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Pharmacology

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Title: Pharmacology


1
Pharmacology
  • Unit VIII

2
Review of Hemodynamics
  • Circulatory system heart and blood vessels
  • Arteries transport blood to tissues
  • Arterioles regulate local blood flow
  • Capillaries sites of exchange, fluid O2, CO2,
    nutrients etc.
  • Venules collect blood from capillaries

3
  • Veins transport blood back to heart
  • Blood moves within vessels higher pressure to
    lower pressure
  • Resistance to flow depends on vessel diameter,
    length and vicosity of blood

4
Regulation of cardiac output
  • 5L /minute
  • COHR X SV
  • Heart rate
  • Stroke volume
  • Preload
  • Afterload

5
Starlings Law
  • Ventricular contraction is proportional for
    muscle fiber stretch
  • Increased venous return increase cardiac output
    up to a point!

6
Venous return
  • Systemic filling pressure
  • Auxiliary muscle pump
  • Resistance to flow between peripheral vessels and
    right atrium
  • Right atrial pressure - elevation

7
Regulation of Arterial Pressure
  • Arterial pressureperipheral resistancecardiac
    output
  • Arterial pressure 1.The autonomic nervous
    system (fast) 2. The renin-angiotensin system
    (hours or days) 3. The kidneys (days or weeks)

8
Drugs acting on the Renin-Angiotensin System
  • Angiotensin-converting enzyme (ACE) inhibitors
  • Angiotensin II receptor blockers (ARBs)
  • Primary indications hypertension, heart
    failure, myocardial infarction, diabetic
    nephropathy

9
Renin-angiotensin system how does it work?
  • Angiotensin I, II, III
  • Most potent angiotensin II
  • Produces profound vasoconstriction and stimulates
    release of aldosterone and may also cause
    pathologic structural changes in the heart and
    blood vessels (especially bad after an MI)

10
Captopril
  • First ACE inhibitor
  • Given po
  • Inhibits ACE
  • Reduction in blood volume, vasodilation, prevent
    remodeling
  • Take on empty stomach

11
Adverse effects
  • Cough, first-dose hypotension, hyperkalemia,
    renal failure, fetal injury, angioedema, rash,
    neutropenia, impaired taste

12
Enalapril - Enalaprilat
  • Enalaprilat active form (converted by liver)
    trade Vasotec
  • Can be given IV for severe hypertension
  • Lisinopril - newer

13
Angiotensin II Receptor blockers
  • Block actions of angiotensin II
  • Losartan (Cozaar) does not cause angioedema or
    cough
  • Approved for hypertension only
  • Doesnt appear to cause hyperkalemia
  • Contraindicated in pregnancy

14
Calcium Channel Blockers
  • Prevent calcium from entering cells
  • Used for hypertension, angina, cardiac
    dysrhythmias
  • Calcium channels in vascular smooth muscle when
    blocked prevents contraction and therefore,
    vasodilation

15
Calcium in the heart
  • Positive inotropic effect
  • Slows heart rate if blocked
  • If blocked slows conduction thru AV node
  • Calcium channels are coupled with beta1
    adrenergic receptors have identical effects

16
Verapamil
  • Blocks calcium channels in the blood vessels and
    heart
  • Given for angina, hypertension and dysrhythmias
  • Vasodilation most noticeable effect
  • Given orally or IV

17
  • Adverse effects constipation, dizziness, h/a,
    bradycardia, hypotension, edema of ankles and feet

18
Diltiazem
  • Vasodilation lowers blood pressure
  • Given for hypertension, angina, dysrhythmias

19
Nifedipine
  • Dihydropyridines act mainly on vascular smooth
    muscle
  • Blocks calcium channels in vascular smooth muscle
    vasodilation
  • Given for angina, hypertension
  • Adverse effects dizziness, h/a, reflex
    tachycardia

20
Other Dihydropyridines
  • Nicardipine Cardene
  • Amlodipine Norvasc
  • Felodipind Plendil
  • Nimodipine Nimotop selective blockade of
    calcium channels in cerebral blood vessels

21
Vasodilators
  • Indications hypertension, angina, heart failure
  • Some only arterioles, some only veins
  • Some have effects on both

22
Adverse effects related to vasodilation
  • Postural hypotension
  • Reflex tachycardia
  • Expansion of blood volume

23
Hydralazine
  • Apresoline dilation of arterioles
  • Treats hypertension
  • Less postural hypotension

24
Others
  • Minoxidil severe hypertension
  • Diazoxide hyperstat
  • Nitroprusside hypertensive emergencies causes
    venous and arteriolar dilation given IV

25
Drugs for hypertension
  • Should include lifestyle modification and drug
    therapy
  • Primary (essential)
  • Secondary
  • Treatment is usually life-long and non-compliance
    is a problem

26
Consequences of hypertension
  • Heart disease, kidney disease, blindness, stroke
  • Virtually no symptoms
  • Goal of treatment systolic lt 140 and diastolic
    lt 90

27
Management - lifestyle
  • Weight loss
  • Sodium restriction
  • Alcohol restriction
  • Exercise
  • Smoking cessation
  • Maintenance of potassium and calcium intake

28
Pharmacologic Therapy
  • Sites of action and effects produced
  • 1. Brainstem
  • 2. Sympathetic Ganglia used for emergencies
  • 3. Terminal of adrenergic nerves
  • 4. Beta 1 receptors on the heart
  • 5. Alpha 1 adrenergic receptors on blood vessels

29
  • 6. Vascular smooth muscle
  • 7. Renal tubules
  • 8. Beta 1 receptors on juxtaglomerular cells
  • 9. Angiotensin-converting enzyme
  • 10. Angiotensin II receptors

30
Initial Drug Selection
  • With no other conditions may be diuretics and
    beta blockers
  • Comorbid conditions
  • Benefits of multi-drug therapy
  • Dosing
  • Step-down therapy

31
Co-morbid conditions
  • Renal disease ACE inhibitors, diuretics
  • Diabetes ACE inhibitors, alpha blockers,
    low-dose diuretics

32
Populations at risk
  • African americans
  • Children and adolescents
  • Elderly

33
Promoting compliance
  • Little to no symptoms
  • No effects from medications unless side effects
  • Expensive

34
Promoting compliance
  • Educate patient
  • Teach self-monitoring
  • Work to minimize side effects
  • Make the patient a partner
  • Simple as possible!
  • Make appts easy

35
Drugs for Angina
  • Goals prevent MI and death
  • Prevention of pain and myocardial ischemia

36
3 types of angina
  • Chronic stable angina
  • Variant angina (Prinzmetals)
  • Unstable angina

37
Nitroglycerin
  • Organic nitrate
  • Acts on vascular smooth muscle to promote
    vasodilation
  • Primarily works on veins
  • Modest dilation arterioles
  • Decreases oxygen demand by decreasing venous
    return stable angina

38
Routes of administration
  • Oral, sublingual, IV, buccal, transdermal
  • Crosses membranes easily
  • Adverse effects headache, tachycardia,
    hypotension
  • Do not combine with other drugs causing
    vasodilation (Viagra) or hypotensive drugs

39
  • Tolerance can occur give lowest dose possible
  • Drug free period every day
  • Long acting preparations vs preparations for
    acute attack

40
Indications for Nitroglycerin
  • Acute angina
  • Prophylaxis against angina
  • IV therapy blood pressure, MI, unstable angina

41
Drugs for Heart Failure
  • ACE inhibitors
  • Diuretics
  • Beta blockers
  • Digoxin
  • Spironolactone

42
Heart failure
  • Major causes hypertension, myocardial
    infarction
  • Inadequate tissue perfusion from a failing pump,
    volume overload

43
The vicious cycle
  • Cardiac dilation
  • Increased sympathetic tone
  • Water retention and increased blood volume

44
Classification of severity
  • I no limitation of physical activity
  • II slight limitation
  • III marked limitation
  • IV symptoms occur at rest

45
Non drug therapy
  • Sodium limitation
  • Avoid large amounts fluid
  • Lose weight if indicated
  • Avoid alcohol
  • Mild activity

46
Drug therapy
  • ACE inhibitors
  • Adequate dosing is important often too low
  • Maybe angiotensin II receptor blockers
  • Hydralazine and isosorbide combo if cannot
    tolerate ACE

47
Additional drug therapy
  • Diuretics
  • Beta blockers Coreg
  • Spironolactone aldosterone receptor blocker
    works with ACE inhibitors
  • Inotropic agents

48
Digoxin
  • Cardiac glycoside improves cardiac performance
    positive inotrope
  • Narrow therapeutic range
  • Competes with potassium for binding when
    potassium is low, Digoxin is high

49
Effects of Digoxin
  • Increases cardiac output
  • Decreased sympathetic tone
  • Increased urine output
  • Decreased renin release
  • Does not prolong life
  • Also effects electrical activity decreased
    conduction thru AV node, decreases automaticity
    of SA node

50
Adverse effects
  • DYSRHYTHMIAS
  • TOXICITY very narrow therapeutic index
    hypokalemia makes it easier for toxicity to occur
  • GI disturbances
  • Fatigue
  • Visual disturbances

51
Therapeutic blood levels
  • Important to know - .5-2.0ng/ml
  • But patient may be toxic even if within the
    normal range
  • Measures to treat toxicity pacemaker,
    antidysrhythmics, digibind

52
Antidysrhythmic drugs
  • Tachydysrhythmias vs bradydysrhythmias
  • Alteration in electrical impulses in heart
  • Conduction system of the heart

53
  • Supraventricular vs ventricular tachydysrhythmias

54
Certain medications
  • Amiodarone Class III potassium channel blockers
    delays repolarization prolongs refractory
    period
  • Reduced automaticity SA node, reduced conduction
    thru AV node

55
  • Long half-life
  • Bad side effects pulmonary toxicity
  • Bluish discoloration of skin
  • GI side effects
  • Liver dysfunction
  • Thyroid dysfunction

56
Adenosine
  • Stops supraventricular tachycardia
  • Extremely short half-life

57
Nonpharmacologic treatment
  • AICD
  • Catheter Ablation

58
Drugs that lower LDL cholesterol levels
  • Why do we have cholesterol?
  • Where does it come from?
  • Diet
  • Liver enzyme helps to make it (HMG CoA) Drugs
    inhibit this enzyme
  • Saturated fats cause greater increases in
    cholesterol than increases in dietary cholesterol

59
Lipoproteins
  • Help to carry lipids (triglycerides and
    cholesterol in blood)

60
VLDLs
  • Contain mostly triglycerides in blood
  • Carries from liver to adipose tissue
  • May have link with atherosclerosis?

61
Low-density lipoproteins
  • Contain cholesterol as primary core lipid
  • Delivers cholesterol to tissues (nonhepatic)
  • Greatest contribution to coronary atherosclerosis

62
High-density lipoproteins
  • HDLs carry cholesterol from tissues back to the
    liver help remove cholesterol from peripheral
    tissue
  • Elevation of HDLs decreased risk of CAD

63
  • LDLs help promote formation of fatty streak
    surface of arterial wall lumpy
  • Injury inflammatory process

64
Management of high LDL cholesterol
  • Diet modification
  • Reduce risk factors smoking, exercise (lack
    of), hypertension, diabetes mellitus, obesity

65
Drug therapy
  • Statins HMG CoA inhibitors most widely used
    also increase number of LDL receptors on liver
    cells
  • Lovastatin, Fluvastatin, Pravastatin,
    Simvastatin, Atorvastatin, Cerivastatin

66
Effects
  • Lower LDL cholesterol
  • Give in the evening
  • Elevation of HDL cholesterol
  • Additional beneficial effects

67
Clinical trials
  • Support primary and secondary prevention

68
Adverse effects
  • Hepatotoxicity, GI disturbances, myopathy

69
Bile Acid-Binding resins
  • Questran, Prevalite
  • Increase LDL receptors on hepatocytes
  • May be combined with statin

70
Nicotinic acid
  • Reduces LDL
  • Raises HDL
  • Side effects nicotinic flushing, GI
  • Hepatotoxic

71
Lopid
  • fibrates lower VLDL, raise HDL
  • Decreases synthesis of triglycerides
  • hepatotoxic

72
Review coagulation
  • Vessel injury
  • Formation of platelet plug platelets adhere to
    site of injury, activation and aggregation (end
    result is fibrinogen bridges between glycoprotein
    IIb/IIIA receptors
  • Coagulation production of fibrin to reinforce
    platelet plug

73
  • Intrinsic and extrinsic
  • Factors VII, IX, X, and prothrombin require
    vitamin K for synthesis
  • Antithrombin III inhibits clotting factors
    activity (some) so there is not widespread
    clotting

74
Removal of clots
  • Plasminogen to plasmin enzyme that digests the
    fibrin meshwork of the clot

75
Thrombosis
  • Arterial damage to wall or rupture of plaque
    platelet aggregation
  • Venous thrombosis stagnation of blood initiates
    coagulation cascade thrombus breaks off -
    embolus

76
Parenteral anticoagulants
  • Heparin administered by injection
  • Helps inactivate thrombin, factor Xa and others
  • Prophylaxis of venous thrombosis
  • Half-life is short given as bolus initially
    (acute)

77
Therapeutic uses
  • Pregnancy if needed
  • PE
  • CVA
  • DVT acute and prevention
  • Open heart surgery
  • DIC
  • Acute MI

78
Adverse reactions
  • Bleeding
  • Thrombocytopenia heparin induced
  • Hypersensitivity
  • Protamine sulfate for OD
  • Monitoring of APTT
  • Given in units

79
Low Molecular Weight Heparin
  • Can be given on fix-dosed schedule and do not
    require APTT monitoring
  • Less likely to cause thrombocytopenia
  • Can be taken at home
  • Inactivate factor Xa and cannot bind with
    thrombin to inactivate it

80
  • Primary use is prevention of DVT after surgery
    and trauma and spinal injury
  • Increased bioavailability related to Heparin
  • Given SC dosage based on body weight

81
Adverse effects
  • Bleeding
  • Thrombocytopenia
  • Neurological injury with spinal anesthesia
    spinal, epidural bleed

82
  • Enoxaparin - Lovenox
  • Dalteparin
  • Ardeparin

83
Oral anticoagulants
  • Warfarin Coumadin
  • Rat poison
  • Antagonist of vitamin K blocks synthesis of
    vitamin K dependent factors in coagulation
    cascade
  • Peak effects take several days

84
Therapeutic uses
  • Long-term prophylaxis of thrombosis
  • Prosthetic heart valves
  • Atrial fibrillation
  • Must monitor PT (prothrombin time) INR
    (contains a correction factor for PT)
  • PT/INR needs to be monitored frequently

85
Adverse reactions
  • Warfarin has many drug interactions
  • Hemorrhage
  • Vitamin K can be given in case of overdose

86
Differences between heparin and coumadin
  • Tell me what they are

87
Antiplatelet drugs
  • Prevention of thrombosis in arteries
  • ASA suppresses platelet aggregation
  • Indications prophylaxis of MI, prevent
    reinfarction in patients with acute MI, prevent
    stroke in patients with TIA

88
Aspirin
  • Low dose - no greater than 325mg/day
  • Adverse effects

89
Adenosine diphosphate receptor antagonists
  • Block ADP receptors preventing ADP-stimulated
    aggregation
  • Ticlopidin prevent stroke
  • Clopidogrel prevent stroke and MI

90
Glycoprotein IIb/IIIa receptor antagonist
  • Reversible blockade of IIb/IIIa receptors
    inhibits final step in aggregation
  • Used in acute coronary syndrome and Percutaneous
    coronary intervention

91
thrombolytics
  • Remove the clot once it is there
  • clot busters
  • Streptokinase
  • tPA

92
  • END
  • Return to Course Site
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