Toxicology I

1
Toxicology I

• Anticoagulants
• Blood coagulation is an interactive process
  between Damaged endothelial cells, Platelets, and
  Various proteins in blood

2
Toxicology I

• Most of these proteins (if not all) are
  synthesized in the liver and are in the INACTIVE
  FORM
• A series of SERINE PROTEASES convert this
  inactive form ZZZZZ to the active form what?
  Where? How?... In specific sequences
• It is an extremely complex process.

3
Toxicology I

• Three types of natural anticoagulant
• 1. Antithrombins (e.g. Antithrombin III)
• Inhibit the activity of thrombin and other serine
  proteases, particularly factors
• IIa (thrombin)
• IXa (activated Xmas factor)
• Xa (stewart-prower factor)
• XIa
• XII Activated Hageman factor

4
Toxicology I

• Heparin
• How does it work?
• The active heparin molecules bind tightly to
  Antithrombin
• This causes a conformational change in this
  inhibitor (antithrombin)
• This conformational change of antithrombin
  exposes its active site for more rapid
  interaction with the activated clotting factor
  proteases especially
• IIa, IXa, and Xa
• by forming equimolar stable complexes with
  them.

5
Toxicology I

• Heparin catalyzes the antithrombin-protease
  reaction without being consumed. Once the
  antithrombin-protease complex is formed, heparin
  is released for renewed binding to more
  antithrombin.
• Under normal situation, i.e., without heparin.
• Active Clotting Factor
• IIa
• IXa
• Xa Antithrombin III
• XIa binds these factors
• XIIa BUT VERY SLOWLY
• XIIIa
• Inactive Factors

6
Toxicology I

• WITH HEPARIN
• Active Clotting Factors
• IIa, IXa, Xa, XIa, XIIa, XIIIa
• Antithrombin III binds these
• Factors VERY RAPIDLY
• In the presence of heparin
• Inactive Factors
• Remember that anticoagulant therapy
  provides prophylaxis against venous and arterial
  thrombosis. They CANNOT dissolve clots that have
  already formed but may prevent or slow extension
  of an existing clot.

7
Toxicology I

• They are useful in preventing deep vein
  thrombosis and pulmonary embolism.
• It must be given by s.c. or IV. By IV route it
  has an ALMOST IMMEDIATE ANTICOAGULANT EFFECT.
• 1. It is obtained from porcine intestine or
  bovine lung tissue and should be used cautiously
  in patients with allergy.
• 2. Reversible alopecia (baldness)
• 3. Long term therapy associated with
  osteoporosis and spontaneous fractures.
• 4. Causes transient thrombocytopenia in 25 or
  more of patients and severe in 5.
• 5. Bleeding complications ? factor X

8
Toxicology I

• There is high molecular weight heparin
  (unfractionated MW 5,000-30,000).
• Commercial heparin consists of a family of mols.
  Of different mol. Wts. This means that the
  correlation between the concentration of a given
  heparin preparation or its anticoagulant effect
  is often poor.
• UFH is often standardized by bioassay.
• Heparin Na USP must contain at least 120 USP
  units per mg.
• The shorter chain low molecular weight fractions
  of heparin inhibit activated factor X but have
  less effect on thrombin (IIa) and on coagulation
  in general.
• Examples of LMW Heparins
• Enoxaparin
• Dalteparin
• Tinzaparin

9
Toxicology I

• LWM Heparins are effective in certain
  thromboembolic conditions.
• They have good efficacy
• Increased bioavailability from the subcutaneous
  site
• Require less frequent dosing.
• Reversal of Heparin action But protamin-forms a
  stable complex
• Excess Protamine MUST BE AVOIDED.
• It also has an anticoagulant effect.

10
Toxicology I

• Direct Thrombin Inhibitors (DTI)
• Relatively new class of agents
• They directly bind to the active site of thrombin
  II thereby inhibiting thrombins downstream
  effects. Note Activated thrombin (IIa)
  converts fibrinogen to fibrin.
• DTIs bind thrombin WITHOUT additional binding
  proteins-such as, antithrombin.
• They do NOT bind to other plasma proteins, such
  as platelet factor IV.
• Examples Hirudin
• Bivalirudin
• Argatroban
• Melagatran

11
Toxicology IHirudin

• Hirudin is a specific, irreversible thrombin
  inhibitor obtained from the LEECH. Note It is
  now available in a recombinant form and is known
  as LEPIRUDIN
• How does it work?
• It can reach fibrin-bound thrombin in thrombi and
  inactivate it.
• Lepirudin has little effect on platelets or the
  bleeding time.
• Lepirudin is used for treatment of patients who
  have thrombosis and thrombocytopenia as a result
  of an antibody-mediated reaction to heparin (this
  autoantibody binds to a complex of heparin and
  platelet factor IV).

12
Toxicology IHirudin (continue)

• Lepirudin has a short half life.
• It accumulates in renal insufficiency !!!
• Lepirudin is used to prevent thrombosis in the
  fine vessels of reattached digits.
• Up to 40 of patients on long term infusions
  develop an antibody directed against the thrombin
  lepirudin complex. These complexes are NOT
  cleared by the kidney and may result in an
  ENHANCED ANTICOAGULANT EFFECT.
• No ANTIDOTE AVAILABLE.

13
Toxicology I

• BIVALIRUDIN
• IV with a rapid onset of action
• Short half-life
• Inhibits platelet aggregation
• FDA approved for use in percutaneous angioplasty

14
Toxicology I

• ARGATROBAN
• FDA approved for use in patients with heparin
  induced thrombocytopenia (HIT) with or without
  thrombosis. Also, for coronary angioplasty in
  patients with HIT
• Its clearance is NOT affected by renal disease
  but is dependent on the LIVER FUNCTION.
• Requires a dose reduction in patients with liver
  disease.

15
Toxicology IAntithrombin III

• It is a commercial preparation of an endogenous
  human anticoagulant- (antithrombin III)
• Do you remember when we talked about the mode of
  action of heparin?
• Regular heparin binds to and activates endogenous
  antithrombin III. The heparin-ATIII complex
  combines with and inactivates thrombin (activated
  factor II) and several other factors, especially
  factor X.

16
Toxicology IAntithrombin III (cont.)

• Antithrombin III (commercial preparation) is used
  for treatment of patients who NEED
  anticoagulation but are RESISTANT to heparin
  because of a genetic deficiency in antithrombin
  III and ALSO in some cases of acquired
  antithrombin III deficiency (e.g. in disseminated
  intravascular coagulation).
• Important Heparin does not cross the placental
  barrier. Therefore, it is the drug of choice
  when an anticoagulant MUST be used in pregnancy.
  LMW heparins have similar clinical applications.

17
Toxicology IWARFARIN and the COUMARIN
ANTICOAGULANTS

• The oral anticoagulants are vitamin K antagonists
• Several of the protein coagulation factors
  viz.,Factors II, VII, IX, and X REQUIRE vitamin K
  for their activation BEFORE they can participate
  in the clotting process.
• Therefore, the ORAL anticoagulants DELAY
  activation of new coagulation factors.
• They DO NOT affect the factors that have already
  been activated.

18
Toxicology I WARFARIN and the COUMARIN
ANTICOAGULANTS (cont.)

• The above statement means that there is a DELAY
  in the onset of action of the oral anticoagulant.
• The anticoagulant effect of warfarin are NOT
  observed until 8 to 12 hours AFTER drug
  administration.
• The anticoagulant effects of warfarin can be
  overcome by the administration of vit. K
  HOWEVER, REVERSAL by vit. K takes approximately
  24 hours.
• Please note, that the bacteria in the GI tract
  produce vit. K

19
Toxicology IWhat is the mechanism of action of
warfarin?

• Coagulation factors II, VII, and X require gamma
  carboxylation on glutamic acid residues in order
  to bind calcium during coagulation reaction.
• Vitamin K is required for this carboxylation
• While acting as a cofactor vitamin K is converted
  to vitamin k epoxide.

20
Toxicology I What is the mechanism of action of
warfarin? (cont.)

• The epoxide is then recycled via reductase
  reactions to active forms of vitamin k.
• Warfarin INHIBITS the reductase enzymes involved
  in the recycling of vitamin k thus leading to a
  deficiency of procoagulant forms of factors II,
  VII, IX, and X.
• Because some of these factors have prolonged half
  lives anticoagulant action is NOT achieved for
  several days.

21
Toxicology IAbsorption of Warfarin

• Na-salt of warfarin is rapidly and completely
  absorbed (100) after ORAL administration.
• 99 bound to plasma albumin which PREVENTS its
  diffusion into the CSF, urine and breast milk.
• However, drugs having a greater affinity for
  albumin binding site, such as, sulphonamides, can
  displace the anti-coagulant and lead to a
  transient elevated activity.

22
Toxicology IEXCRETION

• Excretion in the urine and stool after
  conjugation to glucouronic acid.
• How to treat adverse effects of warfarin?
• Withdrawal of the drug
• Administration of vitamin K, given by IV
• Whole blood transfusion
• Frozen plasma
• Plasma concentrate of the blood factors
• Note Warfarin CAN CAUSE BONE DEFECTS and
  HEMORRHAGE in the developing fetus therefore,
  is contraindicated in pregnancy.

23
Toxicology IDRUG INTERACTIONS

• Cytochrome P450 inducing drugs (e.g.
  barbiturates, carbamazepine, phenytoin), INCREASE
  warfarins clearance and thereby REDUCE the
  anticoagulant effect of a given dose.
• Cytochrome P450 inhibiting drugs (e.g.
  amiodarone, cimetidine, disulfiran) REDUCE
  warfarins clearance and INCREASE the
  anticoagulant effect of a given dose.

24
Toxicology IWhat is the difference between
anticoagulant/anti-platelet drugs and
thrombolytic drugs?

• Anticoagulant/antiplatelet drugs are administered
  to PREVENT the formation of clots.
• Thrombolytic drugs are used to LYSE already
  formed clots.

25
Toxicology IHow do these thrombolytic or
fibrinolytic drugs act?

• Fibrinolysis is the process of breaking down the
  fibrin that holds the clot together.
• Fibrinolysis is inititated by the activation of
  plasminogen to plasmin. The plasmin then
  catalyzes the degradation of fibrin.
• The activation of plasminogen is normally
  initiated by plasminogen activators.
• THE THROMBOLYTIC DRUGS ARE PLASMINOGEN ACTIVATORS

26
Toxicology IWhat are the TWO generations of
plasminogen activators?

• The First Generation
• The first generation of drugs (streptokinase and
  urokinase) convert ALL plasminogen to plasmin
  THROUGHOUT THE PLASMA !!
• The Second Generation
• The second generation of drugs tissue type
  plasminogen activator (t-PA) SELECTIVELY ACTIVATE
  plasminogen BOUND TO FIBRIN ! In fact, t-PAs
  selectively appears to be quite limited
  (Altepase Reteplase).

27
Toxicology IBasic Pharmacology of Anti-Platelet
Agents

• Platelets are regulated by THREE categories of
  substances
• I. Agents generated OUTSIDE the platelets. They
  interact with platelets membrane receptors.
  e.g.
  catecholamines, collagen, thrombin, prostacyclin.
• II. Agents generated WITHIN the platelets. They
  interact with platelet membrane receptors.
  e.g.
  ADP,PGD2,PGE2, Serotonin
• III. Agents generated WITHIN platelets. They
  act within the platelets.
  
  e.g. Prostaglandin Endoperoxides, thromboxane A2,
  cAMP, cGMP, Caion

28
Toxicology IChemical Signals That OPPOSE
Platelet Activation

• 1. Elevated Prostacyclin (PGI2) Levels
• PGI2 synthesized by the INTACT ENDOTHELIAL cells
• Are released into plasma
• And Binds to a specific set of platelet membrane
  receptors
• That are coupled to the synthesis of cAMP
• As an intracellular message
• Elevated levels of intracellular cAMP INHIBIT
  platelet activation and subsequent release of
  platelet aggregation agents.

29
Toxicology I Chemical Signals That OPPOSE
Platelet Activation (cont.)

• Decreased Plasma Levels of Thrombin and
  Thromboxanes
• The platelet membrane also contains receptors
  that can bind
• THROMBIN (the protease that converts fibrinogen
  to fibrin)
• THROMBOXANES (TXA2) (influence platelet
  aggregation)
• In the INTACT, normal blood vessel, circulating
  levels of THROMBIN and TXA2 are LOW and the
  INTACT endothelium COVERS the collagen present in
  the subendothelial layers.
• The corresponding platelet receptors are thus
  unoccupied and, therefore, remain INACTIVE.
• Platelet activation and aggregation are NOT
  initiated.

30
Toxicology IChemical Signals That Promote
Platelet Aggregation

• 1. Decreased Prostacyclin Levels (PGI2)
• Damaged endothelial cells
• Synthesize LESS PGI2
• Resulting in LOCALIZED decrease in PGI2 levels
• The binding of PGI2 to platelet receptors is
  DECREASED
• Resulting in LOWER LEVELS of intracellular cAMP
• This ENCOURAGES platelet aggregation
• High levels intracellular
• cAMP
• Low Levels of intracellular
• cAMP

31
Toxicology I Chemical Signals That Promote
Platelet Aggregation

• Exposed Collagen
• Within seconds of vascular injury
• Platelets ADHERE (stick) to and virtually cover
  the EXPOSED collagen of the subendothelium (via
  von Willebrands factor from alpha granules of
  platelets)
• Receptor on the SURFACE of the platelets are
  ACTIVATED by the collagen of this underlying
  tissue.
• This triggers the release of platelet granules
  containing
• ADP, Serotonin, histamine, Ca, and
  epinephrine (from delta granules)
• This process is sometimes referred to as the
  platelet release reaction and the platelet is
  then said to be activated.

32
Toxicology I Chemical Signals That Promote
Platelet Aggregation

• Increased Synthesis of Thromboxanes (Txa2)
• Stimulation of platelets by
• THROMBIN (with activation of the coagulation
  cascade thrombin is generated. Thrombin binds to
  a platelet surface receptor and with ADP and TXA2
  results in further aggregation)
• COLLAGEN and
• ADP
• Results in activation of platelet MEMBRANE
  PHOSPHOLIPASES

33
Toxicology I
34
Toxicology IIII. Anti-platelet Agents

• A.
• Acetyl group is transferred to cyclooxygenase.
• Note Acetylated cyclooxygenase is INACTIVE
• Acetylation of cyclooxygenase is IRREVERSABLE
• Mode of action of Low DOSES of Aspirin (i.e. 81
  mg or between 60 to 81 mg. Also known as baby
  aspirin.)

35
Toxicology IWithout Aspirin (or normal
physiological situation)

• THROMBOXANE (TXA2) It is generated within the
  platelets
• 1. Enhances (increases) platelet
  aggregation
• 2. TXA2 also causes
  vasoconstriction (changed from vasodilatation in
  classcheck book!)
• II. Prostacyclins (PGI2) Generated by the
  endothelial cells of the blood vessels.
• 1. Decreases platelet aggregation
• 2. PGI2 also causes
  vasoconstriction (was vasodilatationcheck book!)

36
Toxicology IWith Low Doses of Aspirin

• I. Effect on Thromboxane (TXA2)
• Aspirin can IRREVERSIBLY INHIBIT TXA2
  production in platelets.
• Therefore, There is no platelet aggregation
  and there is no vasoconstriction.
• II. Effect on Prostacyclins (PGI2)
• Aspirin DOES NOT markedly affect the
  production of PGI2 in the endothelial cells of
  the blood vessels (applies only to low doses of
  aspirin).
• Therefore, PGI2 production remains nearly
  to normal levels.
• Therefore, PGI2 will continue to have its
  vasodilating effect.
• Note Lifetime of platelets is 3 to 7
  days.

37
Toxicology I With Low Doses of Aspirin (continue)

• B. CLOPIDOGREL (Plavix)
• and
• C. TICLOPIDINE (TICLID)
• ADP is one of the agents generated within the
  platelets and interacts with platelets membrane
  receptors.

38
Toxicology I With Low Doses of Aspirin (continue)

• Clopidogrel
• A dose of 75 mg/day is used.
• Prolongs the skin bleeding time to a similar
  extent as low-dose aspirin.
• As effective as aspirin in reducing the risk of
  arterial thrombosis in patients with recent
  myocardial infarction, recent ischemic stroke, or
  chronic peripheral arterial disease.
• As safe as aspirin, with a lower risk of
  dyspepsia (upset stomach) but a higher risk of
  diarrhea and skin rash.
• More expensive than aspirin (useful for those
  patients who cannot tolerate aspirin).

39
Toxicology I Clopidogrel (continued)

• Important application The combination of
  clopidogrel and aspirin appears more effective
  than aspirin alone (or anticoagulants) in
  prevention of thrombosis following coronary
  angioplasty with stenting.
• Please NOTE that clopidogrel is an analog of
  TICLOPIDINE. Clopidogrel has replaced
  Ticlpidine, which has a significant risk of
  netropenia (neutrophil is a mature white blood
  cell in a granulocytic series. Netropenia means
  the presence of abnormally less numbers of
  neutrophils in the circulating blood) requiring
  monitoring of the white blood cell count.

40
Toxicology IDipyridamole (Persantine)

• It inhibits the uptake of adenosine into
  platelets, endothelial cells and erythrocytes.
  This inhibition results in an increase in local
  concentrations of adenosine which acts on a
  platelet A_at_ receptor thereby increasing platelets
  cAMP levels. Via this mechanism, platelet
  aggregation is inhibited (we have previously
  discussed this mechanism)
• It also inhibits thromboxane A2 formation which
  is a potent stimulator of platelet activation.

41
Toxicology I Dipyridamole (Persantine)
continued

• It can decrease systemic and coronary vascular
  resistance leading to decreases in systemic blood
  pressure (vasodilating action) and increases in
  coronary blood flow. However, it may WORSEN
  regional myocardial perfusion DISTAL to partial
  occlusion of coronary arteries.
• (can provoke myocardial ischemia)
• It is, therefore, contraindicated in patients
  with angina (particularly unstable angina) IT IS
  FOR THIS REASON THAT IT IS USED IN CARDIAC STRESS
  TESTING.

42
Toxicology I Dipyridamole (Persantine)
continued

• Whether or not the combination of Dipyridamole
  and aspirin is more effective than aspirin alone
  in secondary prevention of cardiovascular events
  after stroke or transient cerebral ischemia is
  CONTROVERSIAL.
• In combination with warfarin, however,
  Dipyridamole is effective in inhibiting
  embolization from prosthetic heart valves.
• It is also used to image regions of myocardium at
  risk for ischemia. (Persantine---Thallium scans).
• Side effects Dizziness, angina, abdominal pain,
  headache, rash.

43
Toxicology ISulfinpyrazone

• It inhibits prostaglandin synthesis
• Inhibits platelet functions, including release of
  platelet factors and adherence to subendothelial
  cells.
• UNLIKE ASPIRIN, Sulfinpyrazone can ALSO PROLONG
  THE SURVIVAL OF PLATELETS in patients with
  various disorders.
• It is therapeutically employed as a uricosuric
  agent.
• Side effects Upper GI Distress
• Rash
• Renal calculi
• Acute gouty arthritis
• Anemia
• Leukopenia
• Aplastic anemia

44
Toxicology INon-Steroid Anti-Inflammatory Drugs
(NSAIDS)/Non-Opiate Analgesias/ Drugs used in
Gout

• TWO primary goals
• The relief of pain
• Slowing or arrest of the tissue-damaging process
• Inflammation is a normal, protective response to
  tissue injury that is caused by
• Physical Trauma
• Noxious chemicals
• Microbial agents

45
Toxicology I Non-Steroid Anti-Inflammatory
Drugs (NSAIDS)/Non-Opiate Analgesias/ Drugs
used in Gout..(cont.)

• Inflammation is the bodies effort to
• Inactivate or destroy invading organisms
• Remove irritants
• And set the stage for tissue repair
• When healing is complete, the inflammatory
  process usually subsides.
• Sometimes inflammatory process becomes CHRONIC
  WITHOUT resolution of the underlying injurious
  process.

46
Toxicology IInflammation (continued)

• CHRONIC INFLAMMATION TRIGGERS the release of
  chemical mediators from injured tissues and
  migrating cells (Note this does not occur in the
  acute response).
• The specific chemical mediators vary with the
  type of inflammatory process and include
• Amines such as histamine and 5-hydroxy
  tryptoamine.
• Lipids such as the prostaglandins
• Small peptides such as bradykinin
• Large peptides such as interleukin-1 (IL-1)

47
Toxicology I

• Discovery of such a variety of chemical mediators
  has clarified the apparent paradox that different
  drugs are effective in treating ONE FORM of
  inflammation BUT NOT OTHERS.
• Cyclooxygenase -1 (COX -1)
• Cox-1 isoform is constitutive and tends to be
  homeostatic in function.
• Cyclooxygenase -2 (COX-2)
• Cox-2 is INDUCED DURING inflammation and tends to
  facilitate the inflammatory process (response).

48
Toxicology I

• Specific inhibitors of cox-1
• Indomethacin (indocine)
• Piroxicam (feldene)
• Aspirin
• Specific inhibitors of cox-2
• Celecoxib (celebrex)
• Rofecoxib (vioxx)
• Valdecoxib (bextra)

49
Toxicology I

• Non-Specific (Inhibits cox-1 and cox-2)
• Ibuprofen (advil)
• Naproxen (anaproxnaprosyn)
• Diclofenac (voltaren)
• Some cox-2 inhibition but still have a potent
  effect on cox-1
• Meloxicam (mobic)
• Nabumetone (Relafen)
• Etodolac (lodine)

50
Toxicology I

• Agents that can bind and dissociate from the cox
  enzymes (simple competitors to cyclooxygenase)
• Ibuprofen (advil)
• Naproxen
• Piroxicam (feldene)
• Sulindac (clinoril)

51
Toxicology I

• Agents that can cause a conformational change in
  the cox enzymes, resulting in robust binding
  which deteriorates over time. Therefore, longer
  acting than the simple competitors.
• Diclofenac (voltaren)
• Flubiprofen (ansaid)
• Indomethacin (indocin)
• Meclofenamate (meclomen)

52
Toxicology ILet Us Revisit Aspirin

• We have already discussed that aspirin is unique
  among the NSAIDS in irreversibly acetylating (and
  thus inhibiting) cyclooxygenase. The other
  NSAIDS are ALL REVERSIBLE inhibitors of
  cyclooxygenase.
• What we have NOT discussed is that aspirin is
  also rapidly deacetylated by ESTERASES in the
  body, PRODUCING SALICYLATE. It is salicylate
  (salicylic acid) which has
• Anti-inflammatory,
• Anti-pyretic, and
• Analgesic effects
• COOH ---------? Aspirin ----------? COOH OH?
  salicylic Acid
• CH3COO- esterases

53
Toxicology IMechanism of Action of Salicylates

• Anti-pyretic and anti-inflammatory effects of the
  salicylates are due primarily to
• Inhibition of PG synthesis at the
  thermoregulatory centers in the hypothalamus and
  also at the peripheral target sites.
• The blockade of PG synthesis prevents the
  sensitization of pain receptors to both
  mechanical and chemical stimuli
• Aspirin may also depress pain stimuli at the
  thalamus and hypothalamus.
• Anti inflammatory action is due to the inhibition
  of PG synthesis.
• Note Aspirin INHIBITS inflammation but NEITHER
  ARRESTS the progress of the disease nor induces
  remission.

54
Toxicology IAnalgesic Action

• PGE2 is thought to SENSITIZE the nerve endings to
  the action of bradykinin, histamine and other
  chemical mediators released locally by the
  inflammatory process.
• Thus, by decreasing PG synthesis aspirin and
  other NSAIDS inhibit the sensation of pain.
• NOTE The salicylates are used mainly for the
  management of pain of Low to Moderate INTENSITY
• The Salicylates are NOT used for pain arising
  from the viscera.

55
Toxicology IAntipyretic Action

• Fever occurs when an ENDOGENOUS fever-producing
  agent (pyrogen) is released from the white cells
  that are activated by infection, hypersensitivity
  or inflammation.
• Aspirin is effective in rapidly reducing the body
  temperature of febrile patients through increased
  heat dissipation as a result of vasodilation.
• Note Aspirin has little effect on normal body
  temperature.

56
Toxicology IRespiratory Actions

• At therapeutic doses aspirin increases alveolar
  respiration
• Higher doses of aspirin work directly on the
  respiratory center, resulting in hyperventilation
  and respiratory alkalosis, which is adequately
  compensated by the kidney.

57
Toxicology IG. I. Effects

• Normally, prostacyclin (PGI2) inhibits gastric
  acid secretion, whereas, PGE2 and PGF2- alpha
  stimulates synthesis of protective mucous
  protection. This may cause epigastric distress,
  ulceration, and/or hemorrhage.
• In the presence of aspirin, PGs and Prostacyclins
  are NOT synthesized, resulting in increased acid
  secretion and diminished mucous protection. This
  may cause epigastric distress, ulceration, and/or
  hemorrhage.

58
Toxicology IAction of the Kidney

• Aspirin PREVENTS the synthesis of PGE2 and PGI2
  which are responsible for maintaining renal blood
  flow, particularly in the presence of circulating
  vasoconstrictors.
• Decreased synthesis of PGs can result in
  retention of sodium and water and may cause edema
  and hyperkalemia in some patients.
• Note Interstitial nephritis can also occur with
  all of the NSAIDS EXCEPT aspirin.

59
Toxicology IAcetominophen aka Tylenol

• Acetominophen has analgesic and antipyretic
  activity but has WEAK anti-inflammatory activity
  and is, therefore, NOT useful in the treatment of
  inflammation such as those seen with rheumatoid
  arthritis.
• NOTE Acetaminophen inhibits PG synthesis in the
  CNS but much less in peripheral tissue.
  Therefore, good analgesic and anti-pyretic
  activity but very weak anti-inflammatory
  activity.

60
Toxicology I Acetominophen. (continued)

• Glutathione normally binds to acetaminophen and
  inactivates formation of N-acetyl-p-benzoquinone
  which can bind to hepatic proteins and cause
  liver necrosis.
• Antidote for overdose of acetaminophen is
  N-acetylcysteine (mucomyst). Mucomyst is thought
  to replenish hepatic stores of glutathione.

61
End of toxicology I material

• Questions?