Study your flashcards anywhere!

Download the official Cram app for free >

  • Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

How to study your flashcards.

Right/Left arrow keys: Navigate between flashcards.right arrow keyleft arrow key

Up/Down arrow keys: Flip the card between the front and back.down keyup key

H key: Show hint (3rd side).h key

A key: Read text to speech.a key

image

Play button

image

Play button

image

Progress

1/93

Click to flip

93 Cards in this Set

  • Front
  • Back
Heparin
Heparin, acting in the blood, is an indirect thrombin inhibitor. Its antithrombotic effect is exerted by its interaction with the plasma protease inhibitor antithrombin.

Heparin exerts its anticoagulant activity by binding to antithrombin, causing a change in the conformation of antithrombin and increasing its anticoagulant properties. Antithrombin inhibits clotting factor proteases, especially thrombin (IIa), IXa, and Xa

Heparin facilitates the antithrombin-protease reaction without being consumed. Once the antithrombin-protease complex is formed, heparin is released intact for renewed binding to more antithrombin molecules. Protamine Sulfate (IV), a mixture of low MW peptides that are rich in arginine residues (highly basic; pKa 13.2) (+ Charged), is an antidote (specific antagonist) for heparin

The major adverse effect of heparin is bleeding. Long-term therapy is associated with osteoporosis and mineralocorticoid deficiency
Lepirudin
The DTIs exert their anticoagulant effect by directly binding to the active (catalytic) site of thrombin, thereby inhibiting thrombin’s downstream effects.

Unlike heparin, they do not bind to antithrombin or other plasma proteins (such as platelet factor 4).

Lepirudin and bivalirudin are bivalent DTIs; they bind to both the active site of thrombin as well as to a substrate recognition site on the thrombin molecule. Argatroban binds only to the active site of thrombin.
Bivalirudin
The DTIs exert their anticoagulant effect by directly binding to the active (catalytic) site of thrombin, thereby inhibiting thrombin’s downstream effects.

Unlike heparin, they do not bind to antithrombin or other plasma proteins (such as platelet factor 4).

Lepirudin and bivalirudin are bivalent DTIs; they bind to both the active site of thrombin as well as to a substrate recognition site on the thrombin molecule. Argatroban binds only to the active site of thrombin.
Argatroban
The DTIs exert their anticoagulant effect by directly binding to the active (catalytic) site of thrombin, thereby inhibiting thrombin’s downstream effects.

Unlike heparin, they do not bind to antithrombin or other plasma proteins (such as platelet factor 4).

Lepirudin and bivalirudin are bivalent DTIs; they bind to both the active site of thrombin as well as to a substrate recognition site on the thrombin molecule. Argatroban binds only to the active site of thrombin.
Coumadin
Warfarin, acting in the liver, blocks the y-carboxylation of several glutamate residues in vitamin K-dependent clotting factors, including prothrombin (factor II) and factors VII, IX, and X, as well as the endogenous anticoagulant proteins C and S.

The carboxylation of prothrombin and other vitamin K-dependent clotting factors is an important step in the biosynthesis of these factors and is physiologically coupled with the oxidative deactivation of vitamin K. Warfarin blocks this protein carboxylation reaction by inhibiting vitamin K epoxide reductase enzyme which catalyzes the reductive metabolism of the inactive vitamin K epoxide back to its active hydroquinone form.

Blocking the carboxylation of prothrombin and other clotting factors results in incomplete molecules that are biologically inactive in coagulation.

Mutational change of vitamin K epoxide reductase can give rise to genetic resistance to warfarin in humans.

Warfarin crosses the placenta and can cause a hemorrhagic disorder in the fetus. In addition, -carboxylation of glutamate residues in fetal proteins found in bone and blood may be affected by warfarin; warfarin can cause a serious birth defect characterized by abnormal bone formation. Consequently, warfarin is contraindicated during pregnancy.

Excessive anticoagulant effect and bleeding from warfarin can be reversed by discontinuing the drug and administering vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin complex concentrates (PCC), and recombinant clotting factor VIIa, in order to reestablish normal activity of the clotting factors
Streptokinase
Streptokinase is a protein derived from Streptococci.

It binds to the proactivator plasminogen to form an enzymatic complex; the complex catalyzes the conversion of inactive plasminogen to active plasmin.

Plasmin formed inside a thrombus by the action of streptokinase is protected from the antiplasmins that are present in plasma, which allows it to lyse the thrombus from within.

The drug Anistreplase consists of a complex of the proactivator plasminogen and bacterial streptokinase that has been acylated to protect the enzyme’s active site.

Inhibition of the process of fibrinolysis (ie, inhibiting the conversion of inactive plasminogen to active plasmin) protects blood clots from lysis and reduces bleeding. The drug Aminocaproic Acid, which inhibits the activation of plasminogen to plasmin, is an effective therapeutic agent in some bleeding disorders
Urokinase
Urokinase is a human enzyme synthesized by the kidney.

It directly converts plasminogen to active plasmin.

Plasmin formed inside a thrombus by the action of urokinase is protected from the antiplasmins that are present in plasma, which allows it to lyse the thrombus from within.

Inhibition of the process of fibrinolysis (ie, inhibiting the conversion of inactive plasminogen to active plasmin) protects blood clots from lysis and reduces bleeding. The drug Aminocaproic Acid, which inhibits the activation of plasminogen to plasmin, is an effective therapeutic agent in some bleeding disorders
Tissue Plasminogen Activator (t-PA)
Plasminogen can be activated endogenously by t-PA.

t-PA preferentially activates plasminogen that is bound to fibrin. Consequently, t-PA preferentially targets the formed thrombus and avoids systemic activation of plasminogen.

The drug Alteplase is a recombinant human t-PA.

The drug Reteplase is another recombinant human t-PA that lacks the major fibrin-binding domain; as a result, it is less fibrin-specific than t-PA.

The drug Tenecteplase is a mutant form of t-PA that has a longer half-life; it is slightly more fibrin-specific than t-PA.

Inhibition of the process of fibrinolysis (ie, inhibiting the conversion of inactive plasminogen to active plasmin) protects blood clots from lysis and reduces bleeding. The drug Aminocaproic Acid, which inhibits the activation of plasminogen to plasmin, is an effective therapeutic agent in some bleeding disorders
Aspirin (Antiplatelet)
The prostaglandin thromboxane A2 (TXA2) is an arachidonic acid product that causes platelets to change shape, release their granules, and aggregate. Drugs that inhibit this particular pathway interfere with platelet aggregation and prolong the bleeding time.

Aspirin inhibits the synthesis of TXA2 by irreversible acetylation of the enzyme cyclooxygenase (COX)
Clopidogrel
Adenosine diphosphate (ADP), generated within the platelet, is a potent inducer of platelet aggregation.

Clopidogrel and ticlopidine reduce platelet aggregation by inhibiting the ADP pathway. They irreversibly block the ADP receptor on platelet membranes.

Unlike aspirin, they have no effect on prostaglandin metabolism.

Both drugs are effective in preventing vascular events among patients with transient ischemic attacks, completed strokes, and unstable angina pectoris.
Ticlopidine
Adenosine diphosphate (ADP), generated within the platelet, is a potent inducer of platelet aggregation.

Clopidogrel and ticlopidine reduce platelet aggregation by inhibiting the ADP pathway. They irreversibly block the ADP receptor on platelet membranes.

Unlike aspirin, they have no effect on prostaglandin metabolism.

Both drugs are effective in preventing vascular events among patients with transient ischemic attacks, completed strokes, and unstable angina pectoris.
Abciximab
The IIb/IIIa complex is a platelet membrane receptor for fibrinogen and vibronectin (mainly) as well as few other blood clotting factors. Activation of this receptor complex is a common pathway for platelet aggregation.

Abciximab is a humanized monoclonal antibody directed against the IIb/IIIa receptor complex.

Eptifibatide and Tirofiban are analogs of the fibrinogen amino acid sequence which mediates the binding of fibrinogen to the IIb/IIIa receptor complex. They specifically inhibit the binding of fibrinogen to the receptor complex by binding to and blocking the fibrinogen binding site which is located within the receptor complex (ie, they are ‘antagonists’); they do not block, however, the vibronectin binding site (also located within the IIb/IIIa receptor complex)
Eptifibatide
The IIb/IIIa complex is a platelet membrane receptor for fibrinogen and vibronectin (mainly) as well as few other blood clotting factors. Activation of this receptor complex is a common pathway for platelet aggregation.

Abciximab is a humanized monoclonal antibody directed against the IIb/IIIa receptor complex.

Eptifibatide and Tirofiban are analogs of the fibrinogen amino acid sequence which mediates the binding of fibrinogen to the IIb/IIIa receptor complex. They specifically inhibit the binding of fibrinogen to the receptor complex by binding to and blocking the fibrinogen binding site which is located within the receptor complex (ie, they are ‘antagonists’); they do not block, however, the vibronectin binding site (also located within the IIb/IIIa receptor complex)
Tirofiban
The IIb/IIIa complex is a platelet membrane receptor for fibrinogen and vibronectin (mainly) as well as few other blood clotting factors. Activation of this receptor complex is a common pathway for platelet aggregation.

Abciximab is a humanized monoclonal antibody directed against the IIb/IIIa receptor complex.

Eptifibatide and Tirofiban are analogs of the fibrinogen amino acid sequence which mediates the binding of fibrinogen to the IIb/IIIa receptor complex. They specifically inhibit the binding of fibrinogen to the receptor complex by binding to and blocking the fibrinogen binding site which is located within the receptor complex (ie, they are ‘antagonists’); they do not block, however, the vibronectin binding site (also located within the IIb/IIIa receptor complex)
Lovastatin
They are most effective in reducing LDL levels

HMG-CoA reductase enzyme mediates the first committed step in sterol biosynthesis (including cholesterol biosynthesis). It converts HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) to mevalonate.

HMG-CoA reductase inhibitors (the statins) are structural analogs of the HMG-CoA intermediate that is formed during the reductive conversion of HMG-CoA to mevalonate.

The statins are competitive inhibitors of HMG-CoA reductase enzyme. They inhibit the de novo synthesis of cholesterol, leading to a decrease in cholesterol levels.

In addition, the statins induce an increase in high-affinity LDL receptors (as a result of decreased cholesterol levels), leading to an increase in the catabolic rate of LDL and an increase in the liver’s extraction of LDL precursors (IDL). Consequently, plasma LDL levels are reduced.

The statins also cause modest decreases in plasma triglycerides and small increases in HDL levels.

All statins have high first-pass extraction by the liver; as a result, the majority of their effect is on the liver.

Elevation of serum aminotransferase activity which may or may not be associated with serious hepatic toxicity.

Elevation of serum creatine kinase activity which may be associated with pain or weakness in skeletal muscles. Myopathy may occur.
Niacin
Niacin (vitamin B3) decreases VLDL and LDL levels in most patients. In addition, niacin often increases HDL levels significantly

Niacin inhibits VLDL secretion from the hepatocytes, which leads to a decrease in the production of LDL.

It inhibits the intracellular lipase of adipose tissue via receptor-mediated signaling, which leads to a decrease in the flux of free fatty acids to the liver. This effect may reduce VLDL production in the liver; however, sustained inhibition of lipolysis by niacin has not been demonstrated.

It induces the clearance of VLDL via the LPL pathway, which leads to a decrease in triglyceride levels.

It decreases the catabolic rate for HDL (Increasing HDL levels)

It reduces the levels of fibrinogen and increases the levels of tissue plasminogen activator (t-PA). Increasing the effects of coumarin and anticoags

Prostaglandin-mediated cutaneous vasodilation (flushing), pruritus, skin rash, and GI upset

Hyperuricemia, which may precipitate gout
Gemfibrozil
Fibrate therapy decreases the levels of VLDL in plasma (only modest reductions of LDL occur)Fibrates are useful in hypertriglyceridemias in which VLDL predominate

They bind to PPAR- and induce lipolysis of VLDL triglycerides via LPL, which results in a decrease in VLDL levels.

They decrease intracellular lipolysis in adipose tissue, which decreases the flux of free fatty acids to the liver. This effect results in decreased VLDL production in the liver and decreased VLDL secretion by the liver, leading to a decrease in VLDL levels. (same mech of action as niacin)

The decrease in VLDL triglycerides (which results from the action of gemfibrozil and fenofibrate) also leads to a moderate increase in HDL cholesterol levels

Risk of myopathy increases when the fibrates are given in combination with the statins.

Increased risk of cholesterol gallstones due to an increase in the cholesterol content of the bile
Fenofibrate
Fibrate therapy decreases the levels of VLDL in plasma (only modest reductions of LDL occur)Fibrates are useful in hypertriglyceridemias in which VLDL predominate

They bind to PPAR- and induce lipolysis of VLDL triglycerides via LPL, which results in a decrease in VLDL levels.

They decrease intracellular lipolysis in adipose tissue, which decreases the flux of free fatty acids to the liver. This effect results in decreased VLDL production in the liver and decreased VLDL secretion by the liver, leading to a decrease in VLDL levels. (same mech of action as niacin)

The decrease in VLDL triglycerides (which results from the action of gemfibrozil and fenofibrate) also leads to a moderate increase in HDL cholesterol levels

Risk of myopathy increases when the fibrates are given in combination with the statins.

Increased risk of cholesterol gallstones due to an increase in the cholesterol content of the bile
Colestipol
They are used for the treatment of patients with primary hypercholesterolemia, producing ~ 20% reduction in LDL cholesterol

Bile acid-binding resins are large polymeric cationic exchange resins that are insoluble in water. They are not absorbed from the GIT.

They bind to anionic bile acids in the intestinal lumen and prevent their reabsorption.

As a result, the resins are able to increase the excretion of bile acids (in feces) by up to tenfold, which decreases bile acid levels in the liver.

The decrease in bile acid levels in the liver results in an increase in the metabolic conversion of cholesterol to bile acids by the liver (a process normally controlled by negative feedback)

Increased uptake of LDL and IDL from plasma results in a decrease in plasma LDL levels

Constipation, bloating, heartburn, and dry flaking skin.

Absorption of a number of drugs, including digitalis glycosides, warfarin, thiazides, tetracyclines, iron salts, statins, folic acid, ascorbic acid, and aspirin, may be impaired by the resins (by binding to the resins). Colesevelam does not bind to digoxin, warfarin, or the statins
Cholestyramine
They are used for the treatment of patients with primary hypercholesterolemia, producing ~ 20% reduction in LDL cholesterol

Bile acid-binding resins are large polymeric cationic exchange resins that are insoluble in water. They are not absorbed from the GIT.

They bind to anionic bile acids in the intestinal lumen and prevent their reabsorption.

As a result, the resins are able to increase the excretion of bile acids (in feces) by up to tenfold, which decreases bile acid levels in the liver.

The decrease in bile acid levels in the liver results in an increase in the metabolic conversion of cholesterol to bile acids by the liver (a process normally controlled by negative feedback)

Increased uptake of LDL and IDL from plasma results in a decrease in plasma LDL levels

Constipation, bloating, heartburn, and dry flaking skin.

Absorption of a number of drugs, including digitalis glycosides, warfarin, thiazides, tetracyclines, iron salts, statins, folic acid, ascorbic acid, and aspirin, may be impaired by the resins (by binding to the resins). Colesevelam does not bind to digoxin, warfarin, or the statins
Colesevelam
They are used for the treatment of patients with primary hypercholesterolemia, producing ~ 20% reduction in LDL cholesterol

Bile acid-binding resins are large polymeric cationic exchange resins that are insoluble in water. They are not absorbed from the GIT.

They bind to anionic bile acids in the intestinal lumen and prevent their reabsorption.

As a result, the resins are able to increase the excretion of bile acids (in feces) by up to tenfold, which decreases bile acid levels in the liver.

The decrease in bile acid levels in the liver results in an increase in the metabolic conversion of cholesterol to bile acids by the liver (a process normally controlled by negative feedback)

Increased uptake of LDL and IDL from plasma results in a decrease in plasma LDL levels

Constipation, bloating, heartburn, and dry flaking skin.

Absorption of a number of drugs, including digitalis glycosides, warfarin, thiazides, tetracyclines, iron salts, statins, folic acid, ascorbic acid, and aspirin, may be impaired by the resins (by binding to the resins). Colesevelam does not bind to digoxin, warfarin, or the statins
Ezetimibe
Ezetimibe is a selective inhibitor of the intestinal absorption of cholesterol and phytosterols (plant sterols).

It is effective even in the absence of dietary cholesterol because it inhibits reabsorption of the cholesterol excreted in the bile.

Its primary clinical effect is reduction of LDL levels in plasma

Ezetimibe also appears to be synergistic with the statins in reducing LDL cholesterol levels. (It can be combined with a statin to increase efficacy)

Reversible impaired hepatic function (the incidence increases when given in combination with a statin)
Aspirin (NSAID)
Aspirin is a nonselective inhibitor of both COX (cyclooxygenase) isoforms (COX-1 and COX-2), causing irreversible inhibition by acetylating the enzyme.

In addition, aspirin inhibits platelet aggregation by inhibiting COX-1.

At the therapeutic dose, the main adverse effects of aspirin include gastric upset and gastric and duodenal ulcers. Less frequent toxicities include hepatotoxicity, asthma, rashes, and renal toxicity.

At higher doses, toxicities include vomiting, tinnitus, vertigo, and decreased hearing (‘salicylism’).

At larger doses, metabolic acidosis, respiratory depression, and cardiotoxicity can occur.
Celecoxib
The coxibs were developed to inhibit COX-2 isozyme, which is induced at sites of inflammation, without affecting the action of COX-1 isozyme. They selectively bind to and block the active site of COX-2 much more effectively than that of COX-1

They have analgesic, antipyretic, and anti-inflammatory effects similar to those of the nonselective NSAIDs.

They do not inhibit platelet aggregation (because they are not effective inhibitors of COX-1); as a result, they do not exhibit cardioprotective effects (unlike the traditional nonselective NSAIDs, such as aspirin).

The coxibs exhibit fewer GI side effects than the nonselective NSAIDs.

They cause renal toxicities similar to those associated with traditional NSAIDs because COX-2 is constitutively active in the kidneys. They are not recommended for patients with severe renal insufficiency. They increase the incidence of edema and hypertension
Ibuprofen
Ibuprofen is one of the least toxic nonselective COX inhibitors. The anti-inflammatory effect of 2400 mg of ibuprofen daily is equivalent to the anti-inflammatory effect of 4 g of aspirin. At doses of < 2400 mg/day, ibuprofen has analgesic but not anti-inflammatory efficacy.

GI irritation and bleeding can occur with ibuprofen therapy (less frequently than with aspirin).

Other toxicities of ibuprofen include rash, pruritus, tinnitus, dizziness, and fluid retention.

Concomitant administration of ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin. As a result, ibuprofen therapy in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin.

As with all NSAIDs, ibuprofen can cause renal toxicity, including acute renal failure and nephritic syndrome, but these occur very rarely. And can slao cause hepatotoxicity
Acetaminophen
Acetaminophen is used for the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary

It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and has no significant anti-inflammatory effects

It is equivalent to aspirin as an effective analgesic and antipyretic agent; however, it does not exhibit any significant anti-inflammatory properties.

It does not inhibit platelet aggregation and has no effect on uric acid levels

It does not cause GI bleeding.

It is preferable to aspirin in patients with hemophilia or peptic ulcer as well as those in whom bronchospasm is precipitated by aspirin. It is also preferable to aspirin in children for the treatment of pain and fever associated with viral infections.

Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents; as a result, it may be used as an analgesic in combination with probenecid in patients with gout.

At therapeutic doses, a reversible mild increase in hepatic enzyme levels may occur.

At higher doses, dizziness and disorientation may occur.

Ingestion of 15 g or more of acetaminophen may be fatal due to severe hepatic necrosis (caused by P450 metabolism of acetaminophen in the liver to a toxic metabolite); its hepatotoxicity may be associated with acute renal tubular necrosis
Colchicine
Colchicine does not alter the metabolism or excretion of uric acid.

It exerts its anti-inflammatory effects by binding to the intracellular protein tubulin and preventing its polymerization into microtubules.

Inhibition of the polymerization of tubulin leads to the inhibition of leukocyte migration and phagocytosis. Colchicine also inhibits the formation of leukotriene B4

Colchicine often causes diarrhea. It may also cause nausea, vomiting, and abdominal pain
Indomethacin
Indomethacin and other NSAIDs inhibit the phagocytosis of uric acid crystals in the joint.

Indomethacin is commonly used as initial treatment of gout.

The use of aspirin is not recommended for the treatment of gout. In addition, aspirin should not be used for analgesia in patients with gout (Why ??). It increases levels of uric acid

Although oxaprozin lowers uric acid level in plasma, it is not recommended in patients with uric acid stones because it increases the excretion of uric acid in urine
Probenecid
Uricosuric drugs are organic acids (just like uric acid). They act at the anionic transport sites of the renal tubule.

Uricosuric drugs compete with uric acid for the Transporter, thereby inhibiting its reabsorption via the urate-anion exchanger system.

Depending on dosage, a uricosuric agent may either decrease or increase the excretion of urate. Low dosage usually results in decreased excretion (mostly due to inhibition of the renal tubular secretion of uric acid), while higher dosage results in increased excretion of urate. However, due to the complexity of the transport mechanism of urate, not all uricosuric agents exhibit this phenomenon (both aspirin and sulfinpyrazone exhibit this phenomenon)

Aspirin and other salicylates are also organic acids.

At high doses (4-5 g daily), aspirin is capable of inhibiting the reabsorption of uric acid in the proximal tubule (ie, at high doses, aspirin acts as a uricosuric agent by increasing the urinary excretion of uric acid). However, aspirin should not be used as a uricosuric agent for the treatment of gout because high doses of aspirin are toxic.

At low (analgesic/antipyretic) doses (1-2 g daily), aspirin decreases the urinary excretion of uric acid by inhibiting the secretory transporter responsible for its renal tubular secretion; this effect leads to retention of uric acid and an increase in its plasma levels. In addition, aspirin antagonizes the uricosuric effect of both probenecid and sulfinpyrazone

Both agents cause GI irritation (sulfinpyrazone causes more irritation than probenecid). They may also cause skin rash. Probenecid may cause nephritic syndrome
Sulfinpyrazone
Uricosuric drugs are organic acids (just like uric acid). They act at the anionic transport sites of the renal tubule.

Uricosuric drugs compete with uric acid for the Transporter, thereby inhibiting its reabsorption via the urate-anion exchanger system.

Depending on dosage, a uricosuric agent may either decrease or increase the excretion of urate. Low dosage usually results in decreased excretion (mostly due to inhibition of the renal tubular secretion of uric acid), while higher dosage results in increased excretion of urate. However, due to the complexity of the transport mechanism of urate, not all uricosuric agents exhibit this phenomenon (both aspirin and sulfinpyrazone exhibit this phenomenon)

Aspirin and other salicylates are also organic acids.

At high doses (4-5 g daily), aspirin is capable of inhibiting the reabsorption of uric acid in the proximal tubule (ie, at high doses, aspirin acts as a uricosuric agent by increasing the urinary excretion of uric acid). However, aspirin should not be used as a uricosuric agent for the treatment of gout because high doses of aspirin are toxic.

At low (analgesic/antipyretic) doses (1-2 g daily), aspirin decreases the urinary excretion of uric acid by inhibiting the secretory transporter responsible for its renal tubular secretion; this effect leads to retention of uric acid and an increase in its plasma levels. In addition, aspirin antagonizes the uricosuric effect of both probenecid and sulfinpyrazone

Both agents cause GI irritation (sulfinpyrazone causes more irritation than probenecid). They may also cause skin rash. Probenecid may cause nephritic syndrome
Allopurinol
Allopurinol decreases uric acid levels in the plasma by inhibiting its biosynthesis in the body. As with the uricosuric agents, treatment of gout with allopurinol should continue for years if not for life.

Most of the purines in the body are derived from amino acids, formate, and carbon dioxide. Purines derived from the human diet are not a major source of uric acid.

Purine ribonucleotides derived from the degradation of nucleic acids, as well as those that were not incorporated into nucleic acids, are converted to xanthine or hypoxanthine.

The last step in the metabolism of purines involves the oxidation of xanthine and hypoxanthine to uric acid by xanthine oxidase.

Allopurinol is a competitive inhibitor of xanthine oxidase enzyme; it inhibits the synthesis of uric acid by inhibiting the oxidative conversion of xanthine and hypoxanthine to uric acid.

The action of allopurinol also leads to an increase in plasma levels of the more soluble xanthine and hypoxanthine (more soluble than uric acid). (These high levels are harmless compared to high levels of uric acid)

Acute attacks of gouty arthritis occur early in allopurinol therapy, when urate crystals are being reabsorbed from the tissues. Acute attacks can be prevented by administering colchicine or indomethacin. (this is due to the movement of uric acid crystals off of the joints)
Diuretics
Diuretics lower blood pressure by depleting the body of sodium and reducing blood volume.

Sodium contributes to PVR by increasing vessel stiffness and neural reactivity, possibly due to increased sodium-calcium exchange which leads to an increase in intracellular calcium. These effects are reversed by diuretics or sodium restriction.

Initially, diuretics reduce blood pressure by decreasing blood volume and cardiac output (which may lead to an increase in PVR due to the body’s reaction to the drop).

After 6-8 weeks of therapy, CO returns to normal while PVR decreases

Diuretics alone often provide adequate therapy for mild or moderate essential hypertension.

In severe hypertension, diuretics are used in combination with sympathoplegic and vasodilator drugs to control the retention of sodium caused by these agents

The most common adverse effect of diuretics (except potassium-sparing diuretics) is potassium depletion (hypokalemia).

Potassium loss is coupled to reabsorption of sodium; consequently, a decrease in dietary sodium intake will minimize potassium loss.
Methyldopa
Its antihypertensive action is attributed to direct stimulation of central a-adrenoceptors by a-methylnorepinephrine or a-methyldopamine; they bind more tightly to a1- than to a2-adrenoceptors.

It lowers blood pressure by reducing PVR, with a variable reduction in heart rate and CO. The reduction in BP is not markedly dependent on maintenance of upright posture

The most frequent undesirable effect of methyldopa is sedation.

Long-term therapy may cause impaired mental concentration, mental depression, nightmares, and vertigo
Reserpine
Reserpine blocks the uptake and storage of biogenic amines (serotonin, Norepi, Dopamine) in aminergic transmitter vesicles throughout the body by inhibiting the uptake mechanism that depends on Mg2+ and ATP.

This effect results in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons.

The effects of reserpine on adrenergic vesicles appear irreversible. Low doses of reserpine, which are clinically effective, cause inhibition of neurotransmission that is roughly proportionate to the degree of amine depletion.

Depletion of peripheral amines accounts for much of the antihypertensive effect of reserpine; however, reserpine also exerts a central effect (on the CNS).

Reserpine readily enters the brain; as a result, it causes depletion of cerebral amine stores, resulting in sedation, mental depression, and parkinsonism symptoms.

At the low doses used for the treatment of mild hypertension, reserpine lowers BP by decreasing both CO and PVR.

Reserpine often causes mild diarrhea and GI cramps; it also increases gastric acid secretion (it should not be given to patients with a history of peptic ulcer).

Less frequently, reserpine produces extrapyramidal effects resembling Parkinson’s disease as a result of dopamine depletion in the corpus striatum.
Guanethidine
Reserpine blocks the uptake and storage of biogenic amines (serotonin, Norepi, Dopamine) in aminergic transmitter vesicles throughout the body by inhibiting the uptake mechanism that depends on Mg2+ and ATP.

This effect results in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons.

The effects of reserpine on adrenergic vesicles appear irreversible. Low doses of reserpine, which are clinically effective, cause inhibition of neurotransmission that is roughly proportionate to the degree of amine depletion.

Depletion of peripheral amines accounts for much of the antihypertensive effect of reserpine; however, reserpine also exerts a central effect (on the CNS).

Reserpine readily enters the brain; as a result, it causes depletion of cerebral amine stores, resulting in sedation, mental depression, and parkinsonism symptoms.

At the low doses used for the treatment of mild hypertension, reserpine lowers BP by decreasing both CO and PVR.

Reserpine often causes mild diarrhea and GI cramps; it also increases gastric acid secretion (it should not be given to patients with a history of peptic ulcer).

Less frequently, reserpine produces extrapyramidal effects resembling Parkinson’s disease as a result of dopamine depletion in the corpus striatum.
Clonidine
Its antihypertensive action is attributed to direct stimulation of central a-adrenoceptors by a-methylnorepinephrine or a-methyldopamine; they bind more tightly to a1- than to a2-adrenoceptors.

It lowers blood pressure by reducing PVR, with a variable reduction in heart rate and CO. The reduction in BP is not markedly dependent on maintenance of upright posture

The most frequent undesirable effect of methyldopa is sedation.

Long-term therapy may cause impaired mental concentration, mental depression, nightmares, and vertigo
Propranolol
In severe hypertension, B-blockers are useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. B-blockers are particularly useful for treating hypertension in patients with heart failure; they have been shown to reduce mortality in those patients

Propranolol is a nonselective B-blocker. It inhibits the stimulation of renin production by the catecholamines (mediated by B1-adrenoceptors). Inhibition of the renin-angiotensin-aldosterone system by propranolol is likely to contribute to its overall antihypertensive effect.

In mild to moderate hypertension, propranolol reduces BP significantly without prominent postural hypotension

The major toxicities of propranolol result from its ability to block cardiac, vascular, or bronchial -adrenoceptors.

B2-Receptor blockade causes worsening of preexisting asthma and other forms of airway obstruction

B-Blockers are not recommended in insulin-dependent diabetic patients who are subject to frequent hypoglycemic reactions if alternative therapies are available

Some patients experience a withdrawal syndrome (nervousness, tachycardia, hypertension, and/or myocardial infarction) as a result of abruptly discontinuing B-blocker therapy after chronic use
Prazosin
Prazosin is a a1-selective blocker. a-Blockers reduce arterial pressure by dilating both resistance (arterioles) and capacitance (venules) vessels

Retention of salt and water occurs when a-blockers are administered without a diuretic.

a-Blockers are more effective when used in combination with other antihypertensive agents, such as a a-blocker and a diuretic

Nonselective a-blockers produce reflex tachycardia by blocking both presynaptic and postsynaptic a-receptors (a1- and a2-receptors)

BP is reduced more in the upright than in the supine position with a-blocker therapy

Some patients, particularly salt- and volume-depleted patients, may experience a precipitous drop in standing BP shortly after the first dose is absorbed (first-dose phenomenon); the mechanism of this phenomenon is not clear. A small first dose should be given at bedtime
Minoxidil
Minoxidil is a very effective, orally active vasodilator.

It lowers BP by opening the potassium channels in smooth muscle membranes, which stabilizes the membrane at its resting potential and makes contraction less likely.

Like hydralazine, minoxidil dilates arterioles but not veins. Its antihypertensive effect, however, is greater than that of hydralazine

Decreased systemic vascular resistance and decreased arterial BP, which result from the action of vasodilators, lead to ‘compensatory’ responses (mediated by baroreceptors and the sympathetic nervous system, as well as renin, angiotensin, and aldosterone).

Vasodilators are most effective when used in combination with other antihypertensive drugs (diuretics and B-blockers) that can block the compensatory cardiovascular responses.

Vasodilators do not affect sympathetic reflexes; as a result, they do not cause orthostatic hypotension or sexual dysfunction

Minoxidil therapy is associated with reflex sympathetic stimulation and sodium and fluid retention.

It must be used in combination with a B-blocker and a loop diuretic

Tachycardia, palpitations, angina, and edema occur when doses of diuretics and B-blockers are inadequate.

Other common toxicities include headache, sweating, and hirsutism (topical minoxidil, as Rogaine®, is used as a stimulant to hair growth for correction of baldness)
Sodium Nitroprusside
Sodium Nitroprusside is a parenteral vasodilator used for the treatment of hypertensive emergencies and severe heart failure. It is administered by IV infusion.

It dilates both arterial and venous vessels, resulting in reduced PVR and venous return

Nitroprusside activates guanylyl cyclase enzyme, either via release of nitric oxide or by direct induction of the enzyme.

Induction of guanylyl cyclase results in an increase in intracellular cGMP, which relaxes vascular smooth muscle.

In the absence of heart failure, the action of nitroprusside leads to a decrease in vascular resistance and BP; CO does not change or decreases slightly

The most serious toxicities of nitroprusside are excessive hypotension and accumulation of cyanide.

Prophylaxis or treatment of cyanide poisoning involves the administration of sodium thiosulfate (a sulfur donor, which facilitates the metabolism of cyanide) and hydroxocobalamin (which combines with cyanide to form the nontoxic cyanocobalamin, not toxic).

Prolonged nitroprusside therapy may also lead to accumulation of thiocyanate, particularly in patients with renal insufficiency. Thiocyanate toxicity is associated with disorientation, psychosis, muscle spasms, and convulsions
Fenoldopam
Fenoldopam is a parenteral vasodilator used for hypertensive emergencies and postoperative hypertension.

It is a racemic mixture; the R-isomer is the active isomer. It is administered by IV infusion.

It acts as an agonist of dopamine D1 receptors, resulting in dilation of peripheral arteries.

As with other direct vasodilators, its major toxicities include reflex tachycardia, headache, and flushing. It increases intraocular pressure and should not be given to patients with glaucoma.
Nifedipine
In addition to their antianginal and antiarrhythmic effects, calcium channel blockers also dilate peripheral arterioles and reduce BP.

They inhibit calcium influx into arterial smooth muscle cells, which results in a long-lasting relaxation.

In general, the dihydropyridines (e.g., nifedipine) have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do verapamil, diltiazem, and bepridil (ie, the dihydropyridines have greater vascular selectivity and vascular potency). As a result, the dihydropyridines cause much less myocardial depression (and much more vasodilation) than do verapamil, diltiazem, and bepridil.

In cardiac muscle, their effect leads to reduction in contractility and decreases in sinus node pacemaker rate and in atrioventricular node conduction velocity (a cardiac depressant effect).

Nifedipine and the other related dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem.

The cardiac depressant effect of these drugs results in a reflex sympathetic activation with slight tachycardia in order to maintain or increase CO.
Verapamil
In addition to their antianginal and antiarrhythmic effects, calcium channel blockers also dilate peripheral arterioles and reduce BP.

They inhibit calcium influx into arterial smooth muscle cells, which results in a long-lasting relaxation. They bind to the L-type calcium channel from the inner side of the membrane, reducing the frequency of opening in response to depolarization.

This results in a marked decrease in transmembrane calcium influx and leads to: a long-lasting relaxation in vascular smooth muscle, vasodilation, reduction in BP, reduction in contractility of the cardiac muscle, reduction in left ventricular wall stress, a decrease in sinus node pacemaker rate, and a decrease in atrioventricular node conduction velocity. Consequently, myocardial oxygen requirements are reduced.

In cardiac muscle, their effect leads to reduction in contractility and decreases in sinus node pacemaker rate and in atrioventricular node conduction velocity (a cardiac depressant effect).

Nifedipine and the other related dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem.

The cardiac depressant effect of these drugs results in a reflex sympathetic activation with slight tachycardia in order to maintain or increase CO.

Calcium channel blockers are the most effective agents for the prophylactic treatment of ‘variant angina’.

In the vascular system, arterioles appear to be more sensitive than veins to the vasodilation caused by these blockers; as a result, orthostatic hypotension is not a common adverse effect of the calcium channel blockers.

Verapamil causes the greatest depressant effect on the heart and may decrease heart rate and CO. Diltiazem has intermediate actions
Diltiazem
In addition to their antianginal and antiarrhythmic effects, calcium channel blockers also dilate peripheral arterioles and reduce BP.

They inhibit calcium influx into arterial smooth muscle cells, which results in a long-lasting relaxation.

In cardiac muscle, their effect leads to reduction in contractility and decreases in sinus node pacemaker rate and in atrioventricular node conduction velocity (a cardiac depressant effect).

Nifedipine and the other related dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem.

The cardiac depressant effect of these drugs results in a reflex sympathetic activation with slight tachycardia in order to maintain or increase CO

Verapamil causes the greatest depressant effect on the heart and may decrease heart rate and CO. Diltiazem has intermediate actions
Captopril
The ACE inhibitors inhibit the converting enzyme peptidyl dipeptidase (ACE) that hydrolyzes angiotensin I to angiotensin II; the same enzyme is also responsible for inactivating the potent vasodilator bradykinin (it inhibits the renin-angiotension system and activates the bradykinin system)

ACE inhibitors reduce BP by decreasing PVR; CO and heart rate are not significantly affected.

Unlike direct vasodilators, the ACE inhibitors do not cause reflex sympathetic activation (ie, reflex tachycardia) and can be used safely in patients with ischemic heart disease

ACE inhibitors are particularly useful in patients with diabetic nephropathy because they reduce proteinuria, improve intrarenal hemodynamics, and stabilize renal function.

ACE inhibitors are also very useful in the treatment of heart failure, and in treating patients after myocardial infarction

Severe hypotension can occur after initial doses in patients who are hypovolemic due to salt restriction or the use of diuretics.

Other toxicities common to all ACE inhibitors include acute renal failure (particularly in patients with renal artery stenosis), hyperkalemia, dry cough, and angioedema (bradykinin and substance P are responsible for the cough and angioedema)

With potassium supplements or potassium-sparing diuretics, resulting in hyperkalemia.

NSAIDs may inhibit the hypotensive effects of the ACE inhibitors by blocking bradykinin-mediated vasodilation (which is, at least in part, prostaglandin-mediated)
Losartan
Drugs in this class block the angiotensin II type 1 (AT1) receptor.

They have no effect on bradykinin metabolism; as a result, they are more selective than the ACE inhibitors in blocking the effects of angiotensin II.

Angiotensin receptor blockers are also capable of providing more complete inhibition of the effects of angiotensin II, compared with the ACE inhibitors, because there are enzymes other than ACE that can generate angiotensin II.

Toxicities of the angiotensin receptor blockers are similar to those of the ACE inhibitors; however, cough and angioedema are less common with the angiotensin receptor blockers (Why ??). They do not activate the bradykinin pathway.
Nitroglycerin
Nitroglycerin is a nitric and nitrous acid esters of polyalcohols. They act by relaxing vascular smooth muscle of large arteries and veins, including the large epicardial coronary arteries, causing vasodilation. They have practically no direct effect on cardiac or skeletal muscle. Nitroglycerin is denitrated first by glutathione S-transferase enzyme; a free nitrite ion is released, which is then converted to nitric oxide (NO)

Vasodilation decreases arterial pressure, venous return to the heart, and intracardiac volume, leading to a reduction in myocardial oxygen consumption.

In ‘variant angina’, nitrates dilate the epicardial coronary arteries and relieve coronary artery spasm.

In ‘unstable angina’, nitrates exert their beneficial effects by dilating the epicardial coronary arteries, reducing myocardial oxygen demand, and decreasing platelet aggregation.

The sublingual route of administration, which avoids the hepatic first-pass effect, is preferred for achieving therapeutic blood levels rapidly; however, the duration of action of the sublingual route is brief (15-30 min) because the administered dose must be limited to avoid excessive effect.

The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation, including orthostatic hypotension, reflex tachycardia, and throbbing headache, and contraindicated in patients with intracranial pressure.

Continuous exposure to nitrates causes tolerance (tachyphylaxis), particularly when long-acting preparations (oral, transdermal, continuous IV infusion) are used for more than a few hours without interruption. Diminished release of NO may be partly responsible for tolerance to the nitrates.
Ranolazine
Ranolazine is indicated for the treatment of chronic angina in patients who have not achieved an adequate response with other antianginal drugs and have no other treatment alternatives.

It should be used in combination with a nitrate, a beta-blocker or the dihydropyridine calcium-channel blocker amlodipine (Norvasc®), and appears to be more effective in men. (Contraindicated with diltiazem or verapamil)

The antianginal and anti-ischemic mechanism of action of ranolazine is unknown, but it does not depend on decreasing heart rate, blood pressure or vascular resistance.

A proposed mechanism involves the inhibition of the late inward sodium current, which is thought to reduce intracellular calcium concentrations and improve left ventricular function.

Dose-related increases in the QTC interval (up to 15 msec) have been observed.

Although it increases QTc interval, ranolazine has been shown to suppress experimentally induced arrhythmias seen when QTc intervals are prolonged by other drugs (possibly due to its inhibition of the late sodium current).

Other side effects of ranolazine include constipation, nausea, dizziness, and headache.

Ranolazine is a substrate for CYP3A4, CYP2D6 and P-glycoprotein. It is also an inhibitor of CYP3A (weak), CYP2D6 and P-glycoprotein.

It should not be used with inhibitors of CYP3A, such as diltiazem, verapamil, the azoles, erythromycin, …etc, which could increase its serum concentrations and QTc interval prolongation.
Cardiac Glycosides (Digitalis)
Digoxin is the prototype for this particular class of drugs. Digitalis has multiple direct and indirect cardiovascular effects, with both therapeutic and toxic consequences; it also has undesirable effects on the CNS and gut.

Cardiac glycosides bind to and inhibit Na+/K+ ATPase, the membrane-bound transporter protein also known as the ‘sodium pump’.

Na+/K+ ATPase consists ofa and B subunits; the binding sites for Na+, K+, ATP, and the cardiac glycosides all appear to reside on the alpha subunit.

This inhibitory action is largely responsible for the therapeutic effect (positive inotropy) of the cardiac glycosides in the heart. Cardiac glycosides increase the intensity of the interaction of the actin and myosin filaments of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole.

This increase in calcium is due to an increase in intracellular sodium concentration because of the inhibition of the sodium pump, and a relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger caused by the increase in intracellular sodium.

The effects of cardiac glycosides on the electrical properties of the heart are a mixture of direct and autonomic actions.

At therapeutic concentrations, direct actions on the membranes of cardiac cells include an early, brief prolongation of the action potential, followed by a protracted period of shortening. The decrease in the action potential duration, which contributes to a decrease in the atrial and ventricular refractory period, is the result of increased potassium conductance that is caused by increased intracellular calcium.

Overdosing can cause digitalis-induced cardiac arrhythmias include AV junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, and second-degree AV blockade. (It is claimed that digitalis can cause virtually every variety of arrhythmia !)

Potassium ions compete with cardiac glycosides for binding to the Na+/K+ ATPase protein pump; as a result, hyperkalemia reduces the inhibitory action of digitalis, whereas hypokalemia facilitates the action of digitalis.

Hyperkalemia inhibits abnormal cardiac automaticity; therefore, moderately increased extracellular potassium reduces the effects of digitalis, especially the toxic arrhythmic effects.

Calcium ions accelerate the overloading of intracellular calcium stores which is responsible for digitalis-induced arrhythmia; as a result, hypercalcemia increases the risk of a digitalis-induced arrhythmia.

The effects of magnesium ion appear to be opposite to those of calcium; therefore, hypomagnesemia increases the risk of a digitalis-induced arrhythmia.

Because of the significance of these interactions, evaluation of serum electrolytes is necessary in patients with digitalis-induced arrhythmias.
Bipyridines (Inamrinone & Milrinone)
Inamrinone and milrinone are used only IV for acute heart failure or for an exacerbation of chronic heart failure.

The bipyridines are phosphodiesterase (PDE) inhibitors.

They are relatively selective for PDE-3 isozyme, an isoform of PDE found in cardiac and smooth muscle.

Inhibition of PDE-3 results in an increase in intracellular cAMP, which leads to vasodilation and an increase in myocardial contractility (positive inotropy).

They increase myocardial contractility by increasing calcium influx in the heart during the action potential; they may also alter the intracellular movements of calcium by influencing the sarcoplasmic reticulum.

Toxicities of inamrinone include arrhythmias, bone marrow toxicity (thrombocytopenia), and liver enzyme changes.

Milrinone is less likely to cause bone marrow and liver toxicity than inamrinone; however, milrinone does cause arrhythmias.
B-Adrenoceptor Agonists
(Dobutamine & Dopamine)
Dobutamine is a selective B1-agonist used in patients with heart failure. It may benefit some patients with chronic heart failure.

It is a positive inotropic agent; it produces an increase in CO and a decrease in ventricular filling pressure.

It may cause tachycardia and may increase myocardial oxygen consumption. In addition, it has the potential to produce angina or arrhythmias in patients with coronary artery disease.

Dopamine has been used in acute heart failure; it may be particularly useful if there is a need to raise BP.
Lidocaine (Class 1B)
Lidocaine is very effective in arrhythmias associated with acute myocardial infarction. It has a low incidence of toxicity (safest). Lidocaine is the drug of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia. Generally, it is administered only to patients with arrhythmias. It is given IV.

Lidocaine blocks activated and inactivated sodium channels with rapid kinetics.

Blocking inactivated channels produces greater effects on cells with long action potentials such as Purkinje and ventricular cells, compared with atrial cells.

The rapid dissociation kinetics at normal resting potentials ensure recovery from block between action potentials.

Lidocaine selectively depresses conduction in depolarized cells as a result of slower dissociation kinetics (slower than those at normal resting potentials) and increased inactivation of sodium channels.

The most common adverse effects of lidocaine are neurologic, including tremor, nausea of central origin, hearing disturbances and convulsions.
Amiodarone (Class 3)
Amiodarone is used IV and orally to treat serious ventricular arrhythmias. It is also highly effective for the treatment of supraventricular arrhythmias such as atrial fibrillation.

Amiodarone markedly prolongs the duration of the action potential (and the QT interval on the ECG) by blocking the potassium channels.

The action potential duration is prolonged uniformly over a wide range of heart rates, ie, the drug does not exhibit a ‘reverse use-dependent action’.

In addition to blocking potassium channels, amiodarone also markedly blocks inactivated sodium channels, which contributes to its significant action potential prolonging effect.

It also has weak adrenergic and calcium channel blocking actions, which result in slowing of the heart rate and AV node conduction.

The broad spectrum of actions may account for its high efficacy and low incidence of drug-induced arrhythmias (torsade de pointes) despite significant QT interval prolongation.

Amiodarone may cause bradycardia and heart block in patients with preexisting sinus or AV node disease.

The most important extracardiac adverse effect of amiodarone is dose-related pulmonary toxicity.

Amiodarone blocks the peripheral conversion of thyroxine (T4) to triiodothyronine (T3); it is also a potential source of large amounts of inorganic iodine. As a result, it may cause hypothyroidism or hyperthyroidism.
Verapamil (Class 4)
Verapamil is used mainly for the treatment of arrhythmic supraventricular tachycardia.

Verapamil blocks both activated and inactivated L-type calcium channels. (causes the greatest effect of all CCB)

Its blocking action is ‘use-dependent’, ie, its blocking action is highly significant in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the SA and AV nodes.

It prolongs the AV nodal conduction and effective refractory period.

It slows the SA node by its direct action; however, its hypotensive effect may result in a small reflex increase of SA nodal rate.

It can cause hypotension and ventricular fibrillation if administered to patients with ventricular tachycardia.

It can cause AV block when used in large doses or in patients with AV nodal disease. This block can be treated with atropine and B-agonists.
Adenosine
It activates an inward rectifier potassium current and inhibits calcium current; this leads to significant hyperpolarization and suppression of calcium-dependent action potentials.

It directly inhibits AV nodal conduction and increases the AV nodal refractory period; it has lesser effects on the SA node.

It is currently the drug of choice for converting paroxysmal supraventricular tachycardia to normal sinus rhythm because of its high efficacy and very short duration of action (its half-life in the blood is < 10 sec). It is given as a bolus dose.

Major toxicities include flushing and shortness of breath or chest burning (caused by bronchospasm). In addition, short-lived AV block and atrial fibrillation may occur.
Methazolamide
Site 1 diuretics inhibit CA, located both intracellularly and in the luminal membrane of proximal tubule cells. An increase in Na and bicarbonate excretion is the result of the following:

 Inhibition of intracellular CA, leading to a decrease in available H ions that normally are exchanged for luminal fluid Na ions, thus decreasing proximal tubule reabsorption of Na.

 Inhibition of CA on the luminal membrane, leading to a decrease in the production of carbon dioxide within the luminal fluid and a decrease in the proximal tubule uptake of carbon dioxide. The net result is a decrease in the reabsorption of bicarbonate.

Na reabsorption sites downstream from Site 1, especially Site 2, can compensate for the action of CA inhibitors by reabsorbing much of the additional Na presented to them. Thus, the actions of CA inhibitors ultimately result in the urinary loss of only 2-5% of filtered Na and up to 30% of filtered bicarbonate. CA inhibitors enhance the urinary excretion of a substantial amount of K. The urinary conc. of chloride (Cl), on the other hand, is decreased by the inhibition of CA.

Metabolic acidosis due to the urinary loss of bicarbonate.

Hypokalemia due to the urinary loss of K.

20% reduction in GFR. (these drugs decrease plasma volume)

Sulfonamide-associated hypersensitivity reactions. (allergic to sulfa drugs)

CA inhibitors can exacerbate the symptoms associated with cirrhosis of the liver.

This drug is mainly used to treat Glaucoma.
Dichlorphenamide
Site 1 diuretics inhibit CA, located both intracellularly and in the luminal membrane of proximal tubule cells. An increase in Na and bicarbonate excretion is the result of the following:

 Inhibition of intracellular CA, leading to a decrease in available H ions that normally are exchanged for luminal fluid Na ions, thus decreasing proximal tubule reabsorption of Na.

 Inhibition of CA on the luminal membrane, leading to a decrease in the production of carbon dioxide within the luminal fluid and a decrease in the proximal tubule uptake of carbon dioxide. The net result is a decrease in the reabsorption of bicarbonate.

Na reabsorption sites downstream from Site 1, especially Site 2, can compensate for the action of CA inhibitors by reabsorbing much of the additional Na presented to them. Thus, the actions of CA inhibitors ultimately result in the urinary loss of only 2-5% of filtered Na and up to 30% of filtered bicarbonate. CA inhibitors enhance the urinary excretion of a substantial amount of K. The urinary conc. of chloride (Cl), on the other hand, is decreased by the inhibition of CA.

Metabolic acidosis due to the urinary loss of bicarbonate.

Hypokalemia due to the urinary loss of K.

20% reduction in GFR. (these drugs decrease plasma volume)

Sulfonamide-associated hypersensitivity reactions. (allergic to sulfa drugs)

CA inhibitors can exacerbate the symptoms associated with cirrhosis of the liver.

This drug is mainly used to treat Glaucoma.
Hydrochlorothiazide
Site 3 diuretics differ primarily in potency and duration of action (they are equiefficacious) as compared to site 1 diuretics.

Site 3 diuretics block the reabsorption of Na and Cl ions by inhibiting the luminal membrane-bound Na/Cl cotransport system. This leads to a urinary loss of 5-8% of filtered Na.

Inhibition of Na reabsorption at Site 3 results in the delivery of more Na, at a faster rate, to Site 4. Consequently, there is an increase in K excretion due to enhanced exchange of the luminal fluid Na for the principal cell K ions.

Most thiazide diuretics possess a residual degree of CA-inhibitory activity that leads to a slight increase in the renal excretion rate of bicarbonate. Long-term use of thiazide diuretics leads to a reduction in calcium excretion.

Sulfonamide hypersensitivity reactions can occur (all of the Site 3 diuretics possess a sulfamoyl moiety similar to site 1 diuretics). Hypokalemia, Reduction in plasma volume and blood pressure occur upon continued use. This leads to an increase in the proximal tubule reabsorption of water and solutes, aldosterone secretion, and the renal release of renin.

Hypercalcemia or hyperuricemia may occur after chronic use of thiazide diuretics. All thiazide diuretics cause an acute reduction in GFR, with the exceptions of metolazone and indapamide.

Long-term thiazide diuretic therapy increases the reabsorption of lithium, resulting in an increase in lithium plasma levels and serious lithium toxicity.

Treatment of edema associated with mild to moderate CHF, liver cirrhosis, or nephrotic syndrome. Diuretic therapy is indicated when treatment of the underlying disease does not result in the removal of the edema fluid.

Due to thiazide-induced hypokalemia, which enhances the toxicity of cardiac glycosides used for the treatment of CHF, a combination diuretic therapy (thiazide diuretic + K-sparing diuretic) is recommended to prevent K loss.
Indapamide
Site 3 diuretics differ primarily in potency and duration of action (they are equiefficacious) as compared to site 1 diuretics.

Site 3 diuretics block the reabsorption of Na and Cl ions by inhibiting the luminal membrane-bound Na/Cl cotransport system. This leads to a urinary loss of 5-8% of filtered Na.

Inhibition of Na reabsorption at Site 3 results in the delivery of more Na, at a faster rate, to Site 4. Consequently, there is an increase in K excretion due to enhanced exchange of the luminal fluid Na for the principal cell K ions.

Most thiazide diuretics possess a residual degree of CA-inhibitory activity that leads to a slight increase in the renal excretion rate of bicarbonate. Long-term use of thiazide diuretics leads to a reduction in calcium excretion.

Sulfonamide hypersensitivity reactions can occur (all of the Site 3 diuretics possess a sulfamoyl moiety similar to site 1 diuretics). Hypokalemia, Reduction in plasma volume and blood pressure occur upon continued use. This leads to an increase in the proximal tubule reabsorption of water and solutes, aldosterone secretion, and the renal release of renin.

Hypercalcemia or hyperuricemia may occur after chronic use of thiazide diuretics. All thiazide diuretics cause an acute reduction in GFR, with the exceptions of metolazone and indapamide.

Long-term thiazide diuretic therapy increases the reabsorption of lithium, resulting in an increase in lithium plasma levels and serious lithium toxicity.

Treatment of edema associated with mild to moderate CHF, liver cirrhosis, or nephrotic syndrome. Diuretic therapy is indicated when treatment of the underlying disease does not result in the removal of the edema fluid.

Due to thiazide-induced hypokalemia, which enhances the toxicity of cardiac glycosides used for the treatment of CHF, a combination diuretic therapy (thiazide diuretic + K-sparing diuretic) is recommended to prevent K loss.
Furosemide
Both furosemide and bumetanide (Site 2 diuretics) are excreted mainly in urine, which provides for the delivery of substantial amounts of each diuretic to their luminal site of action. They inhibit the 1Na/1K/2Cl cotransport system located on the luminal membrane of Site 2, leading to the excretion of 20-25% of filtered Na and Cl.

They also inhibit the removal of water from the luminal fluid (which normally takes place by osmosis when Na is reabsorbed at Site 2). As a result, large amounts of water, Na, and Cl are excreted.

They do not cause a reduction in GFR as a result of the increase in the flow rate of luminal fluid. This is attributed to the fact that they block the tubuloglomerular feedback mechanism. However, long-term use of loop diuretics may lead to reduction in plasma volume and, consequently, a reduction in GFR.

They increase total renal blood flow by enhancing the intrarenal release of vasodilatory PGs. They enhance the urinary loss of K and H ions

Hypokalemic alkalosis as a result of enhanced urinary loss of K and H ions. Caution should be exercised when concurrent therapy with loop diuretics and cardiac glycosides is indicated for CHF because hypokalemia intensifies the toxicity of cardiac glycosides.

Long-term use of loop diuretics leads to reduction in plasma volume and, consequently, a reduction in GFR. This will also lead to an increase in the reabsorption of solutes, causing hyperuricemia and severe lithium toxicity (when administered concurrently).

Sulfonamide hypersensitivity reactions (furosemide and bumetanide possess a sulfamoyl moiety). Ototoxicity; hearing loss is temporary, but on occasion it may be permanent.

Treatment of edema associated with CHF, liver cirrhosis, and the nephrotic syndrome. Most importantly, treatment of pulmonary edema.

Loop diuretics may induce the renal excretion of 20-30% of filtered calcium, provided there is no reduction in plasma volume. As a result, they may be used to treat symptomatic hypercalcemia, provided there is no reduction in plasma volume (Why ??) and the fluid used for replacement of the urinary loss is calcium-free.
Bumetanide
Both furosemide and bumetanide (Site 2 diuretics) are excreted mainly in urine, which provides for the delivery of substantial amounts of each diuretic to their luminal site of action. They inhibit the 1Na/1K/2Cl cotransport system located on the luminal membrane of Site 2, leading to the excretion of 20-25% of filtered Na and Cl.

They also inhibit the removal of water from the luminal fluid (which normally takes place by osmosis when Na is reabsorbed at Site 2). As a result, large amounts of water, Na, and Cl are excreted.

They do not cause a reduction in GFR as a result of the increase in the flow rate of luminal fluid. This is attributed to the fact that they block the tubuloglomerular feedback mechanism. However, long-term use of loop diuretics may lead to reduction in plasma volume and, consequently, a reduction in GFR.

They increase total renal blood flow by enhancing the intrarenal release of vasodilatory PGs. They enhance the urinary loss of K and H ions

Hypokalemic alkalosis as a result of enhanced urinary loss of K and H ions. Caution should be exercised when concurrent therapy with loop diuretics and cardiac glycosides is indicated for CHF because hypokalemia intensifies the toxicity of cardiac glycosides.

Long-term use of loop diuretics leads to reduction in plasma volume and, consequently, a reduction in GFR. This will also lead to an increase in the reabsorption of solutes, causing hyperuricemia and severe lithium toxicity (when administered concurrently).

Sulfonamide hypersensitivity reactions (furosemide and bumetanide possess a sulfamoyl moiety). Ototoxicity; hearing loss is temporary, but on occasion it may be permanent.

Treatment of edema associated with CHF, liver cirrhosis, and the nephrotic syndrome. Most importantly, treatment of pulmonary edema.

Loop diuretics may induce the renal excretion of 20-30% of filtered calcium, provided there is no reduction in plasma volume. As a result, they may be used to treat symptomatic hypercalcemia, provided there is no reduction in plasma volume (Why ??) and the fluid used for replacement of the urinary loss is calcium-free.
Torsemide
Like furosemide, torsemide induces diuresis by inhibition of the Na/K/Cl cotransport system on the luminal membrane at Site 2.

At low doses (2.5-5 mg/day), torsemide is used to treat mild to moderate hypertension (as effective as 25 mg of hydrochlorothiazide but without producing diuresis).

High doses (10-20 mg) produce significant diuresis and are effective in treating edema associated with CHF and liver cirrhosis.

Torsemide is metabolized by cyt. P450 enzyme system in the liver to an active metabolite.
Ethacrynic Acid
It is a Site 2 diuretic that is biotransformed to the glutathione conjugate, which is further converted to the ethacrynic acid-cysteine and ethacrynic acid-N-acetyl-cysteine (mercapturic acid) conjugates.

Ethacrynic acid-cysteine conjugate is unstable in vivo; it readily releases cysteine and ethacrynic acid. As a result, ethacrynic acid and its two conjugates, the glutathione and cysteine conjugates, are equiefficacious diuretics.

Similar to the mechanism of action of furosemide.

Ethacrynic acid blocks the reabsorption of 20-25% of filtered Na at Site 2 by inhibiting the Na/K/Cl cotransport system, leading to an increase in renal excretion of Na, Cl, K, and Ca.

Ethacrynic acid does not contain a sulfamoyl group, unlike furosemide and bumetanide. As a result, it does not cause sulfonamide-related hypersensitivity reactions.

It is more ototoxic than furosemide and bumetanide, and produces more serious GI effects (GI hemorrhage) than observed with the sulfamoyl-containing loop diuretics.

As with furosemide, serious drug interactions may occur when ethacrynic acid is administered concurrently with lithium, cardiac glycosides, aminoglycoside antibiotics, or NSAIDs.

Ethacrynic acid has the same indications as furosemide; however, furosemide is preferred because it is less toxic.

When a loop diuretic is indicated to treat a patient with a known hypersensitivity to sulfa drugs, ethacrynic acid is an appropriate substitute.

It is important to note that all loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid) have, in the parent compound or active metabolite, an anionic moiety (COO-) that is responsible for their ability to compete with Cl ions for the Cl binding site on the Na/K/Cl cotransport system at Site 2.
Spironolactone
Site 4 diuretics increase Na and Cl excretion without a concomitant increase in the urinary excretion rate of K (Potassium-Sparing Diuretics) (unlike Site 1, 2, and 3 diuretics).

It is biotransformed rapidly and extensively (80%) by the liver to Canrenone, an active metabolite.

Spironolactone inhibits the reabsorption of 2-3% of filtered Na by competitively inhibiting the actions of aldosterone at the mineralocorticoid receptor (aldosterone increases the reabsorption of Na in exchange for K and H ions). As a result, it enhances water, Na, and Cl excretion. It is an antikaliuretic agent.

Unlike the other K-sparing diuretics, spironolactone requires the presence of endogenous aldosterone to exert its diuretic effect.

All K-sparing diuretics have an extremely low efficacy (Site 4 is a low-capacity site for Na reabsorption). Therefore it's primary use has been in combination with Site 2 or Site 3 diuretics in order to reduce the urinary K loss associated with these latter groups of diuretics.

Toxicities include Hyperkalemia and mild metabolic acidosis (due to retention of K and H ions), especially in individuals with poor renal function
Triamterene
Triamterene blocks Na channels in the luminal membrane of the principal cells at Site 4, thereby inhibiting the reabsorption of 2-3% of filtered Na ions. This effect is associated with a reduction in the excretion rate of K and H ions. The presence of aldosterone is not a prerequisite for triamterene’s diuretic action.

Its primary use is in combination with Site 2 or Site 3 diuretics to prevent hypokalemia. It should not be given to patients with renal insufficiency. It should not be used alone in treating hypertension (low efficacy).

Toxicities include Hyperkalemia an the Formation of renal stones (1 in 1500 individuals; the only Site 4 diuretic that causes renal stone formation).
Amiloride
Amiloride contains a strongly basic guanidine moiety (pKa 8.7). Consequently, it exists as the charged guanidinium ion in the pH range of most body tissues and fluids. This leads to incomplete absorption from the GIT (GIT absorption involves passive diffusion of the uncharged form of most drugs). It has the same mechanism of action as Triamterene.

May be used alone in the treatment of edema or hypertension. Most commonly used in combination with Site 2 or Site 3 diuretics to prevent hypokalemia.

Toxicities include Hyperkalemia, NVD, headache
Levothyroxine
Synthetic levothyroxine (T4) is the preparation of choice for thyroid replacement and suppression therapy because of its stability, low cost, lack of allergenic foreign protein, and long half-life (7 days), which permits once-daily administration. In addition, administration of T4 produces both hormones because T4 is converted to T3 intracellularly. (No hypersensitivity reactions)
Liothyronine
Liothyronine (T3), although more potent than T4, has a short half-life (24 hours) and is not recommended for routine replacement therapy. T3 should also be avoided in patients with cardiac disease because of its greater hormone activity and consequent greater risk of cardiotoxicity. T3 is best used for short-term suppression of thyroid-stimulating hormone (TSH).
Liotrix
Synthetic T4 + T3 hormones used for the treatment of hypothyroidism.
Methimazole
This drug is used for the treatment of hyperthyroidism (thyrotoxicosis). Methimazole is about ten times more potent than propylthiouracil.

The thioamides prevent thyroid hormone synthesis by inhibiting the thyroid peroxidase enzyme and blocking the process of ‘iodine organification’. (Inhibiting the synthesis not the release)

In addition, they block coupling of the iodotyrosines (MIT and DIT).

They do not block the uptake of iodide by the thyroid gland.

Propylthiouracil and methimazole also inhibit the peripheral deiodination of T4 and T3; methimazole is a weak inhibitor of this particular process.

Since the synthesis rather than the release of hormones is affected, the onset of action for these drugs is slow, often requiring 3-4 weeks before stores of T4 are depleted.

The most common adverse effect of the thioamides is maculopapular pruritic rash.

The most serious complication is agranulocytosis, an infrequent but potentially fatal adverse reaction; the risk may be increased in older patients and in those receiving high-dose methimazole therapy (> 40 mg/day).
Propylthiouracil
This drug is used for the treatment of hyperthyroidism (thyrotoxicosis). Methimazole is about ten times more potent than propylthiouracil.

The thioamides prevent thyroid hormone synthesis by inhibiting the thyroid peroxidase enzyme and blocking the process of ‘iodine organification’. (Inhibiting the synthesis not the release)

In addition, they block coupling of the iodotyrosines (MIT and DIT).

They do not block the uptake of iodide by the thyroid gland.

Propylthiouracil and methimazole also inhibit the peripheral deiodination of T4 and T3; methimazole is a weak inhibitor of this particular process.

Since the synthesis rather than the release of hormones is affected, the onset of action for these drugs is slow, often requiring 3-4 weeks before stores of T4 are depleted.

The most common adverse effect of the thioamides is maculopapular pruritic rash.

The most serious complication is agranulocytosis, an infrequent but potentially fatal adverse reaction; the risk may be increased in older patients and in those receiving high-dose methimazole therapy (> 40 mg/day).
Iodides
At pharmacologic doses (> 6 mg/day), the iodides inhibit thyroid hormone release, possibly by inhibiting thyroglobulin proteolysis.

They also inhibit the process of ‘iodine organification’.

As a result, rapid improvement in thyrotoxic symptoms occurs within 2-7 days. (They inhibit both the synthesis and release)

In addition, the iodides decrease the size, vascularity, and fragility of a hyperplastic thyroid gland, making these drugs very valuable as preoperative preparation for surgery.

Iodide therapy can increase the intraglandular stores of iodine, which may delay onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks. Thus, iodide therapy should be initiated after onset of thioamide therapy and avoided if treatment with radioactive iodine is likely.

Iodide should not be used alone because the thyroid gland will recover from the iodide block in 2-8 weeks, and its withdrawal may produce severe exacerbation of thyrotoxicosis in an iodine-enriched gland.

Adverse reactions to iodine (‘iodism’) are uncommon and in most cases reversible upon discontinuance; they include acneiform rash, swollen salivary glands, conjunctivitis, fever, and bleeding disorders.
Radioactive Iodine (131I)
131I is the only iodine isotope used for the treatment of thyrotoxicosis (others are used in the diagnosis).

It is administered orally in solution as Na131I; it is absorbed rapidly, concentrated by the thyroid gland, and incorporated into storage follicles.

Its therapeutic effect depends on emission of B rays with an effective half-life of 5 days and a penetration range of 400-2000 um.

Within a few weeks after administration, destruction of the thyroid parenchyma is demonstrated by epithelial swelling and necrosis, edema, and follicular disruption.

Advantages of radioactive iodine therapy include oral administration, effectiveness, and absence of pain.

There have been no reports of radiation-induced genetic damage, leukemia, and neoplasia as a result of the antithyroid radioiodine therapy.

Radioactive iodine should not be administered to pregnant women or nursing mothers because it crosses the placenta and is excreted in breast milk.
Explain Polyfunctional Alkylating Agents (Cell-Cycle Nonspecific) (Anti-Cancer)
The alkylating agents exert cytotoxic effects via transfer of their alkyl groups to various cellular constituents, particularly DNA; alkylation of DNA and other cellular constituents lead to cell death. The general mechanism of action of these drugs involves intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent (e.g., DNA).

In addition to DNA alkylation, the nitrosoureas are also capable of carbamoylating lysine residues of cellular proteins through the formation of isocyanate species (Cl-CH2-CH2-N=C=O). The major site of alkylation within DNA is the N7 position of guanine; however, other bases are also alkylated to lesser degrees as well as phosphate atoms and proteins associated with DNA.

Covalent binding interactions of the alkylating agents with DNA can occur on a single strand (Monofunctional – cannot cross-link DNA) or on both strands of DNA through cross-linking (most major alkylating agents are bifunctional). The higher efficacy of bifunctional alkylating agents in cancer chemotherapy, as compared to monofunctional agents, is attributed to their ability to cross-link DNA. (Cells have trouble repairing cross-linked DNA, making bifunctional alkylating agents the most affective).  Although alkylating agents are CCNS, replicating cells (ie, cells in late G1 and S phases) are most susceptible to alkylation.

Cyclophosphamide is the most widely used alkylating agent. It is administered orally. It is relatively a less reactive alkylating agent; it requires activation to its cytotoxic forms by the cyt. P450 enzyme system in the liver.

The active metabolites of cyclophosphamide are first delivered by the general circulation to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic (electrophilic) forms (phosphoramide mustard & acrolein) occurs. The liver protects itself from the cytotoxic effect of cyclophosphamide by further metabolizing the active metabolites to inactive metabolites.

Resistance includes:
 Increased capability to repair DNA.

 Decreased permeability of the cell to the drug.

 Increased production of glutathione which inactivates the electrophilic alkylating agent via conjugation.

 Increased glutathione S-transferase (an endogenous peptide that inactivates the enzymatic activation of the drug) activity (the enzyme that catalyzes the glutathione conjugation reaction).

Cross-resistance exists among the alkylating agents; however, there are exceptions to the rule depending on the specific type of tumor. Cross-resistance to the nitrosoureas is less likely. The most common toxicities of the alkylating agents include nausea, vomiting, and bone marrow depression.
Explain Methotrexate (Antimetabolite) (Cell-Cycle Specific)
Methotrexate is a folic acid antagonist that binds to the active catalytic site of dihydrofolate reductase (DHFR) enzyme, inhibiting the enzyme and interfering with the synthesis of tetrahydrofolic acid (THF).

The lack of THF inhibits the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine, thereby inhibiting the formation of DNA, RNA, and proteins. (Inhibits DNA synthesis in cancer and normal cells)

Intracellular formation of polyglutamate derivatives during methotrexate therapy is important for its anticancer activity. The polyglutamates are selectively retained in cancer cells and have increased inhibitory effects on enzymes involved in folate metabolism, resulting in an increase in the duration of action of methotrexate.

Tumor cell resistance to methotrexate has been attributed to:

1. Decreased drug transport into the cell.

2. Decreased polyglutamate formation.

3. Synthesis of increased levels of DHFR via gene amplification.

4. Altered DHFR with reduced affinity for methotrexate.

5. Active efflux through activation of a MDR P170 glycoprotein transporter. (All anticancer drugs are susceptible to this)

Toxicities of methotrexate include diarrhea and bone marrow depression with leucopenia and thrombocytopenia.

Methotrexate inhibits the synthesis of purines and DNA in normal cells. To reverse these effects and rescue normal cells, one particular agent is administered: Leucovorin. Leucovorin prevents the lethal effects of methotrexate on normal cells by overcoming the blockade of THF production and rescuing the biosynthesis of purines in normal cells. In addition, leucovorin inhibits the active transport of methotrexate into normal cells and stimulates its efflux. Leucovorin does not reach adequate concentrations in tumor cells; as a result, it will not rescue tumor cells. (This is known as rescue therapy)
Mercaptopurine (6-MP) (Antimetabolite) (Cell-Cycle Specific)
6-MP must be bioactivated first by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to the nucleotide form 6-thioinosinic acid, which in turn inhibits a number of the enzymes involved in purine nucleotide interconversions. Consequently, DNA synthesis is inhibited.

Resistance to 6-MP is most commonly attributed to a decrease in HGPRT activity (This enzyme is needed to bioactivate the drug). Another mechanism of resistance involves increased levels of alkaline phosphatase which inactivates 6-MP by dephosphorylation.

Toxicities of 6-MP include myelosuppression (bone marrow suppression), immunosuppression, and hepatotoxicity. 6-MP is converted in the body to an inactive metabolite, 6-thiouric acid, by xanthine oxidase enzyme. The purine analog allopurinol is a potent inhibitor of xanthine oxidase; as a result, allopurinol is capable of enhancing the activity and toxicity of 6-MP. (Increasing the plasma levels and half-lifes of 6-MP) (If allopurinol is administered with 6-MP, then the dose of 6-MP must be reduced).

Allopurinol is frequently administered with chemotherapy to cancer patients in order to prevent hyperuricemia (which is caused by the release of purines into the general circulation following tumor cell lysis).
Explain Fluorouracil (5-FU) (Antimetabolite) (Cell-Cycle Specific)
5-FU must be bioactivated first to ribosyl and deoxyribosyl nucleotide metabolites. Its cytotoxicity is attributed to effects on both DNA- and RNA-mediated events. (It is a uracil analog)

5-FU is bioconverted to fluorodeoxyuridine monophosphate (FdUMP), which inhibits thymidylate synthase enzyme and the synthesis of thymidylate. This results in inhibition of DNA synthesis.

5-FU is also bioconverted to fluorouridine triphosphate (FUTP), which is incorporated into RNA, where it interferes with RNA processing and mRNA translation.

In addition, 5-FU is bioconverted to fluorodeoxyuridine triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function.

5-FU is normally given IV. It is not administered orally because of decreased bioavailability due to high levels of the enzyme dihydropyrimidine dehydrogenase present in the gut mucosa; this particular enzyme inactivates 5-FU following oral administration.

Toxicities of 5-FU include nausea, diarrhea, myelosuppression, and neurotoxicity.
Explain Vinca Alkaloids (Vinblastine, Vincristine, Vinorelbine) (Plant Product) (Cell-Cycle Specific)
Vinblastine and vincristine are plant alkaloids derived from the periwinkle plant (Vinca rosea). Vinorelbine is a semisynthetic vinca alkaloid. All vinca alkaloids exhibit the same mechanism of action and are closely related in their chemical structures.

The vinca alkaloids cause depolymerization of microtubules, which are an important part of the cytoskeleton and the mitotic spindle. They bind specifically to the microtubule protein tubulin in dimeric form. The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly, and depolymerization of the microtubules then occurs.

Depolymerization of the microtubules results in mitotic arrest at metaphase (the M phase), dissolution of the mitotic spindle, and interference with chromosome segregation.

Toxicities of vinblastine include nausea, vomiting, bone marrow suppression, and alopecia. The main dose-limiting toxicity of vincristine is neurotoxicity (including neuropathy, ataxia, seizures, coma). While myelosuppression can occur, it is generally milder and much less significant than with vinblastine.

The dose-limiting toxicity of vinorelbine is myelosuppression with neutropenia. Other toxicities include nausea, vomiting, transient elevations in liver function tests, and neurotoxicity.
Explain Epipodophyllotoxins (Etoposide & Teniposide) (Plant Product) (Cell-Cycle Specific)
Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum). Both agents exhibit the same mechanism of action and are closely related in their chemical structures.

Etoposide and teniposide block cell division in the late S-G2 phase of the cell cycle.

They inhibit topoisomerase II enzyme, which results in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme.

Toxicities of the epipodophyllotoxins include nausea, vomiting, alopecia, and bone marrow depression.
Explain Camptothecins (Topotecan & Irinotecan) (Plant Product) (Cell-Cycle Specific)
The camptothecins are natural products derived from a tree, Camptotheca acuminata.

Irinotecan is a prodrug; it is converted mainly in the liver by a carboxylesterase enzyme to the active metabolite.

They inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of Topo I results in DNA damage.

The most common toxicities of irinotecan are diarrhea and myelosuppression. Toxicities of topotecan include nausea, vomiting, myelosuppression, and arthralgias.
Explain Taxanes (Paclitaxel & Docetaxel) (Plant Product) (Cell-Cycle Specific)
Paclitaxel (Taxol®) is a natural product derived from the pacific yew tree (Taxus brevifolia). Docetaxel is a semisynthetic taxane derived from the European yew tree (Taxus baccata). Both agents exhibit the same mechanism of action and are structurally related.

The taxanes function as mitotic spindle poisons through high-affinity binding to microtubules with enhancement of tubulin polymerization. (Work the opposite way of Alkaloids) (Alkaloids promote depolymerization)

This promotion of microtubule assembly by the taxanes can occur in the absence of microtubule-associated proteins and guanosine triphosphate and results in inhibition of mitosis and cell division.

Toxicities of paclitaxel include nausea, vomiting, arrhythmias, hypersensitivity reactions, bone marrow depression, and peripheral sensory neuropathy.
Explain Anthracyclines (Cell-Cycle Nonspecific)
The anthracyclines are among the most widely used cytotoxic anticancer drugs. Daunorubicin and doxorubicin were the first agents in this class to be introduced. Idarubicin is a semisynthetic analog of daunorubicin. Epirubicin is a doxorubicin analog.

Daunorubicin is used in the treatment of acute myeloid leukemia. Doxorubicin has a broad spectrum of clinical activity against hematologic malignancies as well as a wide range of solid tumors.

The anthracyclines exert their cytotoxic effect through four major mechanisms (because the molecules are so flat, they can bind to the bases (intercalation) and inhibit DNA synthesis):

1. Inhibition of topoisomerase II. (This causes DNA damage)

2. High-affinity binding to DNA through intercalation, leading to inhibition of the synthesis of DNA and RNA as well as DNA strand breakage.

3. Binding to cellular membranes to alter fluidity and ion transport.

4. Generation of semiquinone free radicals and oxygen free radicals through an enzyme-mediated reductive process. Generation of free radicals (superoxide) has been shown to be the cause of the cardiac toxicity of the anthracyclines.

The main dose-limiting toxicity of the anthracyclines is myelosuppression with neutropenia.

Two forms of cardiotoxicity are observed during anthracycline therapy:

1. Acute Cardiotoxicity which occurs within the first 2-3 days of therapy and is characterized by arrhythmias and myocarditis. This form of cardiotoxicity is usually transient and is asymptomatic in most cases.

2. Chronic Cardiotoxicity which results in a dose-dependent, dilated cardiomyopathy associated with heart failure. This form of cardiotoxicity is caused by increased production of free radicals within the myocardium.

A decrease in the dose or the use of continuous infusion appear to reduce the incidence of cardiac toxicity.
Explain Mitomycin (Mitomycin C) (Anti-Tumor Antibiotic) (Cell-Cycle Nonspecific)
Mitomycin is a CCNS alkylating agent. It is the best available drug for use in combination with radiation therapy to kill hypoxic tumor stem cells of solid tumors. It is used in combination chemotherapy for the treatment of squamous cell carcinoma of the anus and cervix as well as adenocarcinomas of the stomach, pancreas, and lung.

Mitomycin is metabolically activated via an enzymatic reduction reaction to generate an alkylating electrophilic species that is capable of cross-linking DNA. (They form covalent bonds that make it very strong) (It is a bi-functional drug that forms two covalent bonds)

Hypoxic tumor stem cells of solid tumors exist in an environment conducive to reductive reactions and, as a result, are more sensitive to the cytotoxic effects of mitomycin than normal cells and oxygenated tumor cells.

Toxicities of mitomycin include nausea, anemia, thrombocytopenia, and leucopenia.
Explain Bleomycin (Anti-Tumor Antibiotic) (Cell-Cycle Specific)
Bleomycin is a peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. (Bonding to the two forms a complex)

It acts by binding to DNA, which results in single-strand and double-strand breaks following free radical formation, and inhibition of DNA synthesis.

The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe (II) complex and leads to chromosomal aberrations.

Bleomycin is a CCS anticancer drug that causes accumulation of cells in the G2 phase of the cell cycle. (Less efficient than the other two drugs)

Toxicities of bleomycin include allergic reactions, fever, alopecia, and pulmonary fibrosis.

The dose-limiting toxicity for bleomycin is pulmonary toxicity which is characterized by pneumonitis with cough, dyspnea, and infiltrates. The incidence of pulmonary toxicity is increased in patients older than 70 years of age and with cumulative doses greater than 400 units; in rare cases, pulmonary toxicity can be fatal.(The symptoms are dose related)
Explain Tamoxifen (Hormonal Agent)
Tamoxifen is a selective estrogen-receptor modulator (SERM). Tamoxifen has estrogen-agonist effects on bone and uterus; it has anti-estrogen effects on the breast tissue.

The anti-estrogen tamoxifen has proved to be extremely useful for the treatment of both early-stage and metastatic breast cancer. It is also used as a chemopreventive agent in women at high risk for breast cancer. It is given orally.

Raloxifene, a related SERM, differs from tamoxifen mainly in having anti-estrogen effects on the uterus (acts as an antagonist). Preliminary results from a new NCI study (STAR) suggest that raloxifene might be a better choice than tamoxifen for prevention of breast cancer in high-risk postmenopausal women. The study showed a lower incidence of uterine (mainly endometrial) cancer with raloxifene; however, the incidence of non-invasive breast cancer was lower with tamoxifen. The study also showed a lower incidence of deep vein thrombosis or pulmonary embolism (known toxicities of SERMs) with raloxifene. Longer studies (> 4 years) are needed to evaluate mortality and the efficacy or risk of switching from tamoxifen to raloxifene. (Tamoxifen increases the risk of endometrial cancer) (Raloxifene has a lower chance for cancer) (Tamoxifen is the drug of choice against breast cancer)

Tamoxifen acts as a competitive partial agonist (ie, an antagonist) of estrogen and binds to the estrogen receptors of estrogen-sensitive tumors. It has a much longer biologic half-life (7-14 days) than estradiol.

Tamoxifen has a tenfold lower affinity for the estrogen receptor than does estradiol, indicating the importance of ablation (removal) of endogenous estrogen for optimal antiestrogen effect.

Tamoxifen is well tolerated; its toxicities are generally mild and include menopausal symptoms, fluid retention and edema, and thromboembolic events. Tamoxifen therapy increases the risk/incidence of estrogen-sensitive endometrial hyperplasia and cancer
Explain Fulvestrant (Hormonal Agent)
Fulvestrant is a selective estrogen-receptor downregulator (SERD). SERDs, unlike SERMs, are devoid of any estrogen-agonist activity. SERDs are ‘pure anti-estrogens’ or ‘pure ER-antagonists’. (This will not feed the tumor). SERDs are expected to have a better safety profile, faster onset, and longer duration of action than the SERMs.

Fulvestrant was approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that has progressed despite first-line anti-estrogen therapy such as tamoxifen. Fulvestrant is at least as effective in this setting as the aromatase inhibitor anastrozole.

Fulvestrant is a steroidal anti-estrogen that binds to the ER with an affinity more than 100 times that of tamoxifen. Binding of fulvestrant to the ER sterically hinders receptor dimerization, leading to inhibition of receptor dimerization, an increase in ER degradation (turnover), and disruption of nuclear localization.

Unlike tamoxifen, which stabilizes or even increases ER expression, fulvestrant reduces the number of ER molecules in cells, both in vitro and in vivo (ie, downregulation of ER). ER downregulation abolishes ER-mediated transcription, completely suppressing the expression of estrogen-dependent genes. This likely explains why fulvestrant is effective against tamoxifen-resistant breast cancer.

The mechanism of action suggests that fulvestrant should provide more effective anti-estrogen activity than tamoxifen; however, this was not confirmed by comparative clinical trials.

Fulvestrant is generally well tolerated. Most common adverse effects of fulvestrant include nausea, vasodilation (hot flushes), and headache.
Explain Flutamide & Bicalutamide (Hormonal Agents)
Flutamide and bicalutamide are nonsteroidal antiandrogen agents that bind to the androgen receptors of androgen-sensitive tumors and block androgen effects. (They antagonize androgens)

They are used orally, in combination with radiation therapy, for the treatment of early-stage prostate cancer; they are also used in the treatment of metastatic prostate cancer.

Toxicities of the antiandrogen agents include mild nausea, hot flushes, and transient elevations in liver function tests.
Explain Leuprolide & Goserelin (Hormonal Agent)
Leuprolide and goserelin are synthetic peptide analogs of gonadotropin-releasing hormone (GnRH).

They function as GnRH agonists and are more potent than the natural hormone. They stimulate a transient release of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH), followed by inhibition of the release of FSH and LH.

In men, 2-4 weeks of GnRH agonist therapy results in castration levels of testosterone. (Very low levels). Both agents are used for the treatment of advanced prostate cancer and as part of neoadjuvant therapy of early-stage prostate cancer.

Toxicities of the GnRH agonists include hot flushes, impotence, and gynecomastia.
Explain Aminoglutethimide (Aromatase Inhibitor)
Aminoglutethimide is a nonsteroidal inhibitor of the aromatase enzyme. As a result, it inhibits estrogen synthesis in adipose tissue. Aminoglutethimide also inhibits adrenal steroidogenesis (corticosteroid synthesis) and the extra-adrenal synthesis of estrone and estradiol.

Since estrogens promote the growth of breast cancer, estrogen synthesis in adipose tissue can be important in breast cancer growth in postmenopausal women.

It is mainly used in the treatment of metastatic breast cancer in women whose tumors express significant levels of estrogen or progesterone receptors. In addition, it has activity in advanced hormone-responsive prostate cancer.

It is normally administered with hydrocortisone to prevent symptoms of adrenal insufficiency.

Toxicities of aminoglutethimide include mild nausea, skin rash, adrenal insufficiency, and myelosuppression.
Explain Anastrozole (Aromatase Inhibitor)
Anastrozole is a selective nonsteroidal inhibitor of aromatase. (They do not cause adrenal insufficiency) (Don’t need to be combined with a corticosteroid)

Unlike aminoglutethimide, anastrozole has no inhibitory effect on adrenal glucocorticoid or mineralocorticoid synthesis.

It is used as a first-line treatment of postmenopausal women with metastatic breast cancer that is ER-positive (ER = estrogen receptor), as well as women whose tumors have progressed while on tamoxifen therapy. It is also used as adjuvant therapy of postmenopausal women with hormone-positive, early-stage breast cancer.

Toxicities of anastrozole include mild nausea, hot flushes, and arthralgias.

Letrozole is another selective aromatase inhibitor that has the same mechanism of action, toxicities, and clinical indications as anastrozole.
Explain Exemestane (Aromatase Inhibitor)
Exemestane is a steroidal hormonal agent that binds to and irreversibly inactivates the aromatase enzyme.

There is no cross-resistance between exemestane and the nonsteroidal aromatase inhibitors.

It is indicated for the treatment of advanced breast cancer in postmenopausal women whose tumors have progressed on tamoxifen therapy.

Toxicities of exemestane include mild nausea, headache, and hot flushes.
Explain Protein Kinase Inhibitors (Imatinib, Gefitinib, Erlotinib)
Protein kinases are critical components of signal transduction pathways that transmit information concerning extracellular or cytoplasmic conditions to the nucleus, thereby influencing gene transcription and/or DNA synthesis.

Tyrosine kinases are classified into proteins that have an extracellular ligand binding domain (receptor tyrosine kinases) and enzymes that are confined to the cytoplasm and/or nuclear cellular compartment (nonreceptor tyrosine kinases). (Only affective against a certain Tyrosine Kinase)

Abnormal activation of specific protein tyrosine kinases has been demonstrated in many human cancers, making them attractive molecular targets for cancer therapy.

Imatinib has inhibitory activity against the platelet-derived growth factor receptor (PDGFR) tyrosine kinase, the cytoplasmic ABL tyrosine kinase, and the receptor tyrosine kinase KIT.

Imatinib is effective in treating cancers in which the ABL, KIT, or PDGFR have dominant roles in driving the proliferation of the tumor. This dominant role is defined by the presence of a mutation that results in constitutive activation of the kinase, either by fusion with another protein or point mutations.

Imatinib shows remarkable therapeutic efficacy in patients with chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs), chronic myelomonocytic leukemia (CMML), and hypereosinophilic syndrome (HES). It is given orally.

Acquired resistance to imatinib results predominantly from mutations in the kinase domain. The most frequently reported adverse effects of imatinib are nausea, vomiting, edema, and muscle cramps.
Explain Trastuzumab (Herceptin) (Monoclonal Antibody)
Trastuzumab (HERCEPTIN) is the first monoclonal antibody to be approved for the treatment of a solid tumor. It is a humanized monoclonal antibody against the HER2/neu (ErbB-2) member of the epidermal growth factor (EGF) family of cellular receptors.

HER2/neu is overexpressed in up to 30% of breast cancers and is associated with clinical resistance to cytotoxic and hormone therapy. The internal domain of the HER2/neu glycoprotein encodes a tyrosine kinase that activates downstream signals, resulting in increased metastatic potential and inhibition of apoptosis.

Trastuzumab therapy results in downregulation of HER2/neu expression, which leads to antiangiogenetic effects and the inhibition of cell proliferation. Trastuzumab can also initiate FC-receptor-mediated antibody-dependent cellular cytotoxicity and directly induce apoptosis.

Trastuzumab is approved for HER2/neu overexpressing metastatic breast cancer in combination with paclitaxel as initial treatment or as monotherapy following chemotherapy relapse.

Adverse effects of trastuzumab therapy include fever, chills, nausea, dyspnea, and rashes. Allergic reactions and cardiomyopathy may also occur.