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Title: Pharmacology Part 2 for Medical Students and Nurse


1
Pharmacology Part 2
  • IMEC INC.
  • Quick Learning
  • Technique

2
Treatment of Congestive Heart Failure
3
Cardiac Glycosides
  • Digitalis
  • Mode of Action Regulation of cytosolic
    calcium-inhibiting pump activity by reversibly
    binding with sodium-potassium ATPase
  • Increasing the Contractility of the Cardiac
    Muscle
  • Therapeutic uses include-CHF caused by ischemia
    or congenital heart disease
  • Digoxin/Digitoxin- digoxin has a shorter ½ life
    and is eliminated unchanged in the urine, whereas
    digitoxin is extensively metabolized by the liver
    and may be contraindicated in hepatic disease
  • Adverse affects severe toxicity causes V-Tach
  • Anti dig (FAB) fragments are given
  • CNS-headache, confusion, color perception and
    halos on dark objects

4
Digitalis Toxicity
  • Factors predisposing
  • Electrolyte disturbances-HYPOKALEMIA
  • HYPO K is most observed in patients using
    Thiazide diuretics
  • Hypernatremia, hypermagnesemia, and alkalosis are
    also factors
  • Drugs Quinidine reduces renal clearance of
    digoxin and and alters renal clearance-corticoster
    oids, and any potassium clearing diuretics can
    alter this

5
Antiarrythmics
  • Amrinone-Amrinone is a rapid-acting inotropic
    agent that increases cardiac output following IV
    administration. It is a phosphodiesterate (Class
    III) inhibitor that increases myocardial
    contractility and produces systemic vasodilations
    without stimulating either alpha or beta
    adrenergic receptors. Amrinones net hemodynamic
    effects are similar to those of dobutamine,
    however, because the drug does not stimulate beta
    adrenergic receptors, it may be effective in
    patients with CHF who do not respond to
    dobutamine or other inotropic agents.

6
Vasodilators
  • The vasodilator of choice for CHF is the ACE
    INHIBITOR- Captopril
  • Other vasodilators such as nitroprusside are also
    useful in CHF because it opens both venous and
    arterial beds
  • The outpatient vasodilator of choice with an
    equivalent to nitroprusside is Prazosin

7
Antiarrythmic Drugs
8
Actions of Antiarrythmic Drugs
  • Class Mechanism Comment
  • IA Na Channel Blocker
    Slow Phase Zero Depolar
  • IB Na Channel Blocker
    Shortens phase 3 Repolar
  • IC Na Channel Blocker
    Slows Phase Zero Depolar
  • II B Adrenergic Blocker
    Suppresses phase 4 Depolar
  • III K channel Blocker
    Prolongs Phase 3 Repolar
  • IV Ca Channel Blocker
    Shortens Action Potential

9
Myocardial Action Potential
10
Action Potential
11
CLASS (1A) antiarrhythmic
  • Quinidine
  • Procainamide
  • Disopyramide

12
Quinidine
  • Prototype class 1A , bind to open and inactivated
    sodium channel to prevent sodium influx.Thus
    slowing the rapid influx during Phase O
  • It also decreases the slope of phase 4
  • It inhibits ectopic arrhythmias and ventricular
    arrhythmias caused by increased automaticity
  • Also prevents re-entry arrhythmias
  • Used for A-V Junctional, Ventricular Tachycardia
  • Effects are increased by hyperkalemia, can
    increase digoxin levels. It also has a mild alpha
    effect, and atropine like effect

13
Procainamide
  • Class 1A, a derivative of anesthetic
    Procaine-shows action similar to Quinidine
  • Can be given orally
  • Procainamide has a relatively short half life
  • Acetylated in the liver to NAPA-which has
    properties of a CLASS III drug
  • NAPA is eliminated in via the kidney, therefore
    doses may need to be adjusted in renal failure.
  • With chronic use reversible SLE-Syndrome has been
    noted
  • Used mainly for Ventricular Arrhythmias ACLS

14
Disopyramide
  • Class 1A similar to Quinidine
  • Has a greater negative iontropic effect,
    decreasing myocardial contractility
  • Can cause peripheral vasoconstriction
  • ½ is excreted unchanged by the kidney, and about
    30 is converted by the liver to a less active
    metabolite
  • Used for Ventricular arrhythmias as an
    alternative to procainamide or quinidine
  • Adverse effects-shows anticholinergic effects-dry
    mouth urinary retention-blurred
    vision-constipation

15
Class 1B
  • Lidocaine
  • Mexiletene
  • Tocainide
  • Phenytoin

16
Lidocaine
  • Lidocaine, an anesthetic also causes reduction in
    Phase O. Therefore shortens action potential,
  • Lidocaine abolishes Re-entry
  • Lidocaine is useful in treating ventricular
    arrhythmias arising during myocardial ischemia
  • Lidocaine is given IV, because of extensive
    first-pass metabolism by the liver
  • Therefore patients with hepatic disease may need
    adjustments in dosage
  • Lidocaine has a fairly wide toxic to therapeutic
    ratio
  • No negative Ionotropic effect

17
Mexiletine and Tocainide
  • Class 1B similar to Lidocaine
  • MEXILETINE
  • Used in chronic treatment of ventricular
    arhrythmias associated with previous MI
  • TOCAINIDE
  • Treatment of V-Tach
  • Has pulmonary toxicity, which may lead to
    pulmonary fibrosis

18
Phenytoin
  • This antiepileptic drug has antiarrhythmic
    properties similar to lidocaine
  • Phenytoin is useful in Digatilis induced
    arrhythmias.
  • Also used sometimes in children with ventricular
    arrhythmia

19
Class 1C
  • Flecainide
  • Encainide
  • Propoferone

20
Flecainide
  • This Class 1C, slowly dissociates from resting
    sodium channels and shows prominent effects, even
    at normal heart rates
  • These drugs are approved only for refractory
    ventricular arrhythmias
  • Can suppress PVCs
  • Has a negative iotropic effect, and can aggravate
    CHF
  • Flecainide is absorbed orally and undergoes very
    little biotransformation ½ life 16-20 hours
  • Like other Class 1C, it can aggravate
    pre-existing arrhythmias or can induce life
    threatening ventricular tachycardia, resistant to
    treatment

21
Encainide and Propoferone
  • Class 1Cslows conduction in all cardiac tissue
    and are considered broad spectrum antiarrhythmics

22
Class II ANTIARRHYTHMICS
  • BETA-BLOCKERS
  • Review Beta blockers
  • Propanolol (MI)
  • Metaprolol (B1 specific, reduces risk of
    bronchospasm)
  • Pindolol (may decrease frequency of cardiac
    failure)
  • Esmolol (IV)

23
Class III Antiarrhythmics
  • Bretylium
  • Amiodarone

24
Bretylium
  • Class III agents block potassium channels and
    thus diminish the outward potassium current,
    which leads to repolarization of Cardiac Cells.
  • These agents prolong the duration of the action
    potential without altering Phase O of
    depolarization

25
Bretylium(cont)
  • Bretylium differs from Class I in does not slow
    the rise of Phase 0 of the Action Potential and
    does not reduce the slope of phase 4-spontaneous
    depolarization
  • The most prominent is the prolongation of the
    refractory period and raising of the the
    electrical current necessary to induce
    ventricular fibrillation in the His-Purkinje
    system
  • Reserved for life-threatening ventricular
    arrhymias, especially recurrent V-fib and V-tach
  • Must be given parental, do to poor oral
    absorption
  • Can cause postural Hypotension

26
Amiodarones
  • Contains Iodine (Blue discolored skin) and is
    structurally related to Thyroxine
  • It has complex action and show actions of Class
    I, II, III, IV
  • Amiodarone is effective in the treatment Severe
    Refractory V-tach or SVT
  • It is limited to toxicity
  • Has a very long ½ life
  • SE-Interstitial Pulmonary Fibrosis, Liver
    Toxicity, GI intolerance, Hyper-hypothyroidism,
    liver toxicity, photosensitivity, neuropathy,
    blue-skin

27
Class IV Antiarrhythmic Drugs
  • Verapamil
  • Diltiazem

28
Verapamil Diltiazem
  • Calcium Channel blocker
  • Action calcium enters the cells by
    voltage-sensitive channels and by receptor
    operated channels that are controlled by the
    binding of agonist, such as catocholamines, to
    membrane receptors.
  • Therefore are effective are more effective
    against voltage sensitive channels, which cause a
    decrease in the slow inward current that trigger
    cardiac contraction.
  • Therefore usefulness is with SVT
  • USEFUL in ATRIAL ARRHYTHMIAS
  • Can be given via oral route
  • Contraindicated In preexisting depressed
    Cardiac Function

29
ANTI-ANGINAL DRUGS
30
Organic Nitrates
  • Nitroglycerin
  • Isosorbide Dinitrate
  • Amyl Nitrate

31
Nitroglycerin/ Isosorbide
  • Nitroglygerin converts Nitrite to Nitric Oxide,
    which activates Guanylate Cyclase and increase
    cGMP levels. This in turn leads to
    dephosphorylating of the myosin light chain and
    smooth muscle relaxation.
  • AT Low doses Veins dilate and this reduces
    PRELOAD. Little effect on arterioles exists, and
    the stroke output is compensated by tachycardia
  • At Higher doses, Arterioles are dilated, causing
    a decrease in peripheral resistance. This then
    effects AFTERLOAD.
  • NITROGLYCERIN HAS FIRST PASS METABOLISMSO IT CAN
    BE GIVEN SUBLINGUALLY/TRANSDERAML
  • ISOSORBIDE is a oral form that is not as readily
    metabolized by the liver, it does the same thing
    but has a lower potency than nitroglycerin

32
Calcium Channel Blockers
  • Verapamil-slow cardiac conduction and thus
    decreases heart rate. It should be used
    cautiously in digitalis patients, and in
    patients with AV conduction problems.
  • Nifedapine- arteriolar vasodialator, it is
    administered orally
  • Diltiazem,-is similar to other calcium channel
    blockers, specifically used for spasms, therefore
    useful in variant Angina.

33
Antihypertensive Drugs
34
Hydochlorothiazide
  • Thiazide diuretics work specifically on
    inhibiting reabsorption of sodium and chloride in
    ascending loop of Henle and early distal tubules
  • Decreasing extra cellular fluid volume and
    decreasing CO
  • Thiazide diuretics decrease blood pressure
    whether in a supine or standing position
  • Useful in combination with beta blockers and ACE
    inhibitors
  • Thiazide diurectics can induce hypokalemia and
    hyperuricemia 70 of the time and hyperglycemia
    10 of the time
  • Serum Potassium levels should be monitored
    closely, especially in those patient with left
    ventricular hypertrophy, CHF, or ischemic heart.
  • Diuretics should be avoided in hypertensive
    diabetics and hyperlipidemia.
  • Expect decreased K and Mg, and increased Ca

35
Spirolactone
  • Spirolactone inhibits aldosterone mediated
    reabsorption of Na and secretion of K
  • Often used with thiazide diuretics to prevent
    loss of K

36
ACE inhibitors
  • Angiotensin-converting enzyme inhibitors lower
    blood pressure by reducing peripheral vascular
    resistance without reflective increases in
    cardiac output , rate,or contractility.
  • These drugs block to cleavage of angiotensin I,
    therefore stopping the production of Angiotensin
    II a potent vasoconstrictor.
  • It also inhibits bradykinin inactivation a
    vasodilator
  • This combined effects lowers vasoconstriction and
    enhances vasodilation
  • ACE works well in CHF
  • SE ACE can cause acute renal failure, and sever
    bilateral renal artery stenosis

37
Alpha adrenergic blocker
  • Clonidine- a2 agonist that diminishes central
    adrenergic outflow
  • For mild to moderate hypertension
  • Because it causes Na and water retention it is
    administered with diuretic
  • AE- sedation and drying mucosal membranes
  • A-Methyldopa
  • Reduces total peripheral resistance, but cardiac
    output remains normal

38
Direct acting vasodilators
  • Hydrazaline
  • Directly to arteries and arterioles, prompt
    decrease to total peripheral resistance
  • Moderate to severe hypertension
  • In combination with b-blocker and diuretic
  • SE-lupus like syndrome
  • Minoxidil
  • Directly on arterioles but not venule capacitance
  • Also used for alopecia

39
Sodium Nitroprusside
  • Nipride works directly on veins, it has a very
    short T ½, and decreases preload-
  • Requires continuous infusion
  • Cyanide ion production can occur but toxicity is
    rare
  • Rhodanase combines this with a thiosulfate to
    produce a thiocyanate, which can be eliminated by
    the kidneys

40
Diazoxide
  • Used in Hypertensive Emergencies
  • Malignant Hypertension
  • Hypertensive encephalopathy
  • Hypertensive ecclampsia
  • Toxicity--Hypotension

41
Drugs Affecting Blood
42
Heparin
  • Heparin is an injectable, rapid acting
    anticoagulant
  • It acts indirectly by binding to anti-thrombin
    III, Its effects are within minutes
  • Antithrombin III is considered a cofactor and
    inhibits serine proteases, including several
    clotting factors
  • However, Chronic or intermittent administration
    of heparin can lead to reduction in antithrombin
    III.
  • Because of this low dose heparin is usually
    employed.

43
Heparin (cont)
  • Heparin abolishes fibrin formation and thus
    limits the formation of thrombi
  • Surgery-post operatively to prevent venous
    thrombosis
  • Deep vein thrombosis
  • Heparin works rapidly
  • Thrombocytopenia (reduced platelets can happen 8
    days after initiation)
  • Some patients develop a formation of antiplatelet
    antibodies
  • If thomboembolism occurs with heparin therapy,
    another anti coagulent should be substituted
  • Heparin is reversed by protamine sulfate

44
Warfarin
  • Warfarin and Dicumerol have action to the ability
    to antagonize the cofactor functions of Vitamin K
  • Cofactors 1972
  • Unlike heparin-effects are not observed until
    8-12 hours after drug is administered
  • The drug is 99 plasma bound, therefore it does
    not diffuse into CSF, urine, or breast milk
  • Can be displaced by Sulfonamides

45
Problems with thrombosis  
  • Local thrombosis is an important part of the
    normal hemostatic response that limits hemorrhage
    from microscopic or macroscopic vascular injury.
    Physiologic thrombosis is counterbalanced by
    physiologic anticoagulation and physiologic
    fibrinolysis. Under normal conditions, thrombus
    is confined to the immediate area of injury and
    does not obstruct flow to critical areas. Under
    pathological conditions, thrombus can propagate
    into otherwise normal vessels. Thrombus that has
    propagated where it is not needed can obstruct
    flow in critical vessels and can obliterate
    valves and other structures that are essential to
    normal hemodynamic function.
  • Abnormal thrombosis can occur in any vessel at
    any location in the body. The principal clinical
    syndromes that result are acute myocardial
    infarction (MI), deep vein thrombosis, pulmonary
    embolism, acute nonhemorrhagic stroke, acute
    peripheral arterial occlusion, and occlusion of
    indwelling catheters.

46
RETEPLASE
  • Seems to work more quickly and to have a
    lower bleeding risk than the first-generation
    agent alteplase.
  • Reteplase is a synthetic nonglycosylated deletion
    mutein of tissue plasminogen activator containing
    355 of the 527 amino acids of native tissue
    plasminogen activator. The drug is produced in
    Escherichia coli by recombinant techniques.
    Reteplase does not bind fibrin as tightly as
    native tissue plasminogen activator, allowing the
    drug to diffuse more freely through the clot
    rather than binding only to the surface the way
    tissue plasminogen activator does. In high
    concentrations, reteplase does not compete with
    plasminogen for fibrin-binding sites, allowing
    plasminogen at the site of the clot to be
    transformed into clot-dissolving plasmin. These 2
    modifications help explain the faster clot
    resolution seen in patients receiving reteplase
    than in those receiving alteplase.
  • The modifications also resulted in a molecule
    with a faster plasma clearance and shorter
    half-life (about 11-19 min) than alteplase.
    Reteplase undergoes renal (and some hepatic)
    clearance. The shorter half-life makes the drug
    ideal for double-bolus dosing. The result is more
    convenient administration and faster thrombolysis
    with reteplase than with alteplase, which is
    given by a bolus followed by an intravenous (IV)
    infusion.

47
ALTEPLASE (t-PA)
  • Alteplase (t-PA, Activase) was the first
    recombinant tissue-type plasminogen activator and
    is identical to native tissue plasminogen
    activator. In vivo, tissue-type plasminogen
    activator is synthesized and made available by
    cells of the vascular endothelium. It is the
    physiologic thrombolytic agent responsible for
    most of the body's natural efforts to prevent
    excessive thrombus propagation. Alteplase is the
    fibrinolytic agent most familiar to emergency
    departments and is the lytic agent most often
    used for the treatment of coronary artery
    thrombosis, pulmonary embolism, and acute stroke.
  • HIGHEST FIBRIN SPECIFICITY
  • In theory, alteplase should be effective only at
    the surface of fibrin clot. In practice, however,
    a systemic lytic state is seen, with moderate
    amounts of circulating fibrin degradation
    products and a substantial systemic bleeding
    risk.
  • The agent may be readministered as necessary, as
    it is not antigenic and almost never is
    associated with any allergic manifestations.

48
UROKINASE
  • Urokinase (Abbokinase) is the fibrinolytic agent
    most familiar to interventional radiologists and
    the one that has been used most often for
    peripheral intravascular thrombus. At the time of
    this writing, urokinase is not available from the
    manufacturer. Its availability in the immediate
    future is not known. In the meantime, the FDA has
    encouraged the off-label use of reteplase and
    alteplase for local-regional lysis of venous and
    arterial thrombus at any location.
  • Urokinase is a physiologic thrombolytic agent
    that is produced in renal parenchymal cells.
    Unlike streptokinase, urokinase directly cleaves
    plasminogen to produce plasmin. When purified
    from human urine, approximately 1500 L of urine
    are needed to yield enough urokinase to treat a
    single patient. Urokinase is also commercially
    available in a form produced by tissue culture,
    and recombinant DNA techniques have been
    developed for urokinase production in E coli
    cultures.
  • In plasma, urokinase has a half-life of
    approximately 15 minutes. Allergic reactions are
    rare, and the agent can be administered
    repeatedly without antigenic problems
  • GOOD WITH PULMONARY EMBOLI

49
Streptokinase
  • Streptokinase is the least expensive
    fibrinolytic agent, but unfortunately it is
    highly antigenic and produces a high incidence of
    untoward reactions. This drawback limits the
    usefulness of streptokinase in the clinical
    setting.
  • Streptokinase is produced by beta-hemolytic
    streptococci. It was first isolated in 1933 and
    entered clinical use in the mid-1940s.
    Streptokinase by itself is not a plasminogen
    activator, but it binds with free circulating
    plasminogen (or with plasmin) to form a complex
    that can convert additional plasminogen to
    plasmin. Streptokinase activity is not enhanced
    in the presence of fibrin.
  • The principal plasma activity half-life of
    streptokinase is about 20 minutes, but an unbound
    fraction (about 15) has a half-life of 80
    minutes. Since it is produced from streptococcal
    bacteria, it often causes febrile reactions and
    other allergic problems. Streptokinase usually
    cannot be administered safely a second time
    within 6 months, because it is highly antigenic
    and results in high levels of antistreptococcal
    antibodies.

50
Drugs to treat Anemia
  • Iron
  • Folic Acid
  • Cyanobalmin (B-12)
  • Erythropoietan

51
Iron
  • Iron deficiency is a common condition in end
    stage renal disease (ESRD) patients undergoing
    hemodialysis. Iron is a critical structural
    component of hemoglobin, a key protein found in
    normal red blood cells (RBCs) which transports
    oxygen. Without this important building block,
    anemic patients experience difficulty in
    restoring adequate, healthy RBCs that improve
    hemocrit levels. Clinical management of iron
    deficiency involves treating patients with iron
    replacement products while they undergo
    hemodialysis. Body iron stores can be
    supplemented with either oral or intravenous (IV)
    iron products.

52
Folic Acid
  • Action/Kinetics Folic acid (which is converted
    to tetrahydrofolic acid) is necessary for normal
    production of RBCs and for synthesis of
    nucleoproteins. Tetrahydrofolic acid is a
    cofactor in the biosynthesis of purines and
    thymidylates of nucleic acids. Megaloblastic and
    macrocytic anemias in folic acid deficiency are
    believed to be due to impairment of thymidylate
    synthesis. Natural sources of folic acid include
    liver, dried beans, peas, lentils, whole-wheat
    products, asparagus, beets, broccoli, brussels
    sprouts, spinach, and oranges. Synthetic folic
    acid is absorbed from the GI tract even if the
    client suffers from malabsorption syndrome. Peak
    plasma levels after an oral dose 1 hr. It is
    stored in the liver.
  • Uses Treatment of megaloblastic anemias due to
    folic acid deficiency (e.g., tropical and
    nontropical sprue, pregnancy, infancy or
    childhood, nutritional causes). Diagnosis of
    folate deficiency.

53
Cyanocobalamin
  • Anemia
  • Pernicious anemia (Addisonian anemia, Biermers
    anemia) or
  • Macrocytic anemia or
  • Fish tapeworm anemia or
  • Megaloblastic anemia.
  • Gastrointestinal disorders
  • Malabsorption syndromes such as sprue, idiopathic
    steatorrhea, and other malabsorption syndromes
    or
  • Surgical or mechanical disorders such as
    resection of the small intestine, intestinal
    strictures, intestinal anastomosis, blind loop
    syndrome, and gastrectomy (subtotal or total) or
  • Conditions associated with decreased production
    of intrinsic factor.
  • Neuropathy
  • Posterolateral sclerosis or
  • Neuropathies associated with pernicious anemia
    (Addisonian anemia, Biermers anemia) or
  • Acute phase or acute exacerbation of a neuropathy
    due to malnutrition or alcoholics
  • Homocystinuria
  • Retrobulbar neuritis associated with heavy
    smoking, also known as tobacco amblyopia
  • Dementia secondary to vitamin B-12 deficiency
  • Charges by a physician for administering vitamin
    B-12 injection will be covered for diagnoses and
    conditions listed above.
  • In general, initial treatment of accepted
    diagnoses consists of 1000 mg vitamin B-12 daily
    for 5 days, then 1000 mg weekly for 4 weeks.
    Maintenance therapy usually consists of 1000 mg
    every 1 to 3 months. Requests for vitamin B-12
    injections more frequently than the schedule
    stated above should be referred to the Medical
    Director.

54
Erthyropoeiten Therapy
  • Erythropoietin therapy (e.g., EPO, Epogen
    epoetin alfa, epoetin beta, Procrit, r-HuEPO,
    Eprex) is used to stimulate red blood cell
    production in the bone marrow, thereby correcting
    anemia, minimizing the need for transfusion
    requirements, and improving the quality of life
    for patients. Prior to initiation of therapy,
    the patient's iron stores, including transferrin
    saturation and serum ferritin, should be
    evaluated. According to the literature,
    transferrin saturation should be at least 20 and
    ferritin at least 100 ng/ml. In addition, since
    ferritin is an acute phase reactant, it may be
    falsely elevated (to the normal range) in iron
    deficient dialysis patients. Therefore, the best
    guide for iron supplementation in this group of
    patients is an iron saturation gt20. According to
    the literature, dosing should be discontinued if
    the hematocrit has not increased within 8 weeks,
    indicating a nonresponder. Accepted guidelines
    state that dosage should be decreased if the
    hematocrit increases by more than 4 g/dl in any
    2-week period. Dosing is adjusted after 8 weeks
    and at monthly intervals thereafter as necessary
    to maintain a hematocrit of 30-36.

55
Hydroxyurea
  • Inhibits deoxyribonucleic acid synthesis,
    interferes with conversion of ribonucleotides to
    deoxyribonucleotides, and may inhibit
    incorporation of thymidine into DNA.
  •   IndicationsReduce frequency of painful
    crises and need for blood transfusion in adults
    with Sickle Cell Anemia with recurrent
    moderate-to-severe painful crises treatment of
    melanoma resistant chronic myelocytic leukemia
    (CML) recurrent, metastatic, or inoperable
    carcinoma of ovary as an adjunct to irradiation
    in local control of primary squamous cell
    carcinomas of head and neck, excluding lip.

56
Antihyprelipidemic Drugs
57
Type I Hyperlidemia
  • Type I Familial Hyperchylomicronemia
  • Massive fasting hyperchylomicronemia even after
    following normal dietary fat intake
  • Deficiency of lipoprotien lipase or deficiency of
    normal apoprotien CII rare
  • Type I is not associated with an increase in
    coronary heart disease
  • Treatment low fat diet-No drug therapy

58
Type IIA Familail Hyperbetaprotienemia
  • Elevated LDL, with normal VLDLs level due to a
    block in LDL degradation, therefore increase
    serum cholesterol but normal triacylglyerol
  • Caused by a decrease number of LDL receptors
  • Ischemic Heart disease is greatly accelerated
  • TX Low cholesterol/ Low Fat diet
  • Heterozygotes-Cholestyramine or Colestipol, and
    Lovastatin or mevastatin
  • Homozygotes-As above, plus niacin

59
Type II B Familial Combined (mixed)
Hyperlipidemia
  • Similar to IIA, except VLDL is also increase,
    resulting in elevated serum triacylglyerol as
    well as cholesterol
  • Relatively common
  • TxDietary restriction as above, low cholesterol,
    fat and no alcohol
  • Similar to IIA, except heterozygotes also receive
    Niacin

60
Type III Familial Dysbetalipoproteinemia
  • Serum Concentrations of IDL are increased
    resulting in increasing triacyglyerol and
    cholesterol
  • Cause is either overproduction or
    underutilization of IDL, perhaps due to mutant
    apoprotien
  • Xanthomas and accelerated coronarya nd peripheral
    resistance develop by middle age
  • TX-Weight reduction, Dietary restriction of
    cholesterol and alcohol
  • Drug therapy includes niacin, and clofibrate (or
    gemfibrizol), or lovastatin (or mevastaitin)

61
Type IV Familial Hypertriglyceridemia
  • VLDL are increase, while LDL levelas are normal
    or decreased, resulting in normal to elevated
    cholesterol, and greatly elevated circulation
    triacylglycerol
  • Cause is either overproduction or decreased
    removal of VLDL in serum
  • This is relatively common disease. It has few
    clinical manifestations other than accelerated
    ischemic heart disease
  • Weight reduction is of primary importance-Dietary
    restriction of controlled carbohydrate, modified
    fat, low alcohol consumption
  • If necessary, drug therapy includes niacin and or
    gemfibrizol (or Clofibrate), lovastatin or
    mevastatin

62
Type V Familial Mixed Hypertriglyceridemia
  • Serum VLDL and Chylomicroms are elevated, LDL is
    normal or decreased. This results in elevated
    cholestrol and greatly elevated triacylglycerol
  • Cause is either increased production or decreased
    clearance of VLDL and chylomicrons
  • TX Weight rduction is important. Diet should
    include protein, low fat, controlled carbohydrate
    and NO ALCOHOL.
  • Drug therapy include niacin, Clofibrate and/or
    Gemfibrizol , or lovastatin (or mevastatin)

63
NIACIN
  • Niacin strongly inhibits lipolysis in adipose
    tissue
  • Normal liver utilizes these circulating fatty
    acids as a precursor to TG synthesis
  • Thus Niacin causes a decrease in liver
    triaclyglycerol synthesis, which is requires for
    VLDL production. Also LDL which is derived from
    VLDL production
  • THEREFOREreduces VLDL SECRETION
  • Niacin is administered orally-often in
    combination with other antihyperlipidemics
  • Nicotinamide does not decrease plasma lipid
    levels
  • SE cutaneous Flush-which is prostaglandin
    mediated ----nausea and abdominal pain

64
Clofibrate
  • Clofibrate causes a decrease in TG levels by
    increasing the activity of lipoprotien lipase.
    Thereby increasing removal of VLDL from the
    plasma
  • It apparently also inhibits cholesterol
    synthesis, and causes an increase in cholesterol
    secretion via the bile to the feces
  • Very Useful in TYPE III, but also in Type IV
    (elevated VLDL) and Type V ( increase in VLDL and
    Chylomicrons)
  • SE-most common is gastrointestinal, yet because
    there increased cholesterol excretion via the
    bile, it may result in formation of gallstones
  • Note Clofibrate competes with coumarin
    anticoagulants for plasma binding sites, thus
    potentiating anticoagualtion
  • Monitor Prothrombin levels

65
Gemfibrozil
  • Gemfibrozil decreases the rate of incorporation
    of long fatty acid chains into triacylglycerolres
    ulting in a decrease in VLDL
  • Like Clofibrate it increases Lipoprotien lipase
    activity
  • Gemfibrizol also has the effect of increasing HDL
    production in liver
  • Used primarily in Types III, IV, V, where serun
    VLDLs and IDLs are elevated
  • SE-GI disturbances, rash, and like clofibrate it
    potentiates the activity of coumarin
    anticoagulants

66
Cholestyramine/colestipol Bile Acid
Resins
  • Bile Acid Resins are taken orally and are anion
    exchange resins that bind negatively charges bile
    acids in the small intestine. The resin/bile acid
    complex is excreted in the feces, thus preventing
    bile acids from returning to the liver by
    enterohepatic circulation
  • Lowering bile acid concentration in the
    hepatocytes causes increased conversion of
    cholesterol to bile acids resulting in
    replenishment of this bile component
  • TYPE IIA
  • The outcome, is increased uptake of LDL particle,
    and in some patient an increased HDL level is
    observed
  • The final outcome is decreased decreased plasma
    Cholesterol Concentration
  • SE-GI---Intestinal absorption of Tetracycline,
    Phenobarbital, digoxin, warfarin
  • Also Fat Soluable Vitamins A, D, E, K can be
    impaired

67
Probucol
  • Probucol lowers serum cholesterol by causing an
    increased uptake of LDL particle from the plasma.
  • Activates a normal low-affinity uptake mechanism
  • Unfortunately it also effects HDL
  • Can be used in Type IIA, but Bile Acid Resins are
    much more effective

68
STATINS
  • Over the past few years, the management of
    cardiovascular disease has changed with the
    addition of the 3-hydroxy-3-methylglutaryl
    coenzyme A reductase inhibitors, more commonly
    known as statins. These agents have been used for
    primary and secondary prevention of coronary
    artery disease. Vaughan and associates reviewed
    the various effects of statins and current
    recommendations for using these medications.
  • The basic mechanism of action of statins is the
    reduction of low-density lipoprotein (LDL)
    cholesterol levels. Statins also cause minor
    reductions of triglyceride levels and minor
    increases in high-density lipoprotein (HDL)
    cholesterol levels. Dyspepsia, abdominal pain and
    flatulence, the most common side effects, are
    usually mild, transient and reversible. The most
    important adverse effects of statins are
    elevations of the serum transaminase levels and
    development of myositis. These adverse effects
    are more common when statins are used in
    combination with other medications that inhibit
    the cytochrome P450 system, such as azole
    antifungal agents, cimetadine and methotrexate.
    The risk for statin-related myositis increases in
    patients taking gemfibrozil, nicotinic acid or
    macrolides.
  • Statins have been shown to decrease morbidity and
    mortality rates related to coronary artery
    disease. This reduction can occur through primary
    prevention and by treating hypercholesterolemia
    before the development of coronary artery
    disease.

69
Lovastatin
  • Mevacor, Zocor, Prevachol are Statins, that are
    structural analogs of 3-hydoxy 3-methylglutarate
    (HMG), a precursor of cholesterol. These drugs
    inhibit HMG-CoA reductase thereby inhibiting
    denova synthesis, and depleting intracellualr
    supply of cholesterol.
  • Depleting intracellular cholesterol causes and
    increase in the number of specific cell-surface
    LDL receptors, thus synthesis of cholesterol is
    decreased and catabolism of LDL is increase
  • These drugs are almost entirely removed via
    portal circulation
  • Useful in Type III, IV and V
  • Studies are continually be done with the statin
    drugs
  • ---These drugs are contraindicated in pregnancy
    and should not be used in children.

70
Acetalzolamide
  • The carbonic anhydrase inhibitor have only weak
    effects on Naretention, since the loop of henle,
    which is downstream from the proximal
    tubuleAcetylzolamides major side of action.
  • It is able to absorb a large amount of NaCl in
    the fluid leaving the proximal tubule
  • Uses TX of Glaucoma-reduce elevated intraocular
    pressure-decreasing the pressure of the aqueous
    humor
  • Epilepsy-Reduces the magnitude of the seizure
  • Mountain Sickness-side effects related to
    cerebral and pulmonary edema

71
Loop Diuretics-Lasix, Bumex, E-Acid
  • Loop diuretics inhibit the Na/K/Cl co-transport
    of the luminal membrane in the ascending limb of
    the loop of henle.
  • Because the ascending limb accounts for the
    absorption of 30-40 of filtered NaCl ,
    downstream sites are not able to compensate for
    increased Na excretion
  • Conjugate with Aminoglycosides
  • Loop diuretics act promptly
  • Use in edematous states, hypercalcemia and
    elevated ICP
  • SE-ototoxity, hyperurcemia, POTASSIUM DEPLETION

72
Thiazide Diuretics
  • Chlorothiazide
  • Chlorothalidone
  • Hydrochlorothiazide
  • Metolazone
  • Indapamide

73
Chlorothiazide
  • The thiazide dirivitive acts directly mainly in
    the Distal tubule
  • Causes diuresis with increased Na and Cl-
    secretion, which can result in the excretion of
    very hyperosmolar urine
  • Does cause Kdepletion, hyperuricemia,
    hyperglycemia, Hypersensitivty (interstital
    nephritis) (bone marrow suppression)
  • In contrast to loop diuretic, there is an
    increase in Ca concentrations in the urine
  • Eventual reduced PVR-relaxation of arterioles
  • Use Besides hypertension is Hypercalcemias, CHF,
    Diabetes Insipidus
  • DRAW PERIODIC URIC ACID LEVELS

74
Hydrochlorothiazides
  •   Action SAME AS PARENT DRUG
  • Enhances excretion of sodium, chloride, and water
    by interfering with transport of sodium ions
    across renal tubular epithelium.
  •   IndicationsAdjunctive therapy for edema
    associated with CHF, hepatic cirrhosis, renal
    dysfunction, and corticosteroid and estrogen
    therapy treatment of hypertension. Unlabeled
    use(s) Prevention of formation and precurrence
    of calcium nephrolithiasis therapy for
    nephrogenic diabetes insipidus.
  •   ContraindicationsHypersensitivity to
    thiazides, related diuretics, or
    sulfonamide-derived drugs anuria renal
    decompensation.

75
Spirolactone-Potassium Sparing
  • Blood levels in edematous states, usually
    aldosterone levels are high
  • S INDUCES P450
  • Thus the drug antagonizes the affect of the
    hormone causing K retention
  • S is the only potassium sparing antibiotic
    routinely used
  • MAY INDUCE GYNACOMATSIA

76
Amiloride/Triamterene
  • Block Na transport channel resulting in a
    decrease Na-K exchange.
  • They have a potassium sparing action
  • Triamterene causes increased BUN and possible leg
    cramps

77
Mannitol
  • Osmolarity
  • Speaks for itself
  • Increased water excretion

78
Gastrointestinal Drugs
79
H2 Blockers
  • Cimetidine
  • Rantidine
  • Famotidine
  • Nizatidine

80
H2 receptor blockers
  • Histimine has a powerful effect on the secretory
    cells of the stomach (an to a lesser extent
    pepsin) secretion. It does so by biding the H2
    receptor to the parietal cells of the stomach ,
    thereby initiating cyclic AMP-mediated cascade of
    activity
  • H2 blockers are very useful in treating the
    promotion of healing of ulcers
  • H2 blockers are also helpful in treating
    gastrin-secreting tumor such as Zollinger-Ellison
    Syndrome

81
Prostaglandins
  • Misoprostol is a analog of prostaglandin E1
  • It is superior to H2 blockers in mucosal damage
    caused by NSAIDS
  • It also heals a majority of Duodenal Ulcer that
    do not respond to H2 Blockers

82
Proton Pump Inhibitors
  • Omeprazole is a H-K adenosine triphosphate
    antagonist
  • Inhibits the gastric ATPase
  • Pepsin and Intrinsic Factor are not affected
  • Also very effective in hyper-secretion situations

83
Antimuscurinic
  • Cholinergic antagonists shows greater specificity
    against secretory function.

84
Systemic Antacids
  • Sodium Bicarbonate
  • NaHCO3 raises Ph to an alkaline level, which can
    be undesirable because it increases acid secretion

85
Non-systemics Antacids
  • Calcium Carbonate-
  • It can reduce pain an Aid healing, approxiamately
    10 is neutralized to calcium chloride
  • SE-hypercalcemia
  • Aluminum Hydroxide
  • Reacts to HCl to produce aluminum chloride, which
    is insoluable
  • May cause constipation
  • May effect Tetracycline absorption
  • Magnesium Hydroxide
  • Acts as a salt, also works as a good cathartic
    because it brings in fluid to the GI tract

86
Mucosal protective agents
  • Sucralfate- selectively binds to mucosal
    protective tissue. It binds to pepsin and Hcl and
    is particularly helpful in healing duodenal
    ulcers
  • Note-should not be given with beta-blockers or
    antacids

87
Bulk Laxatives
  • These agents include hydrophilic colloids and
    fibers from fruit and vegatable, agar, methyl
    cellulose, pysllium, fruits and bran.
  • Saline cathartic are salts and nonabsorbable
    ions, such as magnesium. They attract fluid in
    the gut by increasing the osmotic pressure.
    Resulting in distension, and peralstasis

88
Irritants and stimulants
  • Castor Oil is broken down in the intestine to
    ricinoleic acid which is very irritating
  • Cascara, senna, and aloe contain EMODIN which
    stimulates colonic activity
  • Phenolphethalien and biscodyl also stimulate the
    colon

89
Hormones of the Pituitary an Thyroid
90
Pituitary Hormones
  • Corticotropin-ACTH
  • Growth Hormone
  • Oxytocin
  • Vasopressin

91
Corticotropin
  • ACTH-is a peptide that is extracted from the
    anterior pituitary of domestic animals
  • It binds to various receptors on the adrenal
    cortex
  • The activated receptorVIA cAMPstimululates the
    rate limiting step in adrenocorticosteroid
    synthetic pathway, causing the release of
    Cortisol, Androgens, and minerlcorticoids
  • PRINCIPLE USE is in ADDISONs Disease
  • Cosyntropin is a synthetic now used routinely in
    diagnostics

92
Growth Hormone
  • Somatotropin influences a wide vaiety of
    biochemical processes.
  • The drug is used in the deficiency of
    Growth-Hormone deficiency
  • It made through recombinant DNA technology
  • A therapuetic equililent, SAMETREM, exists today
    conationing an extra methionyl group

93
OXYTOCIN
  • Is a non-peptide extracted from Posterior
    Pituitaries of animal
  • It is used to induce and reinforce labor

94
Vasopressin
  • IS Antidiuretic Hormone (ADH), like oxytocin it
    is extracted from the posterior pituitary of
    animals.
  • Vasopressin increases water permeability in the
    collecting tubule of the kidney
  • This leads to antidiuretic effect
  • Used in DIABTETIS INSIPIDUS

95
Thyroid Hormones
  • Thyroid hormone synthesis, occurs in a single
    layer of epithelium surroiding a lumen filled
    with colloid (THYROGLOBULIN)
  • Function is controlled by TSH (thryrotropin)
  • Secretion of TSH by the anterior pituitary is
    stimulated by the hypothalmic-thyrotropin
    releasing hormone (TRH) and is inhibited by
    negative feedback

96
Thyroid Regulation
97
Treatment of hyperthyroidism (thyrotoxicosis)
  • Excessive amts of thyroid hormones in the
    circulation can be caused by GRAVES DX, TOXIC
    ADENOMA, GOITER and THYROIDITIS.
  • To treat this they can remove part of the gland
  • Destruction of Gland is via Radioactive Iodine
  • The thiomides. Propylthiouricil and methimazole
    inhibit iodination of tyrosyl groups and the
    coupling of iodotyosines to form T3 and T4
  • They have no effect on thyroglobulin already
    absorbed
  • Iodides inhibit thyroid hormone release, by
    decreasing thyroglobulin stores

98
Insulin and Oral Hypoglycemic Agents
  • Diabetes is not a single disease instead it is a
    hetergenous group of syndromes all characterized
    by an elevation in blood glucose by a relative or
    absolute deficiency of insulin.
  • Frequently the insulin is agreevated by an excess
    of glucogon
  • Diabetic is classifed by Type I and Type II
  • Treatment varies for each type.

99
Type I
  • Type I or insulin-dependent diabetes mellitus is
    the result of a frank deficiency of insulin. The
    onset of this disease typically is in childhood.
    It is due to destruction pancreatic B cells, most
    likely the result of autoimmunity to one or more
    components of those cells. Many of the acute
    effects of this disease can be controlled by
    insulin replacement therapy, but inevitably,
    there are long-term adverse effects on blood
    vessels, nerves and other organ systems.

100
Type II
  • Type II or non-insulin-dependent diabetes
    mellitus begins as a syndrome of insulin
    resistance. That is, target tissues fail to
    respond appropriately to insulin. Typically, the
    onset of this disease is in adulthood. Despite
    monumental research efforts, the nature of the
    defect has been difficult to ascertain - in some
    patients, the insulin receptor is abnormal, in
    others, one or more aspects of insulin signalling
    is defective, and in others, no defect has been
    identified. Because there is not, at least
    initially, an inability to secrete adequate
    amounts of insulin, insulin injections are not
    useful for therapy. Rather the disease is
    controlled through dietary therapy and
    hypoglycemic agents.

101
Insulin Receptor
102
Insulin
  • Insulin is a highly negatively charged because of
    the presence of dicarboxlic acids. This enables
    the hormone to bind to both positively charged
    proteins in the circulation and to insulin
    receptors on receptive cell membranes. Insulin
    secetion is regulated not only by glucose, but
    other hormones and autonomic mediators

103
What insulin does
104
Insulin Rates
105
Rapid Action Insulin Preparations
106
Crystalline Insulin--Regular
  • CZI-or Crystalline Zinc Insulin-is purified
    insulin extracted from pork or beef pancreas or
    synthetic human insulin that is crystalized as a
    zinc salt. Note the positively charges of Zinc
    bind to the negatively charged insulin, causing
    crystalization
  • The CZI is ussually given SubQ
  • ACTION IS WITHIN MINUTES in lowering blood sugar

107
Semilente Insulin
  • PROMPT insulin zinc susoension-is a suspension of
    amorphous insulin derived from beef or pork
  • It is used most commonly as a supplement for
    intermediate or prolonged action forms of insulin
  • Semilente Insulin is given only SUB Q

108
Intermediate Action Insulin Preparation
109
Isophane Insulin Suspension
  • NPH-Neutral protamine Hagedorn is a zinc insulin
    with positively charged peptide mixture called
    protamine
  • It duration is in between CZI and PZI
  • Its delay absorption is because of conjugation
    of the insulin with protamine to form a less
    soluble complex
  • NPH is only given Sub Q and is useful in treating
    all forms of diabetes except ketoacidosis

110
Lente Insulin
  • Insulin Zinc Suspension (Lente Insulin) is a
    Mixture of 30 semilente insulin (prompt) AND 70
    ultra-lente (prolonged0
  • It is given only subQ and is used for patients
    previously untreated diabetics who require insulin

111
Prolonged Action Insulin Preparation
112
Protamine Zinc Insulin
  • PZI is prerared by treating CZI with protamine at
    neutral pH. Resulying in a fine precipatate
  • PZI reaches maximum effectiveness in 24 hours

113
Extended Action Zinc Suspension
  • Ultralente is crystalline insulin that is poorly
    soluble .
  • It is therefore a delayed onset
  • It is usually mixed with semilente insulin to
    produce lente insulin

114
ORAL HYPOGLYCEMIC AGENTSSulfonylureas
115
Tolbutamide
  • Duration is 8 hours
  • Decreases blood glucose by stimulating release of
    insulin from pancreas.
  •   Indications
  • Oral form Adjunct to diet to lower blood glucose
    in patients with non-insulin-dependent diabetes
    mellitus (type 2) whose hyperglycemia cannot be
    controlled by diet alone.
  • IV form (tolbutamide sodium) Aid in diagnosis of
    pancreatic islet cell adenoma

116
Acetohexamide
  • 15 Hour duration
  • Similar to Tolbutamide- different drug
    interactions

117
Tolazamide
  • Decreases blood glucose by stimulating release of
    insulin from pancreas.
  •   IndicationsAdjunct to diet to lower blood
    glucose in patients with non-insulin-dependent
    diabetes mellitus (type 2) whose hyperglycemia
    cannot be controlled by diet alone. Unlabeled
    use(s) Temporary adjunct to insulin therapy in
    selected patients with non-insulin-dependent
    diabetes mellitus to improve diabetic control.
  • 18 HOUR DURATION

118
CHLORPROPAMIDE
  • Decreases blood glucose by stimulating insulin
    release from pancreas.
  •   IndicationsAdjunct to diet to lower blood
    glucose in patients with non-insulin-dependent
    diabetes mellitus (type II) whose hyperglycemia
    cannot be controlled by diet alone. Unlabeled
    use(s) Control of neurogenic diabetes insipidus.
  • Disulfuram Type Reactions
  • Long Duration of Action 48 hours

119
Glipizide
  • Antidiabetic Sulfonylurea
  •   ActionDecreases blood glucose by stimulating
    insulin release from pancreas and by increasing
    tissue sensitivity to insulin.
  •   IndicationsAdjunct to diet to lower blood
    glucose in patients with non-insulin-dependent
    diabetes mellitus (type II) whose hyperglycemia
    cannot be controlled by diet alone.
  • HIGH POTENCY
  • 18 hour Duration

120
Glyburide
  • Decreases blood glucose by stimulating insulin
    release from pancreas. May also decrease hepatic
    glucose production or increased response to
    insulin.
  •   IndicationsAdjunct to diet to lower blood
    glucose in patients with non-insulin-dependent
    diabetes mellitus (type II) whose hyperglycemia
    cannot be controlled by diet alone in
    combination with metformin when diet and
    glyburide or diet and metformin alone do not
    result in adequate glycemic control.
  • Excreted 50 in FECES

121
Metformin-Antidiabeticbiguanide
  • ActionDecreases blood glucose by decreasing
    hepatic glucose production. May also decrease
    intestinal absorption of glucose and increase
    response to insulin.
  •   IndicationsAdjunct to diet to lower blood
    glucose in patients with noninsulin-dependent
    diabetes mellitus (type II) whose hyperglycemia
    cannot be controlled by diet alone.

122
Agents with Intrinsic hypoglycemic activity
  • Insulin
  • Alcohol
  • B-adrenergic antagonist
  • Salicylates
  • MAO inhibitors

123
Drugs that displace sulfonylureas from plasma
protien
  • Clofibrate
  • Phenylbutazone
  • Salicylates
  • Sulfonamides

124
Reduce hepatic metabolism of sulfonylureas
  • Dicumarol
  • Chloramphenical
  • MAO inhibitors
  • Phenylbutazone

125
Drugs that decrease urinary excretion of
Sulfonylureas an metabolytes
  • Allopurinol
  • Probenicid
  • Phenylbutazone
  • Salicylates
  • Sulfonamides

126
STEROID HORMONES
127
Estrogens
  • Estradiol
  • Estrone
  • Estriol
  • Diethystilbestrol
  • Quinestrol
  • Chlorotrianisene
  • Ethinyl Estradiol
  • Mestranol

128
Estradiol, Estrone, Estriol
  • The female produce the above forms of Estrogen.
  • Estradiol is produced in the ovaries
  • The liver converts estradiol to Estrone, and
    Estriol
  • The Adrenal Gland can synthesize estrogens,
    whereas fat cells, muscle cells can convert
    circulating androgens (androstredione) and
    testosterone into estrogens
  • Synthetic estrogens exhibit less of a first pass
    metabolism, therefore increases effectiveness
    when given orally
  • Note it is the adrenal gland by which estrogens
    are produced in men and postmenopausal women
  • The naturally occurring hormones pose first-pass
    metabolism

129
Estrogens-Mechanism of action
  • Steroid hormones cross the cell membrane by
    diffusion and bind with high affinity to specific
    receptors. The activated steroid-receptor complex
    enters the nucleus and interacts with chromatin
    to stimultae hormone-specific RNA synthesis,
    rsulting in the synthesis of specific protiens
    that mediate a number of physiological functions.

130
Therapeutic uses of Estrogens
  • Post-menopausal women-or with women who have
    undergone a hysterectomy, unopposed estrogen
    therapy is recommended.
  • Replacement therapy is usually 1/5 that for oral
    contraception
  • Estrogens in these cases are given versus
    progestin because progestin may alter (HDL/LDL)
    ratio
  • Advantages of estrogen therapy may be
  • Decreases post-menopausal sleep disturbance
  • Cardiovascular-protective (decreasing
    LDL/Increasing HDL)
  • Urogenital tract-minimizes postmenopausal atrophy
  • Osteoporosis-decreases re-absorption of bone (hip
    fractures)
  • VASOMOTOR- Estrogen re-establishes feedback on
    hypothalamic norepinephrine secretion, leading to
    a decrease of HOT FLASHES

131
Therapeutic uses of Estrogens-continued
  • Primary Hypogonadism
  • Usually in combination with progestin, to
    stimulate development of secondary sex
    characteristics
  • Treatment of Metastatic Breast Cancer
  • Large doses may lead to a regression or arrest of
    breast tumor growthnote this is paradoxical
    since estrogens at normal levels stimulate breast
    development
  • Contraception
  • Frequently given with progestin

132
Estrogen Pharmacology
  • Naturally occurring estrogens and their
    esterified or conjugate derivative are readily
    absorbed through the GI, Skin, mucosal membrane.
    They are also absorbes quickly when administered
    IM.
  • Are metabolized quickly by microsomal enzymes of
    the liver
  • The synthetic estrogen analogs (ethinyl
    estradiol) and (mestranol) are well absorbed, and
    ethinyl estradiol come in a patch
  • These are generally metabolized more slowly by
    liver, and are Fat Soluble and stored in adipose
    tissue. This slower release system increases the
    duration of action

133
Adverse Effects of Estrogens
  • Nausea and vomiting (most common)
  • Breast Tenderness-endometrial hyperplasia, and
    post menopausal bleeding
  • Hyper-pigmentation-increased migraine
    headache-hypertension
  • Estrogens can cause edema--Na and H20 Retention
  • Estrogens are contraindicated in Carcinoma of the
    breast
  • Estrogens cause a decreased bile flow, therefore
    can cause cholestasis
  • NOTE-use smallest effective dose

134
Anti-estrogens
  • Clomaphene
  • Interfere with the negative feedback of estrogens
    on the hypothalamus, and pituitary therefore
    causes an INCREASE GnRH and Gonadatropins
  • Tamoxifen
  • Currently used in advanced breast cancer in
    post-menopausal women
  • Bost are Considered competitive antagonists or
    weak agonists of natural estrogens

135
Menstrual Cycle
136
Progestins
  • Progesterone is the most important natural
    progestin.
  • It is produced in females (secreted by the corpus
    luteum, 2nd ½ of the menstrual cycle, and by the
    placenta
  • It is secreted by the testis in men in response
    to LH
  • It is also synthesized in the adrenal cortex in
    bothe sexes
  • Progesterone helps in the development of a
    secretory endometrium that can accommodate the
    implantation of newly formed embryo
  • If conception does not happen, progesterone
    secretion from corpus luteum ceases immediately

137
Mechanism of Action---Progesterone
  • Progesterone-like estrogens-act on target tissue
    by first interacting with specific-receptor
    proteins in the cytoplasm
  • It is transported inot the nucleus where it
    interacts with chromatin, stimulating synthesis
    of specific RNAs

138
Therapeutic uses of Progestins
  • Major clinical applications of progestins are in
    contraception, where they are generally used with
    estrogens.
  • Naturally occurring progesterone is not widely
    used because rapid metabolism, hence low
    bioavailabilty.
  • Synthetic progestins are not rapidly inactivated
    by first pass metabolism, hence good oral
    bioavailabilty
  • Medroxyprogesterone, norethindrone, norgestral,
    hydroxyprogesterone acetate
  • Dysfunctional uterine bleeding
  • Treating dysmenorrhea
  • Suppression of post-partum lactation
  • Management of endometrial carcinoma

139
Pharmacology of Progesterone
  • Rapidly absorbed
  • Short half-life in plasma, since it is almost
    completely metabolized in one passage through the
    liver
  • The glucuronidated metabolite (pregnanidiol
    gluconeride) is secreted by kidney
  • Synthetics are not metabolized as fast.

140
Adverse Effects of Progesterones
  • Weight Gain
  • Edema
  • Depression
  • Thrombophlebitis
  • Pulmonary Emboli

141
ANTIPROGESTIN----RU486
  • MIFEPRISTONE
  • Binds to cyto-plasmic receptor and thereby acts
    as a progestin antagonist
  • Given early in pregnancy, 85 results in abortion
    of fetus.
  • SE-significant uterine bleeding
  • Can be used as a contraceptive, given once a
    month during mid-luteal phase of cycle when
    progesterone levels are high

142
Oral Conceptives
143
Combination Pills
  • Products containing Estrogens and progestin
  • Estrogen component suppresses ovulation
  • Progestin prevents implantation and cervical
    mucous plug
  • Given in 21 on 7 off mode

144
Progestin Pills
  • The Mini-Pill
  • Less effective than combination pills
  • Only has limited acceptance because of increase
    chance of pregnancy an occurrence of menstrual
    irregularities
  • Usually Norethindrone and Norgetsral

145
Progestin Implants
  • Subdermal Capsules
  • Levonestrel
  • Six Capsules the sizeof a matchhead are place
    subQ in the upper arm
  • The progestin is slowly released from the capsule
    with contraceptive protection for up to 5 years

146
Postcoidal Contraception
  • Diethylstilbestrol is the Morning after Pill
  • Within 72 hours and 2X day for 5 days

147
Mechanism of action
  • Estrogen provides a negative feedbaclon the
    release of LH and FSH by the pituitary gland.
  • The progestin stimulates normal bleeding at the
    end of the menstrual cycle

148
Adverse Effects
  • Major Adverse Effects-breast fullness,
    depression, dizziness,edema, headache, nausea,
    vomiting
  • Cardiovascular- thrombophlebitis,
    embolism,thrombosis, hypertension, especially
    with women over 35 and smoke
  • Carcinogenic-increased incidence of vaginal,
    uterine, and benign liver tumors
  • Metabolic-abnormal glucose tolerance
    effects--similar to pregnancy
  • Serum Lipids---estrogen dominant preparations
    cause positive changes/ Yet a progestin dominant
    may effect LDL/HDL adversely

149
OCP-contraindicated
  • Contraindicated in the presence of
    cerebrovascular disease, thromboembolitic
    disease,estrogen-dependant neoplasm, liver
    disease, a
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