and progestins
 Thyroid hormone, retinoids and vitamin D
 Through all these receptors that bind the steroidal
hormones these are all intracellular receptors (as
opposed to many of the other receptors we have
discussed) whose main goal is to work as hormone
activator TF (differential expression of genes mRNA
transcription  translation into proteins)
o Therapeutic consequences:
 Delayed drug effect (hours)
 Persistence of drug effect (days)
 Long duration of action of these drugs b/c the cessation of the drugs is dependent on the half life of the
newly synthesized proteins that are formed in response to the drug
When there is stress, you need energy. So body wants to
release glucose. Glucocorticoids scavenges muscle proteins
The hypothalamic–pituitary–adrenal axis plays a central role in
regulating signaling by the glucocorticoid receptor, which is
expressed in virtually all cells. In brief, neural, endocrine, and
cytokine signals converge at the level of the periventricular nucleus
of the hypothalamus to control the secretion of corticotropinreleasing hormone into the hypophyseal portal system In turn,
corticotropin-releasing hormone stimulates the release of
corticotropin from the anterior pituitary. Corticotropin induces the
synthesis and secretion of cortisol by the adrenal cortex. Most of
the secreted cortisol (approximately 90 percent) is bound to
corticosteroid-binding globulins in the blood.9 Free cortisol is the
biologically active form of the hormone and is converted to
cortisone by type 2 11β-hydroxysteroid dehydrogenase.10
Conversely, type 1 11β-hydroxysteroid dehydrogenase converts
cortisone into cortisol
The glucocorticoid receptor is a member of the steroid-hormone–
receptor family of proteins.11,12 It binds with high affinity to
cortisol; the bound cortisol promotes the dissociation of molecular
chaperones, including heat–shock proteins, from the receptor).
Within the cell, cortisol acts in three ways. First, the cortisol–
glucocorticoid receptor complex moves to the nucleus, where it
binds as a homodimer to DNA sequences called glucocorticoidresponsive elements. The resulting complex recruits either
coactivator or corepressor proteins that modify the structure of
chromatin, thereby facilitating or inhibiting assembly of the basal
transcription machinery and the initiation of transcription by RNA
polymerase II.13 This process is highly dynamic in cell culture and is
presumably so in vivo.14 Second, regulation of other
glucocorticoid-responsive genes involves interactions between the
cortisol–glucocorticoid receptor complex and other transcription
factors, such as nuclear factor-κB (NF-κB). These latter actions
seem to occur at lower cortisol levels than the cortisol–
glucocorticoid receptor–glucocorticoid-responsive element
complex needs to change transcription. The third mechanism is
glucocorticoid signaling through membrane-associated receptors
and second messengers (so-called nongenomic pathways).
Evidence indicates that the glucocorticoid receptor inhibits
inflammation through all three mechanisms: direct and indirect
genomic effects and nongenomic mechanisms.
53
UNIT 5 DRUG LECTURES
(alanine) and send them to the liver where they can convert the AA into glucose. They also go to adipose tissue and
lypolysis and release the FA and the liver makes ketoacids/glucose

PHYSIOLOGICAL ACTIONS OF GLUCOCORTICOIDS
o Anabolic:
 stimulate gluconeogenesis
 increase serum glucose
o Catabolic:
 stimulate conversion of proteins to amino acids then glucose
 stimulate lipolysis
o Electrolyte balance:
 impairment of calcium absorption by antagonism of Vit D (GR)
 antagonize the effects of vitamin D
 Direct effect on resorption of bone (GR)
 stimulate sodium retention and potassium excretion (MR)
o Immune system:
 decrease infiltration by lymphocytes
 impair phagocytosis by macrophages
 suppress cell mediated hypersensitivity
 decrease lymphocyte and thymocyte proliferation

How Glucocorticoids Block Growth Factor Induction of Lymphocyte Growth
Example Target cells: T lymphocytes
o
o
IkB is an inhibitor of NFkB
Glucocorticoids can control the expression of IkB so you can  their expression and essentially block the
NFkB activation and so you block the cytokine proliferation
COMMONLY USED NATURAL AND SYNTHETIC CORTICOSTEROIDS
Activity1
AntiTopical (ability to
Salt- Retaining
Inflammatory
be absorbed by
(retain salt by the
the skin—these
kidneys and control
are often used to
BP)
treat skin rashes
and problems)
SHORT-ACTING GLUCOCORTICOIDS
1 (b/c has some
Hydrocortisone (cortisol)
mineralcorticoid
1
1
activity b/c can bind
to mineralcorticoid
receptors)
Prednisone—Most commonly Rx glucocorticoid b/c
4 (4x’s
its not active—fmust be converted by the liver to
antiinflamm
0.3 (diminished salt
0
prednisolone for it to be active which is why its
activity than
retaining capability)
different than prednisolone
cortisol)
Agent
Equivalent
Oral Dose
(mg)
20
Forms
Available
Oral,
injectable,
topical
Oral
5
54
UNIT 5 DRUG LECTURES
Prednisolone
5
4 (very topical
activity)
0.3
5
5
5
0
4
5
5 (100 for
acetonide)
0
4
0
2
Methylprednisolone
INTERMEDIATE-ACTING GLUCOCORTICOIDS
Triamcinolone—can modulate it to acetonide and
its topical activity 100x’s ( lipid solubility coeff is
beneficial in the tx of asthma)
Paramethasone
Fluprednisolone
LONG-ACTING GLUCOCORTICOIDS(true pure
glucocorticoid agents)
Betamethasone
Dexamethasone (these drugs are so potent so you
run the risk of unintended side effects—you use this
for cerebral edema; Motorcycle accident w/ severe
trauma to the head leading to  inflammation and
swelling in the head so to treat inflammation and
not  blood pressure so you would reach for
dexamethasone; but for chronic dz’s these are not
used b/c too potent!)
MINERALOCORTICOIDS
Fludrocortisone
Desoxycorticosterone acetate
10
15
7
0
1.5
25-40
10
0 (no salt retaining
activity)
0.6
30
10
10
10
250
0
0
20
0
Oral,
injectable,
topical
Oral,
injectable,
topical
Oral,
injectable,
topical
Oral,
injectable
Oral
Oral,
injectable,
topical
Oral,
injectable,
topical
0.75
2
Oral,
injectable,
topical
Injectable,
pellets
Cant use aldosterone orally b/c very high first pass
metabolism by the liver
1
Potency relative to hydrocortison


PHARMACODYNAMICS
o The table above summarizes the relative potencies of commonly-used natural and synthetic corticosteroids. The
anti-inflammatory and salt-retaining activities of each drug have been standardized relative to cortisol.
o General Considerations:
 synthetic corticosteroids have longer half-lives than natural compounds (cortisol, cortisone)
 synthetic drugs have higher affinities for receptors at target tissues
o Specific Considerations:
 cortisol and cortisone have anti-inflammatory and salt-retention activities. Consequently, can be used for
replacement therapy
 prednisone and prednisolone are the most commonly prescribed synthetics. If used in replacement
therapy, a mineralocorticoid must also be administered.
 fludrocortisone has 250X more salt-retention and is the most commonly prescribed mineralocorticoid, as
deoxycorticosterone is not absorbed by the GI.
 betamethasone and dexamethasone have no salt-retention activity and very strong anti-inflammatory
effects. However, are difficult to control and seldom prescribed.
THERAPEUTIC USES
o Replacement Therapy (Low potency drugs at low chronic dosing)
 Adrenal insufficiency due to:
 adrenalectomy
 Addison's disease –defect that causes atrophy or complete loss of adrenal glands
 congenital adrenal hyperplasia –defect in glucocorticoid producing enzymes b/c overstimulated
by corticotropin so it becomes hyperplastic
 Typical Treatment:
 Hydrocortisone and Fludrocortisone
55
UNIT 5 DRUG LECTURES
o
Palliative Therapy (Low to high potency drugs, acute dosing (high doses over a short period of time) )
 To take advantage of the Anti-inflammatory & immunosuppressive action:
 Arthritis and tendinitis
o relief prompt and dramatic only for acute episodes
o Prednisolone injected into the effected joint
 Allergy and asthma
o reserved for patient unresponsive to bronchodilators
o  side effects
 Oral: prednisone
 IV: Methyprednisolone
o Aerosol: Triamcinolone acetonide, Budesonide, Gluticasone
 Very high lipid solubility coeff. Means they can be aerosolized and administer
them via the airway. Can be used for chronic treatment b/c of the  systemic
side effects and effectivity
 15-30x’s more potent than prednisone
 90% first pass metabolism so this also minimizes systemic effects
 Dermatological disorders
o widely used
o topical preparations
o Very responsive
 Seborrheic dermatitis
 Psorisasis on the face
 DOC 1% hydrocortisone, 0.5% prednisolone
 Autoimmunity
o Auto immune hemolytic anemia
 Liver function gets compromised b/c the blood cells swell and rupture
 His cat was given steroids b/c vet had no idea thought it was liver cancer and it
was actually THIS! HELPED SAVE THE CAT 
o SLE, etc
 DOC: Oral prednisone
 Organ transplantation
o Renal, heart, bone marrow and liver transplants b/c must temporarily suppress the
immune system
 DOC prenisone & cyclosporine (new drugs not by the same mechanism but
they do suppress immune system)
 Malignancies
o Acute leukemia
o Lymphomas
o Myelomas
 DOC prednisone & anti-neoplastics
 Exploits its effects to Suppress proliferation of T and B cells
 Premature birth (fetal lung development)
o 8-10 weeks premature babies now a day will survive
o Glucocorticoids are essential for baby development of their first breath
o During birth babies go through a lot of stress. When mother goes into labor fetal cortisol
levels go sky high to survive this intense stress
o Glucocorticoid allow the baby to stop relying on moms blood for O2 to relying on their
lungs to breath and get O2
 Cause lung cells to secrete surfactant (type II pneumocytes) a couple hours
before birth
o To get a premature baby to have this happen you give mom glucocorticoids before birth
and after to stimulate secretion of cortisol
 Gastrointestinal disorders
 Cerebral edema
 Hypercalcemia
56
UNIT 5 DRUG LECTURES





Shock
Collagen vascular disorders
Neuromuscular disorders
Renal diseases
Hematological disorders

ADVERSE EFFECTS
o Cardiovascular and Renal System
 Sodium retention
 Hypertension
 Edema
 Hypokalemia
o Musculoskeletal System and Skin
 Myopathy –muscle breakdown b/c send AA to liver (catabolistic thing)
 Osteoporosis
 Growth suppression in children
 Prolonged wound healing
o Ophthalmic System
 Increased intraocular pressure
o Immune System
 Infections ( risk for infection b/c of the suppression of the immune system and will suppress the
symptoms seen in an infection—so used ATB not these for infections)

ANTI-ADRENOCORTICOSTEROIDS
o Useful in the treatment of diseases of adrenal hyperactivity:
 Cushing’s Syndrome –too much cortisol
 Hyperplasia secondary to a pituitary adenoma
 Tumors of the adrenals
 Aldosteronism
 Hyperplasia and tumors
o INHIBITORS OF ADRENAL STEROID BIOSYNTHESIS:
 Aminoglutethimide
 Inhibits the conversion of cholesterol to 20-alpha- hydroxycholesterol.
 If you block this you are blocking the production of all steroids from the adrenal cortex

This is the first step in the synthesis of the steroids from cholesterol.
 Decreases hypersecretion of cortisol in autonomous adrenal tumors and hypersecretion caused
by ectopic ACTH-producing tumors. Like metyrapone, sometimes used as adjunct in treatment of
Cushing’s.
 Used to treat breast and prostate cancer b/c  estrogen production all over the body (so block it
at the adrenal glands)
 Metyrapone
 Inhibits 11-beta-hydroxylation of steroids.
o Blocks the formation of corticosterone and cortisol (blocks aldosterone and cortisol)
 Sometimes used as adjunct to surgery in treatment of Cushing’s Syndrome.
 More typically used to test the ability of the pituitary to respond to depressed levels of
glucocorticoids.
o ANTAGONISTS:
 Spironolactone
 Competitive Antagonist to both mineralocorticoid and androgen receptors
 Used alone in the treatment of aldosteronism or as adjunct to surgery
 Effective in treatment of hirsutism and as a diuretic (to  BP)
 Side effect Hyponatremia/hyperkalemia, Metabolic acidosis, gynecomastia, impotence
 Eplerenone
 Recently approved by FDA
 Selective aldosterone antagonist (doesn't touch the androgen receptor at all)
57
UNIT 5 DRUG LECTURES

RU486 (Mifepristone)
 A synthetic anti-progesterone which is also a potent anti- glucocorticoid
o Antagonist to these
 Binds to the glucocorticoid receptor with greater affinity than synthetic agonists (e.g.,
dexamethasone) and inactivates its gene transcription function
 Effective in the treatment of Cushing's Syndrome
 Shows promise in the treatment of steroid- dependent tumors, aging and degenerative disorders.
THYROID PHARMACOLOGY
(Basic and Clinical Pharmacology, Katzung, 11th ed., Chapter 38)
THE THYROID GLAND

SOURCE OF TWO FUNDAMENTALLY DIFFERENT CLASSES OF HORMONE:
o Thyroid Hormones: vital for normal growth and development; promote general energy metabolism and
thermogenesis; potentiate catecholamine action.
 Thyroxine (T4) –4-5x’s more than T3



Triiodothyronine (T3)—produces this to a lesser extent
 Produced to a lesser extent than T3 but this is 4-5x’s more potent than T4

o Calcitonin (plasma hypocalcemic hormone): peptide hormone involved in calcium and phosphate metabolism.
THE HYPOTHALAMUS-PITUITARY-THYROID AXIS
o ENDOCRINE CONTROL OF THYROID HORMONE SECRETION
 Sensory input at the hypothalamus leads to secretion of a tripeptide hormone, Thyrotropin Releasing
Hormone (TRH).
 Severe stress (e.g. physical trauma) exerts a negative effect.
 TRH stimulates synthesis and release of Thyroid Stimulating Hormone (TSH aka Thyrotropin) by the
anterior pituitary.
 TSH stimulates thyroid hormone production by binding to a plasma membrane receptor on thyroid follicle
cells.
 Negative feedback by circulating T3 and T4 is exerted on both the hypothalamus and pituitary.
 Dietary iodide deficiency results in reduced T3 and T4 levels, as well as thyroid enlargement (non-toxic
goiter).
 High circulating iodide levels will actually inhibit T3 and T4 production.
 Iodide is actually a component of active thyroid hormone but insufficiency causes hypothyroidism
historically b/c now we have a ton of iodide in salt but when it does happen you get a transient hormone
b/c endocrine system responds w/  TSH which proliferation of follicle cells that produce the thyroid
hormones to make up for the  in thyroid hormone
 Very high doses of iodide have paradoxical effect on later stages of thyroid hormone biosynthesis
(proteolitically cleaved from thyroglobulin—this gets inhibited by acute  in iodide)
58
UNIT 5 DRUG LECTURES

REGULATION OF T4 AND T3
BIOSYNTHESIS: The figure below
illustrates the major steps in the
synthesis of these hormones in the
thyroid gland.

BIOSYNTHETIC STEPS RESPONSIVE TO
DRUG THERAPY:
o Block activity of peroxidase so
you block the 3 things it does
o Blockage of iodide active transport by ionic inhibitors
o Inhibition of peroxidase activity by thionamides
o Iodide trapping and storage of iodinated thyroglobulin allows for effective radiation treatment (131I)
o Inhibition of deiodination of T4 to T3 at peripheral tissues by thionamides
o Radioinoculation—follicle cells have the iodide importer so when you give radioactive iodide it will almost
exclusively be taken up by these follicle cells which will lead to necrosis and death of these follicle cells
MECHANISM OF ACTION:
o Member of steroid receptor family
o Acts as hormone-induced transcription factor
o Thyroid receptor expressed in almost all cell types
o Up-regulation of Na+/K+ ATPase, and Uncoupling Proteins in adipose, partially responsible for effect on basal
metabolic rate and thermogenesis.
PHYSIOLOGICAL ROLES OF THYROID HORMONES o Ability of thyroid receptor to regulate basal metabolic rate has profound effects on differentiation, growth and
development, and adaptation to environmental stress.
 GH growth of major organs, bone
 Cretinism (dwarfism & MR)
 Nerve growth factor nerve growth and regeneration
 Myosine heavy chain Tropic effect on hear and other muscles
 PEPCK –promotion of gluconeogenesis
 Na/K ATPase—O2 consumption (all tissue)
 Uncoupling protein  heat production (adipose tissue)
 Maintain BMR and heat regulation
THYROID HORMONE DYSFUNCTION
o Hypothyroidism
 Impaired musculoskeletal system
 Impaired central nervous system
 Abnormal lipid metabolism
 Hypercholesterolemia
 Impaired cardio-renal function
 Reduced overall tissue metabolism –so cold sensitive
 Effects on hematopoietic system
 Effects on reproductive system
 Extreme cases



This is a thyroid follicle (single layer of endothelial cells that make a lumen where the
thyroid hormone is store). Has a sodium iodide importer (take in iodide actively
against gradient using ATP) so concentrate iodide in the follicle cells. Once in it transits
into the lumen of the follicle via the __________. In the lumen it is acted on by thyroid
peroxidase which 1) oxidized iodide into free radical form to covalently conjugate it to
benzene ring of tyrosine residues on thyroglobulin. This carrier protein has a lot of
tyrosine residues. 2) Iodination which 2covalently couples 2 iodide molecules or 1
iodidne molecule to benzene rings 3) Conjugation/coupling step—now the enzyme will
take one benzene ring and bind it to other (2 rings w/ 2 iodides= T4 and 2 rings—one
with 1 iodide and the other with 2= T3. Hormone-thyroglobulin complex is stored in
the lumen of the follicle as colloid. TSH signals follicle cell to release thyroid hormone
into blood stream by endocytosis from lumen back into the follicle cell. Enzymes fuse
w/ the vesicle filled w/ the hormones-thyroglobuln vesicles and cleave to release T3
and T4 (MORE OF THIS IS RELEASED).

Peripheral metabolism of Thyroxine
o Peripheral target cells also have a peroxidase (deiodinase) that convert
T4 T3.
o Or you can turn T4 into reverse T3. This is to attenuate overstimulation
by T4

Thyroid hormones work same as steroids—slow mechanism of action
59
UNIT 5 DRUG LECTURES

 In infants and children, extreme hypothyroidism results in Cretinism.
 In adults, extreme hypothyroidism results in Myxedema.
o Hyperthyroidism (thyrotoxicosis)
 Increase in the basal metabolic rate
  oxygen consumption
 Excess energy expended as heat
 Symptoms:
 increased appetite
 weight loss
--despite  appetite
 high pulse rate
(tachy)
o get light headed go to the doc and this is how they usually find this
 high systolic blood pressure
 increased H2O turnover
 dyspnea
o Acute stress + hyperthyroidism can lead to Thyrotoxicosis (thyroid storm)
 Usually this happens in patients that are hypothyroid followed by an acute bout of stress
hyperthyroidism
 Stress release catecholamines (EPI, etc) and its gong to be  the same physiological conditions that
thyroid hormone does
THERAPEUTIC USES OF THYROID AND ANTI-THYROID DRUGS
o Etiology of Hypothyroidism:
 Hashimoto's thyroiditis: autoimmune disorder most common
 Recognizes thyroid gland as self and attacks
 Goiter is due to inflammation of thyroid gland and over time the thyroid gland becomes
dysfunctional and produces less and less thyroid hormone
 Drug-induced
 Block hormone production and sometimes can give too much and cause hypothyroidism
 Radiation-induced
 Destruction of hyperactive gland and become permanently hypothyroid
 Congenital (cretinism) defect
 Secondary
 Disease of hypothalamus-pituitary axis
o Deficiency of TSH (pituitary)
o Therapeutic Approaches:
 Cessation of drug administration, radiation treatment or dietary modification
 Replacement therapy
o Thyroid Hormone Preparations:
 Powdered thyroid gland (thyroid USP) (Armour Thryoid ®)
 advantage: inexpensive
 disadvantages: dosing difficult to control, hyperallergenicity
 Taking thyroid gland of an animal and crush it up into a powder and have patient take it—it
would work b/c that gland has thyroid hormone. But it also has a lot of other things so now a
days you don't use this but it can be found online
 Levothyroxine sodium (Synthroid ®, Levoxyl ®)
 synthetic, crystalline T4
 disadvantage
o some patients can develop allergies to synthroid (levoxy has fewer filler so you may
want to switch them to this) a filler agent in the pill
 advantages: precise dosage control, hypoallergenic, once daily dosing
 Overall, drug of choice is LEVOTHYROXINE (T4)
 Liothyronine sodium (Cytomel ®)
 chemically pure T3
o if patient present w/ myxedema coma use this to get the patient out of the coma
o this is potent so use in extreme situations
60
UNIT 5 DRUG LECTURES
o
o
 advantage: 4X more active than T4
 disadvantages: cardiotoxicity (cardiac arrhythmias), multiple daily dosing
 Liotrix (Thyrolar ®)
 4:1 ratio of T4 to T3
 advantage?: approximates ratio of secreted T4 and T3
 with more clinical trials this may become more popular and possibly the DOC
Etiology of Hyperthyroidism:
 Grave's syndrome
 autoimmune disorder  Produces Thyroid-stimulating immunoglobulin (TSI) binds TSH receptor and activates it
o Tricks follicle into thinking its getting a signal to produce more thyroid hormone
 Most common in young and females.
 Opthalmopathy present—immune cells accumulating behind eyes
 Toxic Nodular Goiter
 Benign adenomas with abnormal thyroid secretion
 Usually arises from long-standing non-toxic goiter (b/c stimulation of thyroid gland from TSH
which is a growth hormone so it will  thyroid gland and over time this can develop into a tumor
that secrets thyroid hormone)
 Predominant in older patients.
 No opthalmopathy—because this is not immune mediated
THIONAMIDES:
 Most commonly used drugs in the treatment of hyperthyroidism.
 propylthiouracil (PTU)
 methimazole
 Carbimazole (10x’s more potent than PTU)
 Mechanism of action: INHIBIT THYROID PEROXIDASE
 block of tyrosine iodination on TG
 block of iodotyrosine coupling
 PTU also blocks deiodination of T4 to T3
 General considerations:
 PTU has short half-lives (hours) so requires multiple daily dosing
o but accumulation in thyroid allows once daily dosing for methimazole
 Do not block thyroid hormone release
 Days to weeks to see serum thyroid levels to 
 Toxic effects of thionamides:
 Overall incidence rate:
o PTU3%
o Methimazole 7%  Minor side effects include: variety of rashes, fever, vasculitis, arthralgia, cholestatic jaundice,
hepatitis and others
 High incidence of liver failure with PTU (resulting in death or liver transplantation)
 Hypothyroidism after prolonged or excessive treatment
 0.5% incidence of agranulocytosis (can be life threatening)
 Advantages of drug therapy:
 Avoid surgical complications o So thiamides best way to go
 Highly reversible
 Disadvantages:
 High incidence of relapse: 60 - 70%
o Even patient that are taking thaimides they become resistant over the long term
 Successful remission takes several years
 General Usage:
 Methimazole is usually first line drug for young patients w/ mild to moderate disease
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UNIT 5 DRUG LECTURES

o
o
o
PTU is considered second-line drug therapy except in patients who are allergic to or intolerant of
methimazole
 Used as adjuncts to surgical removal or radioactive ablation of hyperthyroid gland
o Give thaimides to normalize the patient and then remove the gland
IONIC INHIBITORS:
 Thiocyanate (SCN-)
 Blocks uptake of iodide
 Not really used anymore b/c of the side effects
 Perchlorate (ClO4)
 Blocks uptake of iodide, once used extensively.
 Now used as diagnostic agent for thyroid function.
IODIDE:
 Inhibits TH synthesis and release
 Iodide is often used along w/  blockers to treat thyroid storm
 Decreases size and vascularity of thyroid gland
 Rapid acting
 Not suitable for long-term therapy
RADIOACTIVE IODINE:
 131I
 only isotope used in treatment of hyperthyroidism.
 Half-life = 5 days  123I
 Used in clinical diagnosis.
 Half-life = 13 hours
 Effect on thyroid: necrosis of follicle cells
 Advantages:
 only thyroid is affected  surgery avoided
 inexpensive treatment
 Disadvantages:
 high incidence of delayed hypothyroidism o you lose most if not all the gland
 potential carcinogenicity ?—there are studies done and apparently there isn’t an  risk—is it
really safe? Ukraine side had very very high incidence of thyroid cancer from Trenoble? So there
probably is a risk.
 Crosses placental barrier –so make absolutely sure the female is not pregnant
 can obliterate the parathyroid gland because the parathyroid glands are so close to the thyroid
gland
TOXICOLOGY


Toxicology
o All substances are poisons; there is none which is not a poison.
o The right dose differentiates a poison from a remedy.
o Study interactions between body and a substance.
o Evaluate safety and risk.
Types of Toxicology
o Occupational
o Environmental
o Clinical
o General Principles
o Examples
How it
gets
removed
from the
body
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UNIT 5 DRUG LECTURES



Toxicant
o Parent compounds as ultimate toxicant: Ethanol
o Metabolites as toxicant: Methanol to formic acid (this is the toxicant)
o Free radicals as toxicant: Paraquat (herbicide) and doxorubicin (drug
used in chemo—cardiotoxic)  superoxide O2METHANOL AND GLYCOLS
o Metabolism leads to acidosis (15 ml—two shots— bilateral blindness;
70 ml death)
 Methanol intoxication—common in cheap Italian wine
 Pyruvate glycolysis allows  NADH to continue this reaction
 Methanol has some direct toxicity but most of its toxicity is in
its byproducts
 Formic acid production is the reason for blindness
o Parent compounds lead to CNS effects (metabolic acidosis)
 Lactate accumulation causes the metabolic acidosis
o Ethylene glycol (antifreeze)  oxidized to aldehyde  oxidized
further Calcium oxalate (oxalic acid—combines w/ Ca in the blood)
Renal damage
 Antidote: Ethanol—will compete w/ alcohol dehydrogenase &  formation of formaldehyde & formic acid
 Also an orphan drug called FOMEPIZOLE
HEAVY METALS
o MERCURY: Elemental, Inorganic , and Organic Mercury
 Most of the mercury exposure comes from organ mercury (methylmercury) and most of this comes from
fish
 Manamata—factory used inorganic mercury for industrial purpose and dumped it into the bay and all of
the organisms ate this and converted it into the organic mercury and it got to such a high level in the food
chain that a lot of people died or became deformed This can lead to minamata disease
 Kinetics and toxicity
 Closely related. 3 diff types of mercury intox
o elementary mercury (mercury vapor—it can get into the circulation through inhalation
and part of that goes through peripheral tissues and some of that go to the CNS so it
gives you both peripheral and central intoxication)
o inorganic mercury (cant pass through BBB, so its toxicity lies in the kidney damage it can
cause)
o organic mercury (methylmercury)
 —this mimicks an amino acids and can pass the BBB and get into the CNS
which is why it is most toxic of these)
 Once you see the intox you need to use the antidote to prevent the interaction of mercury with
the sulfahydra protein (mechanism is below)
o Table 66-3. Estimated average daily retention of total mercury and mercury compounds in the general population
not occupationally exposed to mercury
EXPOSURE
AIR
FOOD

FISH

NONFISH
DRINKING WATER
DENTAL AMALGAMS
TOTAL
o
0.024


0.0
3-17
3-17
ESTIMATED MEAN DAILY RETENTION OF MERCURY COMPOUNDS, μg mercury/day
Mercury Vapor
Inorganic Mercury Salts
Methylmercury
0.001
0.0064
0.0
0.0


0.0035
0.0
0.3


0.04
0.25
2.3
0.0
0.0
0.0
2.31
MECHANISM OF MERCURY POISONING
o Hg2+ + SH-R = Hg(SR)2
 binding of mercury to this activates the mercury and it is irreversible—so to revere must
synthesize new sulfhydra protein
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UNIT 5 DRUG LECTURES
o
o


CH3Hg + SH-R = CH3HgSR
LEAD



No longer allowed in patient but it is in older homes paint and no long allowed in gasoline
Absorption: respiratory and gastrointestinal
Toxicity:
 Blood: anemia (due to inhibition of heme synthesis
and increased membrane fragility) and
basophilic stippling.
 Nerve system: wrist-drop and encephalopathy
o MERCURY
 Renal damage; giogivostomatitis; CNS effects (visual disturbance, muscle tremor and metal deterioration)
o ARSENIC
 As3+ (tri to SH) and As5+ (penta to ATP)
 5+ form mimics ATP and works like a phosphate and that generates arsenic and wastes ATP
(creates a hypoxia)
 long term exposure to arsenic was known to be causing cancer—water in some areas have low
levels of arsenic
 Iron intoxication
o OTHER METALS
 Copper: genetic (WILSONS DISEASE)
CASE STUDY
o A 3 year old child was brought to the ED by his parents. The patient had “vomited 6-7 times with streaks of blood”.
The child had been found with several “vitamin pills” scattered on the kitchen floor
o Physical Exam
 General: The child is lethargic but arousable, in moderate distress.
 Vitals: RR=40, HR=140, BP=80/40, T=99.8
 Heent: PERRL 4MM, EOMI, TM’s Normal.
 Mouth: Dry MM’s, good Gag reflex.
 Lungs: CTA
 Ht: RRR no murmurs.
 Abd: Soft, mild epigastric tenderness, no masses/organomegaly.
 Rectal: Heme positive.
 Skin: WNL
o Diagnostic Studies

CBC: WBC=29.8, H/H 11/33, PLT 310K
 Electrolytes: Na=140, K=4.5, Cl=105, and HCO3=15.
 BUN/Cr. 24/0.6
 Glucose: 293
 ABG: 7.29/32/98/15
 Radiology: Radiopaque in the stomach—iron pills still in the stomach.
o Iron
 Fe2+ (ferrous) Fe3+ & OH radical (Fenton reaction)
 The OH radical reacts with the GI tract and causes damage and bleeding
 vitamin C allows this reaction to continue (because this reduces the ferric ion back to ferrous so
the reaction can occur again)
HEAVY METAL ANTAGONISTS
o Mechanism: antagonize the actions and promote elimination
o Properties: more effective in prevention than reactivation
o EDTA (ETHYLENEDIAMINE TETRAACETIC ACID)
 You give EDTA by a slow injection IV or IM (it is a salt and it cannot be absorbed from the
GI tract)
 It's a chelating agent in a chemistry lab for divalent metal ions (more specifically chelates
calcium)—EDTA goes into the circulation and effects Ca which will effect muscle especially in cardiac and
smooth muscle   BP and patient will die
 Kinetics and mechanism: Used to tx Lead intoxication; also can be used for acute mercury tox
 Side effects: Zn deficiency; renal damage (stones formation and deposition causing tubular damage b/c
lead will ppt out with EDTA)
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UNIT 5 DRUG LECTURES

o


How is EDTA useful in prevent lead toxicity?
 EDTA has a might higher affinity for lead than for Ca so it can replace the Ca bound to lead so
don't have to worry about calcium bound.
 Just give patient calcium and they should be fine
 EDTA ppt out w/ lead so could lead to renal damage.
DIMERCAPROL (British Anti-Lewisite)

 Unstable in aqueous solution
 Inject intramuscularly in peanut oil b/c it must be in solution –it is very painful for the patient
 Used for lead; acute inorganic, elementary mercury and arsenic
 Side effects: hypertension and tachycardia
o SUCCIMER: a water-soluble analog of dimercaprol
 This has better kinetics and  side effects as compared to dimercaprol (most of the time can be
used to replace the dimercaprol in acute settings)—in chronic mercury poisoning it gets
accumulated in the peripheral tissue and the mercury may bind to the sulfhydra groups on this
molecule and convert to organic mercury and go to the brain and  toxicity
 Orally effective
 less side-effects
 Used for Lead; arsenic and mercury
o DEFEROXAMINE: Iron
 Ka=1031, and it compete with loosely bound iron, but not heme iron or irons in cytochromes.
 Has high affinity for iron but not high enough to compete for Iron in cytochromes
 The iron-complex is excreted in urine.
 Administration: IV or IM
o PENICILAMINE: copper (wilson disease)
o PRUSSIAN BLUE (FERRIC HEXACYANOFERRATE):
 Use as oral drug to treat radioactive aesium (13 Cs) (“dirty bomb”) and thallium intoxication by  their
biological half life via reducing intestinal absorption or preventing enterohepatic circulation of these
cations
CARBON MONOXIDE
o Form Carboxyhemoglobin (when it binds to Hb)
o Prevents Oxygen binding and release
 220 x’s more affinity for Hb than O2
 1000ppm = 50% COHb
 Smoker = 6-10% COHb
o Antidote: 100% oxygen
 T1/2-320 min to 80 min
CYANIDE ANION
o nitroprusside
o Binds to Fe3+, inhibiting cytochrome oxidases—prevents the production of ATP in the mitochondria
o Detoxification:
 Sodium nitrite (NaNO2) to methemoglobin
 Can convert ferrous in the Hb into ferric Hb (methemoglobin) so this would compete with the
binding of CN and block its binding
 Sodium thiosulfate to thiocyanate
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UNIT 5 DRUG LECTURES



Rhodanes
Na2S2O3 + CN-
→
SCN- + Na2SO3
o Less toxic and easily removed from the system
o You give this when you give Na nitroprusside
Hydroxocobolamin to cyanocobolamin (B12)
 Binds to CN which converts it into a diff form of B12
CASE STUDY
o A unresponsive 36 year old male fire fighter was air-lifted to the ED after being involved in extinguishing a 5 alarm
factory fire. 100% oxygen was administered in the field
o
o
Physical Exam
 General: Unresponsive, in moderate distress.
 Vitals: HR=60, RR=98.4, BP=190/110
 Heent: NC/AT, pupils midrange sluggish. Soot-tinged secretins.
 Lungs: Scattered rhonchi with exp wheeze.
 Ht: RR S1S2, no murmurs.
 Ext: +2/4 pulses.
 Neuro: No focal defs, moves all 4 exts.
 Skin: Ashen color, cool (indication of some kind of hypoxia intoxication)
Diagnostic Studies
 CBC: WBC=19.7, H/H 15/45, PLT=298K
 Electrolytes: Na=134, K=4.8, Cl=108,
 Glucose: 134
 BUN/Cr. 20/1.5
 L.A.: 18
 MetHgb: 2%
 COHgb 30%
66