Pharmacology

Unit VIII
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
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
Regulation of cardiac output

5L /minute
CO=HR X SV
Heart rate
Stroke volume
Preload
Afterload
Starling’s Law

Ventricular contraction is
proportional for muscle fiber stretch
Increased venous return – increase
cardiac output – up to a point!
Venous return

Systemic filling pressure

Auxiliary muscle pump
Resistance to flow between
peripheral vessels and right atrium
Right atrial pressure - elevation
Regulation of Arterial Pressure

Arterial pressure=peripheral
resistance+cardiac output
Arterial pressure – 1.The autonomic
nervous system (fast) 2. The renin-
angiotensin system (hours or days) 3.
The kidneys (days or weeks)
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
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)
Captopril

First ACE inhibitor

Given po
Inhibits ACE
Reduction in blood volume,
vasodilation, prevent remodeling
Take on empty stomach
Adverse effects

Cough, first-dose hypotension,

hyperkalemia, renal failure, fetal
injury, angioedema, rash, neutropenia,
impaired taste
Enalapril - Enalaprilat

Enalaprilat – active form (converted

by liver) trade – Vasotec
Can be given IV for severe
hypertension
Lisinopril - newer
Angiotensin II Receptor
blockers
Block actions of angiotensin II
Losartan (Cozaar) – does not cause
angioedema or cough
Approved for hypertension only
Doesn’t appear to cause hyperkalemia
Contraindicated in pregnancy
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
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
Verapamil

Blocks calcium channels in the blood

vessels and heart
Given for angina, hypertension and
dysrhythmias
Vasodilation most noticeable effect
Given orally or IV
Adverse effects – constipation,
dizziness, h/a, bradycardia,
hypotension, edema of ankles and
feet
Diltiazem

Vasodilation – lowers blood pressure

Given for hypertension, angina,
dysrhythmias
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
Other Dihydropyridines

Nicardipine – Cardene
Amlodipine – Norvasc
Felodipind – Plendil
Nimodipine – Nimotop – selective
blockade of calcium channels in
cerebral blood vessels
Vasodilators

Indications – hypertension, angina,

heart failure
Some only arterioles, some only veins
Some have effects on both
Adverse effects related to
vasodilation
Postural hypotension
Reflex tachycardia
Expansion of blood volume
Hydralazine

Apresoline – dilation of arterioles

Treats hypertension
Less postural hypotension
Others

Minoxidil – severe hypertension

Diazoxide – hyperstat
Nitroprusside – hypertensive
emergencies – causes venous and
arteriolar dilation – given IV
Drugs for hypertension

Should include lifestyle modification

and drug therapy
Primary (essential)
Secondary
Treatment is usually life-long and
non-compliance is a problem
Consequences of hypertension

Heart disease, kidney disease,

blindness, stroke
Virtually no symptoms
Goal of treatment – systolic < 140 and
diastolic < 90
Management - lifestyle

Weight loss
Sodium restriction
Alcohol restriction
Exercise
Smoking cessation
Maintenance of potassium and calcium
intake
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
6. Vascular smooth muscle
7. Renal tubules
8. Beta 1 receptors on
juxtaglomerular cells
9. Angiotensin-converting enzyme
10. Angiotensin II receptors
Initial Drug Selection

With no other conditions – may be

diuretics and beta blockers
Comorbid conditions
Benefits of multi-drug therapy
Dosing
Step-down therapy
Co-morbid conditions

Renal disease – ACE inhibitors,

diuretics
Diabetes – ACE inhibitors, alpha
blockers, low-dose diuretics
Populations at risk

African americans
Children and adolescents
Elderly
Promoting compliance

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

Educate patient
Teach self-monitoring
Work to minimize side effects
Make the patient a partner
Simple as possible!
Make appts easy
Drugs for Angina

Goals – prevent MI and death

Prevention of pain and myocardial
ischemia
3 types of angina

Chronic stable angina

Variant angina (Prinzmetal’s)
Unstable angina
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
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
Tolerance can occur – give lowest
dose possible
Drug – free period every day
Long – acting preparations vs
preparations for acute attack
Indications for Nitroglycerin

Acute angina
Prophylaxis against angina
IV therapy – blood pressure, MI,
unstable angina
Drugs for Heart Failure

ACE inhibitors
Diuretics
Beta blockers
Digoxin
Spironolactone
Heart failure

Major causes – hypertension,

myocardial infarction
Inadequate tissue perfusion from a
failing pump, volume overload
The vicious cycle

Cardiac dilation
Increased sympathetic tone
Water retention and increased blood
volume
Classification of severity

I – no limitation of physical activity

II – slight limitation
III – marked limitation
IV – symptoms occur at rest
Non drug therapy

Sodium limitation
Avoid large amounts fluid
Lose weight if indicated
Avoid alcohol
Mild activity
Drug therapy

ACE inhibitors
Adequate dosing is important – often
too low
Maybe angiotensin II receptor
blockers
Hydralazine and isosorbide combo if
cannot tolerate ACE
Additional drug therapy

Diuretics
Beta blockers – Coreg
Spironolactone – aldosterone
receptor blocker – works with ACE
inhibitors
Inotropic agents
Digoxin

Cardiac glycoside – improves cardiac

performance – positive inotrope
Narrow therapeutic range
Competes with potassium for binding
– when potassium is low, Digoxin is
high
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
Adverse effects

DYSRHYTHMIAS
TOXICITY – very narrow therapeutic
index – hypokalemia makes it easier
for toxicity to occur
GI – disturbances
Fatigue
Visual disturbances
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
Antidysrhythmic drugs

Tachydysrhythmias vs
bradydysrhythmias
Alteration in electrical impulses in
heart
Conduction system of the heart
Supraventricular vs ventricular
tachydysrhythmias
Certain medications

Amiodarone – Class III potassium

channel blockers – delays
repolarization – prolongs refractory
period
Reduced automaticity SA node,
reduced conduction thru AV node
Long half-life
Bad side effects – pulmonary toxicity
Bluish discoloration of skin
GI side effects
Liver dysfunction
Thyroid dysfunction
Adenosine

Stops supraventricular tachycardia

Extremely short half-life
Nonpharmacologic treatment

AICD
Catheter Ablation
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
Lipoproteins

Help to carry lipids (triglycerides and

cholesterol in blood)
VLDLs

Contain mostly triglycerides in blood

Carries from liver to adipose tissue
May have link with atherosclerosis?
Low-density lipoproteins

Contain cholesterol as primary core

lipid
Delivers cholesterol to tissues
(nonhepatic)
Greatest contribution to coronary
atherosclerosis
High-density lipoproteins

HDL’s carry cholesterol from tissues

back to the liver – help remove
cholesterol from peripheral tissue
Elevation of HDL’s decreased risk of
CAD
LDLs help promote formation of fatty
streak – surface of arterial wall lumpy
Injury – inflammatory process
Management of high LDL
cholesterol
Diet modification
Reduce risk factors – smoking,
exercise (lack of), hypertension,
diabetes mellitus, obesity
Drug therapy

“Statins” – HMG CoA inhibitors –

most widely used – also increase
number of LDL receptors on liver
cells
Lovastatin, Fluvastatin, Pravastatin,
Simvastatin, Atorvastatin,
Cerivastatin
Effects

Lower LDL cholesterol

Give in the evening
Elevation of HDL cholesterol
Additional beneficial effects
Clinical trials

Support primary and secondary

prevention
Adverse effects

Hepatotoxicity, GI disturbances,
myopathy
Bile Acid-Binding resins

Questran, Prevalite
Increase LDL receptors on
hepatocytes
May be combined with statin
Nicotinic acid

Reduces LDL
Raises HDL
Side effects – nicotinic flushing, GI
Hepatotoxic
Lopid

“fibrates” – lower VLDL, raise HDL

Decreases synthesis of triglycerides
hepatotoxic
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
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
Removal of clots

Plasminogen to plasmin – enzyme that

digests the fibrin meshwork of the
clot
Thrombosis

Arterial – damage to wall or rupture

of plaque – platelet aggregation
Venous thrombosis – stagnation of
blood initiates coagulation cascade –
thrombus breaks off - embolus
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)
Therapeutic uses

Pregnancy – if needed
PE
CVA
DVT – acute and prevention
Open heart surgery
DIC
Acute MI
Adverse reactions

Bleeding
Thrombocytopenia – heparin induced
Hypersensitivity
Protamine sulfate for OD
Monitoring of – APTT
Given in units
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
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
Adverse effects

Bleeding
Thrombocytopenia
Neurological injury with spinal
anesthesia – spinal, epidural bleed
Enoxaparin - Lovenox
Dalteparin
Ardeparin
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
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
Adverse reactions

Warfarin has many drug interactions

Hemorrhage
Vitamin K can be given in case of
overdose
Differences between heparin
and coumadin
Tell me what they are
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
Aspirin

Low dose - no greater than

325mg/day
Adverse effects
Adenosine diphosphate receptor
antagonists
Block ADP receptors preventing ADP-
stimulated aggregation
Ticlopidin – prevent stroke
Clopidogrel – prevent stroke and MI
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
thrombolytics

Remove the clot once it is there

“clot busters”
Streptokinase
tPA
END
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