Drugs Used to Treat Disease of Blood and Inflammation - Lecture 8

I. Drugs Used to Treat Diseases of the Blood:

Coagulation

Anemias

Hyperlipidemia

Inflammation

I. Drugs used to treat Disorders of Coagulation

Normal Response to Vascular Trauma

puncture or cut

complex series of interactions between platelets, vessel endothelium and a cascade of coagulation proteins

an unwanted thrombus involves many of the same steps but the triggering is pathological rather than a physical stimulus

terminology:

thrombus -- clot attached to a vessel wall

embolus -- clot floating in circulation - could cause heart attack or stroke

both of these can occlude a vessel and restrict blood flow

Process - 

1. Vascular Spasm - damaged blood vessel - smooth muscle - endothelial cells contract --- usually a sharp cut will bleed longer because less trauma

2. Formation of Platelet plug - very fast - happens first - normally do not adhere to the endothelium, fragments from Megakaryocytes (2 µm)

SUMMARY --- very fast - primary sealer

this is the Platelet Plug -- it forms very quickly

The platelets do not adhere downstream because normal health endothelial tissue releases the PG prostacyclin which prevents platelet activation

prostacyclin binds with receptors that increase cAMP (adenylyl cyclase) on platelet and prevents release of granules that contain aggregating agents (ADP and serotonin)

in contrast thromboxane stimulates release of granules via increasing DAG and IP3.

A. AntiThrombotic Drugs:

platelet aggregation inhibitors--

Aspirin:

blocks thromboxane synthesis from arachidonic acid via acetylating cyclooxygenase -- blocks process for 10 days -take 325 mg/day to prevent heart attacks

other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase but have a shorter duration and thus are not recommended to prevents thrombosis

alternatively -- change diet -- eat a lot of unsaturated fatty acid eicosapentaenoic acid (Eskimos consume a lot of fish) which generates prostacyclin -- inhibits platelets

3. Coagulation

After platelet aggregation (platelet plug) the fibrin plug or clot forms (Coagulation)

Why doesn't blood always clot?

-normally no thrombin

A. Anticoagulants

1) Heparin - very rapid

After IV injection - binds with antithrombin III -- this is a normally occurring blood protease that normally slowly inactivates the activated clotting factors

in the presence of heparin -- antithrombin III rapidly inactivates clotting factors including thrombin -- thus not conversion of fibrinogen to fibrin

Therapeutic Uses:

• Deep vein thrombosis
• Pulmonary Embolism
• Prevent postoperative thrombosis
• Acute phase of myocardial infarction

Pharmacology:

Must be given parenterally - IV or SC -- never IM because it will produce hematoma

Hepatic metabolism - excreted in urine

Adverse Reactions:

• Bleeding - must monitor bleeding time -- if bleeding give protamine sulfate - it inactivates heparin
• Thrombocytopenia - reduced number of platelets - after 8 days of therapy

2) Warfarin - (Coumadin) this is a coumarin anticoagulant - slow 8-12 hours

discovery - of spoiled sweet clover - anticoagulant effect

used as rodenticides as well as for humans

Pharmacology:

Given Orally - 100% bioavailability

99% protein bound

Adverse Reactions:

Bleeding- treat by giving Vit K

Many drugs either attenuate (barbiturates) or potentiate (alcohol intoxication) the effects

Other antithrombotic agents

• Dipryridamole - oral
• Ticlopidine - decreases ADP - oral

C. Fibrinolytic Drugs:

Drugs are used to dissolve clots:

give to heart attack and stroke victims

Normally:

New drug -  aggrastat plus aspirin – new clot dissolver

IV injection for fast administration -- if possible intracoronary administration

• tPA is highly selective because it binds to plasminogen bound to fibrin in a thrombus
• uro and streptokinase act on all plasminogen - thus get thrombolytic state

The t1/2 is very short - 7 minutes for tPA, 15 min for uro. and 24 min for strep.

Vit K - fat soluble vitamin - requires 24 hours to have an effect - activates coagulation factors

Coagulation factors:  Factor VIII -von Willebrand Factor - obtained from human blood donors

Factor IX

II. Drugs Used to Treat Anemias:

defined as a below normal plasma hemoglobin concentration - due to decreased number of RBCs or total hemoglobin content per unit blood

could be due to blood loss, bone marrow abnormalities, infection, hemolysis, endocrine problems, disease states, drugs, diet

Red blood cell formation (Erythropoiesis) requires:

• Iron - hemoglobin formation
• vitamin B₁₂ - needed for DNA synthesis
• folic acid - needed for DNA synthesis

Hemocytoblasts to Reticulocytes to Erythrocytes

A. Iron-70% of iron in body is in form of hemoglobin

women usually have less iron due to menstruation

Given as ferrous salts, etc

this would be given only if iron deficiency is noted - long term treatment (3-6 months)

Toxicity-gastroenteritis, vomiting and abdominal pain

B. Folic Acid -vitamin (found in yeast, liver, green vegetables)

needed for synthesis of DNA - RBCs

decreases in folic acid can be due to dietary deficiency, drugs (methotrexate - cancer treatment-breaks down folic acid) or poor absorption from intestine (pathology or alcoholism)

folate deficiency results in:

• decreased amino acid synthesis
• decreased purine synthesis
• decrease pyrimidine synthesis

these result in Megaloblastic Anemia

No toxic effects

C. Vitamin B12 - meat, eggs, dairy products

needed for synthesis of DNA - RBCs

decreases in Vit B₁₂ can be due to dietary deficiency or poor absorption

an intrinsic factor is needed to absorb B₁₂ in the distal ileum

Pernicious Anemia - defective secretion of intrinsic factor

Must administer B₁₂ for the entire life of patient -- give drug IM or orally if patient refuses injection - only a small amount is absorbed

No toxic effects

D. Erythropoietin - glycoprotein normally produced by kidney

Classified as a hematopoitic growth factor - others include granulocyte colony-stimulating factor, interleukin 3, etc

stimulates RBC production in bone marrow

erythropoietin is now produced by recombinant DNA technology

Used to treat anemia due to renal disease

this may not help aplastic anemia - which is a problem in the bone marrow

Toxicity may be due to rapid increases in hematocrit which increase blood pressure

III. Antihyperlipidemia Drugs

If too much triacylglycerol (triglyceride) and/or too many lipoproteins- results in increased coronary heart disease --- this condition is called hyperlipidemia -

lipoproteins transport lipids – lipoproteins that contain the apoprotein (Apo) B-100 results in atheroscelerosis (leading cause of death in Western countries) -- Apo B-100 transports cholesterol -- thus too much cholesterol is bad

• fatty acids are transported bound to albumin

Lipids are insoluble in water -- thus to transport lipids in the body they must be complexed with proteins -- complexes are called lipoproteins

All lipoproteins are spherical particles consisting of

 

• The liver converts old cholesterol into bile salts - needed for absorption of fats from intestine (forms micelles)
• The dietary fat is absorbed from the intestine and incorporated into the largest of the lipoprotein particles -- chylomicrons (formed in intestine-contain apoproteins A, B-48, C, E)
• once in the circulation-lipoprotein lipase associated with vessel walls breaks down the chylomicron and free fatty acids are released from triglycerides - enter cells and are stored as fat
• triglycerides - glycerol and 3 fatty acid tails
• the remnants of the chylomicron enter the liver and is used to produce triglycerides

VLDL (very low density lipoproteins) are made in the liver and transport endogenously synthesized triglycerides to storage cells and metabolizing cells (cardiac and skeletal) -- (the apoprotein is C, B-100 E)

lipoprotein lipase removes triglycerides and degrades VLDL --- to cholesterol rich LDL

associated with vessel wall- helps triglycerides enter the cell

LDL (lots of cholesterol) travels to peripheral cells and liver (2000 molecules of cholesterol - 1000 phopholipids and 1 Apo B-100) to deliver cholesterol that is needed to synthesize cell membrane - the ligand for endocytosis of the LDL into peripheral tissue is ApoB-100 -- part of ApoB-100 is apolipoprotein (a) - this is strongly correlated with atheroscelerosis

LDL receptors take LDL particles out of the circulation into the cells and prevents incorporation into atherosclerotic plaques

cholesterol can also be produced in cells via HMG-CoA reductace

HDL- is formed in intestine, liver and vascular tissue - transports cholesterol from peripheral cells to the liver

The atherogenic lipoproteins - VLDL and LDL - deliver cholesterol to the tissue - oxidation of the lipoproteins results in phagocytosis (become foam cells) - and proliferation of smooth muscle cells and fibroblasts.

There are several types of Hyperlipoproteinemia - do not have to know types and what drug is used for each type

Want cholesterol < 200 mg/dl and LDL < 130 mg/dl

Drugs:

1. Niacin - water soluble vitamin - inhibits lipolysis in adipose tissue

Niacin results in decreased VLDL and LDL which results in decreased transport of cholesterol

Pharmacology -- administered orally

Adverse Reactions -- cutaneous flush and warmth - inhibited by aspirin

2) Gemfibrozil - similar to first generation clofibrate

increases lipolysis in blood (breakdown of lipoprotein triglycerides) via increasing lipoprotein lipase - associated with vessel wall - the lipoprotein lipase also increases the removal of VLDL

- decreases in the amount of triglycerides in plasma causes decreasing production of VLDL (get glycerol and fatty acids- both are used for energy)

• also get increased HDL (due to decreased triglycerides)
• LDL levels may very well increase

Pharmacology - totally absorbed orally

bound to plasma protein with a t 1/2 of 1.5 hours

Uses - Treat Hypertriglyceridemias (Types III, IV, V hyperpipdemias)

note that hypertriglyceridemias are only modestly linked to heart disease but atherosclerosis is strongly linked in some groups -- thus treatment is need in only some groups

3) Probucol

Inhibits sterol synthesis (needed to produce cholesterol) and also improves transport of cholesterol from periphery to liver -- this process lowers HDL levels

LDL levels are lowered only marginally

Probucol may be antiatherogenic because it acts as an antioxidant --

the cholesterol that enters the vessel wall is not oxidized - this inhibits formation of foam cells in the arterial intima

Pharmacology - very lipophilic and distributes into adipose tissue - oral administration

the drug is so lipophilic it is poorly absorbed orally -- (a drug has to have some ability to dissolve in the water - this drug has difficulty reaching the surface of the cell)

Uses - Hypercholesteremia -- but because lowering HDL is just as bad as high LDL in producing atherosclerosis -- this drugs usefulness is limited

Adverse affects - Arrhythmias

4) Bile Acid-Binding Resins

Cholestyramine and colestipol

Oral Drugs that bind negatively charged bile salts in the small intestine

the complex is excreted in the feces--

Normally the bile salts (needed for absoprtion of fats in intestine) are returned to the liver by the enterohepatic circulation

if they are not returned the liver breaks down more cholesterol to produce bile salts

To make up for the decreased cholesterol there is an increased number of LDL receptors to obtain cholesterol (thus cholesterol does not enter plaques)

As a result there is a decrease in LDL and some increase in HDL

Orally administered -- because they are insoluble in water and very large they are not absorbed - they combine with bile salts and are excreted

Uses - drug of choice (often combined with Niacin) to treat hyperlipedemia

5) Competitive Inhibitors of HMG-CoA Reductase - Statins

Lovastatin (Mevacor) , pravastatin (Pravachol) , fluvastatin (Lescol), etc

15% of cholesterol is from diet -- 85% is made in body

these drugs are structural analogues to HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) - they are prodrugs that are activated in the intestine – some agents are active as given

drugs function in liver cells (hepatocytes)

the decreased cholesterol levels cause the cell to increase the number of LDL receptors (if the cell can’t make cholesterol it will get it from the blood) -- this will increase the rate of uptake of LDL into the hepatocytes -- reducing levels of LDL

there may be some increased HDL

Pharmacology - The drug has a very large first pass and thus the effects are limited to the liver -- these drugs are very lipophilic and thus only 30% of oral dose is absorbed

Uses - Hypercholesteremia -- often combined with Niacin

All of these drugs produce some Gastrointestinal Disturbance

Nonsteroidal analgesic and anti-inflammatory agents - (steroids later)

Inflammation - important mechanism for protection of body from attack by invading organisms ie. bacteria viruses, tissue damage, etc. (trauma), but inflammation has side effects: arthritis, pain, fever, joint destruction, etc.

Inflammation in brief -

1. leukocytes respond to trauma - phagocytosis, release lysosomal enzymes, histamine etc. get production of oxygen radicals

2. most cells release

Cyclooxygenase --- prostaglandins (endoperoxide)

Lipoxygenase --- leukotrienes

platelet activating factor

also oxygen free radicals - H₂O₂

all of these help heal tissue -- sometimes they get carried away.

I. Aspirin

• 1700's used willow bark to treat pain and fever
• active ingredient was salicin
• which is hydrolyzed to --salicylic acid (found in many plants)
• in 1853 synthesized acetylsalicylic acid (aspirin)

A. Pharmacokinetics

1. quickly absorbed from GI tract - causes some damage to mucosa--inhibits COX I which leads to production of protective prostaglandins

due to absorption of undissolved tablet (acid) and inhibition of protecting PGs

2. t_(1/2) 3-5 hours -- low dose -- first order

3. t_(1/2) = 15 hours -- high doses -- zero order

B. Pharmacodynamics

1. Anti-inflammatory - inhibits prostaglandin synthesis- by blocking irreversibly cyclo-oxygenase. - COX I and COX II equally

2. Analgesic - via its effects on inflammation - PG sensitizes pain receptors this would lead to increased Substance P release - but probably also depresses pain stimuli subcortical - later

3. Antipyretic - reduces fever - dilation of skin blood vessels

fever is due to pyrogens from bacterial infection and release of endogenous pyrogen during inflammation

the latter is probably interleukin 1 (IL-1) which is produced by macrophages during inflammation

-- these pyrogens cause increased production of PG in the hypothalamus which resets the temperature

aspirin:

1) blocks PG production

2) blocks the hypothalamus response to IL-1

IL-1 also stimulates lymphocytes

4. Inhibits platelet aggregation by inhibiting thromboxane synthesis

Doses:

from low dose to high dose:

Antiplatelet----Antipyretic----Analgesis----Antiinflammatory

C. Therapeutic uses- one of the most frequently used drugs to relieve moderate to mild pain

a. combined with other analgesics

b. high doses to treat rheumatoid arthritis

c. decreases myocardial infarction by 40% in males (antiplatelet)

if heart pain--cardiologists recommend chewing one aspirin - block thromboxane

also used are Vit E., black tea (flavinoids)

II. Others

A. Ibuprofen- advil, nuprin -- t_1/2 = 2 hours

GI damage less severe than aspirin, analgesic,

anti-inflammatory-inhibits PG - COX I and COX II equally

From PharmInfoNet! - http://pharminfo.com/pin_hp.html

"Aspirin and other traditional nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase (COX), which is involved in the production of prostaglandins. Prostaglandins are intercellular messengers that are found in high concentrations at sites of chronic inflammation. They are capable of causing vasodilatation, increasing vascular permeability and sensitizing pain receptors.

Although many NSAIDs were developed that block the action of COX, all produced gastritis in many patients -- especially the elderly, those patients with a prior history of peptic ulcer disease and patients on corticosteroids.

It is now known that there are two COX enzymes -- cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The traditional NSAIDs bind to the active sites of both COX-1 and COX-2. Gastritis is caused by the inhibition of COX-1, which is a gastric COX that regulates mucosal cell production of mucous. (The mucous acts as a barrier to the acid and pepsin present in gastric secretions.)

The new NSAIDs recently approved by the FDA or recommended for approval -- celocoxib (Celebrex®) and rofecoxib (Vioxx®) -- selectively block only the COX-2 enzyme and thus are less likely to cause gastritis that occurs when COX-1 is inhibited."

B. Naproxen - Naprosyn -- t_1/2 = 14 hours -- similar to ibuprofen

C. Indomethacin - most potent inhibitor of PG - inhibits COX I primarily

D. Celecoxib (Celebrex),  rofacoxib (Vioxx) and nabumetone (relafen) – COX II primarily – long half life (24 hours)

E. Ketoprofen- inhibits cyclo-oxygenase and lipoxygenase

III. Analgesics- not anti-inflammatory

1) Phenactin- no longer in US - was part of anacin (today it is aspirin and caffeine), causes renal damage.

2) Acetaminophen- Tylenol

metabolite of phenactin with little toxic effects except at high doses (kidney and liver damage)- weak PG inhibitor- not anti-inflammatory

-preferred drug for patients allergic to aspirin - good for mild to moderate pain. No platelet inhibition.

Diverse Effects Of Nonsteroidal Anti-Inflammatory Drugs:

INHIBIT PG SYNTHESIS

INHIBIT NEUTROPHIL AGGREGATION

INHIBIT SUPEROXIDE ANION GENERATION

INHIBIT CHEMOATTRACTANT BINDING TO NEUTROPHIL

ALTER MEMBRANE VISCOSITY OF NEUTROPHILS

Glucocorticoids: Diverse effects of steroidal anti-inflammatory agents:

· bind to intracellular receptors and modulate gene expression

· induce production of proteins which are known collectively as lipocortins

· inhibit phospholipase A and thus block prostaglandin and leukotriene production

· decrease intracellular Ca++ due to increased Ca++ pump activity

· inhibit production of various cytokines (IL-1, IL-2)

· inhibit release of PAF from inflammatory neutrophils

· increase number of circulating neutrophils

· promote sequestration of circulating lymphocytes and monocytes in the spleen, lymph nodes and bone marrow

· inhibit granulocyte adherence

· inhibit ICAM and ELAM adhesion receptors on endothelium (6-9 hours)

· inhibit CD11/CD18 adhesion receptors on neutrophils (30 minutes but need 10-2 M)

Recent studies indicate that glucocorticoids exert anti-inflammatory effects at basal concentrations.

IV. Inflammation - a lot of research on this area

Why only in venules? Specific receptors - how do you control LEA? This is first step in inflammation.

Does NSAID block an adhesion receptor?

A. L-selectin (LECAM-1) found on WBCs (selectin) homing receptor- rolling and initial adhesion, always present- down regulated by C5A, LTB4

B. P-selectin (GMP 140) found on endothelium (selectin) upregulated in minutes by histanime, thrombin, etc.

C. CD11/CD18 found on WBCs (integrin) small amount normally upregulated in minutes by C5A, LTB4, FMLP

D. ICAM found on endothelium (integrin) Intracellular Adhesion molecule, small amount normally present - upregulated in hours by released in hours IL-1, TNF, endotoxin

E. E-selectin - Endothelial Leukocyte Adhesion Molecule (ELAM) (selectin),

not present under control conditions, upregulated in hours by IL-1 and TNF

 

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