Title: Pharmacology
1Pharmacology
2Review 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
4Regulation of cardiac output
- 5L /minute
- COHR X SV
- Heart rate
- Stroke volume
- Preload
- Afterload
5Starlings Law
- Ventricular contraction is proportional for
muscle fiber stretch - Increased venous return increase cardiac output
up to a point!
6Venous return
- Systemic filling pressure
- Auxiliary muscle pump
- Resistance to flow between peripheral vessels and
right atrium - Right atrial pressure - elevation
7Regulation 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)
8Drugs 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
9Renin-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)
10Captopril
- First ACE inhibitor
- Given po
- Inhibits ACE
- Reduction in blood volume, vasodilation, prevent
remodeling - Take on empty stomach
11Adverse effects
- Cough, first-dose hypotension, hyperkalemia,
renal failure, fetal injury, angioedema, rash,
neutropenia, impaired taste
12Enalapril - Enalaprilat
- Enalaprilat active form (converted by liver)
trade Vasotec - Can be given IV for severe hypertension
- Lisinopril - newer
13Angiotensin 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
14Calcium 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
15Calcium 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
16Verapamil
- 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
18Diltiazem
- Vasodilation lowers blood pressure
- Given for hypertension, angina, dysrhythmias
19Nifedipine
- 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
20Other Dihydropyridines
- Nicardipine Cardene
- Amlodipine Norvasc
- Felodipind Plendil
- Nimodipine Nimotop selective blockade of
calcium channels in cerebral blood vessels
21Vasodilators
- Indications hypertension, angina, heart failure
- Some only arterioles, some only veins
- Some have effects on both
22Adverse effects related to vasodilation
- Postural hypotension
- Reflex tachycardia
- Expansion of blood volume
23Hydralazine
- Apresoline dilation of arterioles
- Treats hypertension
- Less postural hypotension
24Others
- Minoxidil severe hypertension
- Diazoxide hyperstat
- Nitroprusside hypertensive emergencies causes
venous and arteriolar dilation given IV
25Drugs for hypertension
- Should include lifestyle modification and drug
therapy - Primary (essential)
- Secondary
- Treatment is usually life-long and non-compliance
is a problem
26Consequences of hypertension
- Heart disease, kidney disease, blindness, stroke
- Virtually no symptoms
- Goal of treatment systolic lt 140 and diastolic
lt 90
27Management - lifestyle
- Weight loss
- Sodium restriction
- Alcohol restriction
- Exercise
- Smoking cessation
- Maintenance of potassium and calcium intake
28Pharmacologic 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
30Initial Drug Selection
- With no other conditions may be diuretics and
beta blockers - Comorbid conditions
- Benefits of multi-drug therapy
- Dosing
- Step-down therapy
31Co-morbid conditions
- Renal disease ACE inhibitors, diuretics
- Diabetes ACE inhibitors, alpha blockers,
low-dose diuretics
32Populations at risk
- African americans
- Children and adolescents
- Elderly
33Promoting compliance
- Little to no symptoms
- No effects from medications unless side effects
- Expensive
34Promoting compliance
- Educate patient
- Teach self-monitoring
- Work to minimize side effects
- Make the patient a partner
- Simple as possible!
- Make appts easy
35Drugs for Angina
- Goals prevent MI and death
- Prevention of pain and myocardial ischemia
363 types of angina
- Chronic stable angina
- Variant angina (Prinzmetals)
- Unstable angina
37Nitroglycerin
- 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
38Routes 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
40Indications for Nitroglycerin
- Acute angina
- Prophylaxis against angina
- IV therapy blood pressure, MI, unstable angina
41Drugs for Heart Failure
- ACE inhibitors
- Diuretics
- Beta blockers
- Digoxin
- Spironolactone
42Heart failure
- Major causes hypertension, myocardial
infarction - Inadequate tissue perfusion from a failing pump,
volume overload
43The vicious cycle
- Cardiac dilation
- Increased sympathetic tone
- Water retention and increased blood volume
44Classification of severity
- I no limitation of physical activity
- II slight limitation
- III marked limitation
- IV symptoms occur at rest
45Non drug therapy
- Sodium limitation
- Avoid large amounts fluid
- Lose weight if indicated
- Avoid alcohol
- Mild activity
46Drug therapy
- ACE inhibitors
- Adequate dosing is important often too low
- Maybe angiotensin II receptor blockers
- Hydralazine and isosorbide combo if cannot
tolerate ACE
47Additional drug therapy
- Diuretics
- Beta blockers Coreg
- Spironolactone aldosterone receptor blocker
works with ACE inhibitors - Inotropic agents
48Digoxin
- Cardiac glycoside improves cardiac performance
positive inotrope - Narrow therapeutic range
- Competes with potassium for binding when
potassium is low, Digoxin is high
49Effects 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
50Adverse effects
- DYSRHYTHMIAS
- TOXICITY very narrow therapeutic index
hypokalemia makes it easier for toxicity to occur - GI disturbances
- Fatigue
- Visual disturbances
51Therapeutic 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
52Antidysrhythmic drugs
- Tachydysrhythmias vs bradydysrhythmias
- Alteration in electrical impulses in heart
- Conduction system of the heart
53- Supraventricular vs ventricular tachydysrhythmias
54Certain 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
56Adenosine
- Stops supraventricular tachycardia
- Extremely short half-life
57Nonpharmacologic treatment
58Drugs 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
59Lipoproteins
- Help to carry lipids (triglycerides and
cholesterol in blood)
60VLDLs
- Contain mostly triglycerides in blood
- Carries from liver to adipose tissue
- May have link with atherosclerosis?
61Low-density lipoproteins
- Contain cholesterol as primary core lipid
- Delivers cholesterol to tissues (nonhepatic)
- Greatest contribution to coronary atherosclerosis
62High-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
64Management of high LDL cholesterol
- Diet modification
- Reduce risk factors smoking, exercise (lack
of), hypertension, diabetes mellitus, obesity
65Drug therapy
- Statins HMG CoA inhibitors most widely used
also increase number of LDL receptors on liver
cells - Lovastatin, Fluvastatin, Pravastatin,
Simvastatin, Atorvastatin, Cerivastatin
66Effects
- Lower LDL cholesterol
- Give in the evening
- Elevation of HDL cholesterol
- Additional beneficial effects
67Clinical trials
- Support primary and secondary prevention
68Adverse effects
- Hepatotoxicity, GI disturbances, myopathy
69Bile Acid-Binding resins
- Questran, Prevalite
- Increase LDL receptors on hepatocytes
- May be combined with statin
70Nicotinic acid
- Reduces LDL
- Raises HDL
- Side effects nicotinic flushing, GI
- Hepatotoxic
71Lopid
- fibrates lower VLDL, raise HDL
- Decreases synthesis of triglycerides
- hepatotoxic
72Review 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
74Removal of clots
- Plasminogen to plasmin enzyme that digests the
fibrin meshwork of the clot
75Thrombosis
- Arterial damage to wall or rupture of plaque
platelet aggregation - Venous thrombosis stagnation of blood initiates
coagulation cascade thrombus breaks off -
embolus
76Parenteral 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)
77Therapeutic uses
- Pregnancy if needed
- PE
- CVA
- DVT acute and prevention
- Open heart surgery
- DIC
- Acute MI
78Adverse reactions
- Bleeding
- Thrombocytopenia heparin induced
- Hypersensitivity
- Protamine sulfate for OD
- Monitoring of APTT
- Given in units
79Low 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
81Adverse effects
- Bleeding
- Thrombocytopenia
- Neurological injury with spinal anesthesia
spinal, epidural bleed
82- Enoxaparin - Lovenox
- Dalteparin
- Ardeparin
83Oral anticoagulants
- Warfarin Coumadin
- Rat poison
- Antagonist of vitamin K blocks synthesis of
vitamin K dependent factors in coagulation
cascade - Peak effects take several days
84Therapeutic 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
85Adverse reactions
- Warfarin has many drug interactions
- Hemorrhage
- Vitamin K can be given in case of overdose
86Differences between heparin and coumadin
87Antiplatelet 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
88Aspirin
- Low dose - no greater than 325mg/day
- Adverse effects
89Adenosine diphosphate receptor antagonists
- Block ADP receptors preventing ADP-stimulated
aggregation - Ticlopidin prevent stroke
- Clopidogrel prevent stroke and MI
90Glycoprotein IIb/IIIa receptor antagonist
- Reversible blockade of IIb/IIIa receptors
inhibits final step in aggregation - Used in acute coronary syndrome and Percutaneous
coronary intervention
91thrombolytics
- Remove the clot once it is there
- clot busters
- Streptokinase
- tPA
92- END
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