Pharmacology Part 2 for Medical Students and Nurse

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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

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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

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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.

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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

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Antiarrythmic Drugs
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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

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Myocardial Action Potential
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Action Potential
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CLASS (1A) antiarrhythmic

• Quinidine
• Procainamide
• Disopyramide

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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

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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

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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

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Class 1B

• Lidocaine
• Mexiletene
• Tocainide
• Phenytoin

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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

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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

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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

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Class 1C

• Flecainide
• Encainide
• Propoferone

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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

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Encainide and Propoferone

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

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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)

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Class III Antiarrhythmics

• Bretylium
• Amiodarone

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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

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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

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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

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Class IV Antiarrhythmic Drugs

• Verapamil
• Diltiazem

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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

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ANTI-ANGINAL DRUGS
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Organic Nitrates

• Nitroglycerin
• Isosorbide Dinitrate
• Amyl Nitrate

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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

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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.

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Antihypertensive Drugs
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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

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Spirolactone

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

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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

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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

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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

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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

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Diazoxide

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

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Drugs Affecting Blood
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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.

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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

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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

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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.

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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.

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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.

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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

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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.

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Drugs to treat Anemia

• Iron
• Folic Acid
• Cyanobalmin (B-12)
• Erythropoietan

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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.

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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.

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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.

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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.

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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.

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Antihyprelipidemic Drugs
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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

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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

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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

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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