Wednesday, August 30, 2000Scribe: Eric Chan

Pharmacology: Dr. McMahon (8-9) Joe Roman

Adrenergic Pharmacology III

Scribe note: Dr. McMahon followed her slides pretty close so it will be very useful to download her powerpoints on the web. Anything that is on the powerpoint, we will not repeat but we will include anything she added on the slides.

Correction: on her notes Roman Numeral III which states Receptor Selectivity should actually state Indirect Sympathomimetic

Catecholamines are quickly metabolized and can’t enter the GI tract

-Always given through injection or topical application if applied to eye

-Short-acting

Advantage: if things go wrong, you can stop the reaction quickly and correct it
Disadvantage: have to use it in IV, not by pill

-Response changes with time because of the metabolism (applies more to epinephrine)

Contraindications

-Means that the drug should be used with great caution or should not be used if it is absolute contraindication

-Dr. McMahon is not distinguishing between relative and absolute contraindications for the tests

Ex. if you give Albuterol to a person who has asthma who also has coronary artery disease, there is a possibility of a 1 stimulation that is could be fatal

Agents

-Exogenous to sympathetic nervous system is not found regularly in the sympathetic nervous system

Dobutamine, dopamine, isoproterenol are not found in the sympathetic nervous system
Dopamine is just restricted to peripheral therapeutic effects, won’t look at what it will do in the brain

-Endogenous to sympathetic nervous system means that they are found in the sympathetic system

Look at the pharmacological effects of norepinephrine and epinephrine

Receptor Selectivity for Catecholamines

-Dobutamine

More increase on inotropic (force of contraction) > chronotropic (rate of contraction) response- don’t know reason why

-Dopamine

Very much dose dependent
D1 receptors is in the splanchnic and renal vasculature and causes vasodilation- during low dose
Intermediate dose pick up 1 at the heart
High dose pick up 1 which causes vasoconstriction
Advantages of dopamine is to keep the renal blood flow moving

-Isoproterenol

selective agonists
Cannot distinguish between 1 and 2

-Norepinephrine

Picks up all the receptors except 2 unless at very high dose

-Epinephrine

Hits all the receptors
All receptors are stimulated equally in the laboratory setting
In a clinical setting due to receptor location, low dose will see vasodilation due to 2 and if you give a high dose that vasodilation becomes vasoconstriction
2 receptor is out where the blood circulating levels of epinephrine will hit it
1 is located in the junction which takes longer for the epinephrine to get there

Question from class

-Are there 1 receptors in the skeletal muscle vasculature?

Yes, but depends on the muscle bed
Observation is that high dose of epinephrine will override the vasodilation with strong vasoconstriction
Not just a matter of redistribution of blood flow as you would see in low epinephrine doses

Dobutamine

-Affects mostly heart

-Minimal affects on the vasculature except as cardiac output has an impact on the vasculature

-Will have an affect on blood pressure because the increase in cardiac output

-See an increase in systolic pressure compared to diastolic pressure

-Usually used in short periods of time or intermittently

Because if used constantly can get desensitization

-No affect on total affect on total peripheral resistance or venous return

-Major affect is increase in heart rate, increase in force of contraction

Will still have problems with dromotrophic (conduction responses of heart) with a potential for arrhythmias

-Main affect is on systolic blood pressure

Dopamine

-Low dose, will get vasodilation of the splenic and renal areas

-Main use is to keep renal blood flow going

-Increase dose, get 1 response, will get increase in systolic blood pressure, stimulate the heart to increase force and rate

-At very high levels, see 1 response, we see an increase in diastolic and systolic blood pressure; probably have a narrowing of pulse pressure, and mean pressure will increase

Affects similar to norepinephrine at high dose of dopamine

-Why can give dopamine to a person who’s in cardiogenic shock and it won’t have any affects toward the brain?

Can’t cross blood brain barrier because of polarity of dopamine

Isoproternenol

-1 and 2are about equally potent

-Should see vasodilation because of skeletal muscle vasculature

If get a big decrease in blood pressure, will see a reflex response in the heart (tachycardia)
This will be additive to the direct affect to the 1, you will predict tachycardia because both direct and reflex response

-Blood pressure will get a widening of pulse pressure because systolic is stimulated from increase in force of cardiac output

There will also be a decrease systolic because of the vasodilation

-Mean pressure will go up a little bit but not necessarily very strong

-Main thing is increase in pulse pressure

-2 in lungs can be stimulated causing bronchiodilation

Can still be used for asthma and brochiospasms
Want to however use more of a selective 2

-Affects in GI and bladder dealing with longitudinal muscles

-Can also be used to potentially to block pre-term labor

Is not used that much because of 1 affects

Norepinephrine

-Vasoconstriction in the vasculature

-See significant affects in the liver and kidney

-Stimulate heart rate with 1

If increase heart rate too much, will have a reflex that causes decrease in sympathetics and increase in parasympathetics
Is not an additive response because the reflex can cancel out the 1 stimulation

-Narrowing of pulse pressure and increase in mean pressure

-Not used a lot clinically

-Problem if use in IV, NE can get out on tissue around injection site and cause atrophy due ischemia

Epinephrine

-Hit all receptors

-Affects on extremely time dependent because epinephrine is metabolized quickly

-High dose more affect on 1 on the vasculature

If single high dose, see short increase vasoconstriction and more prolonged vasodilation
Get narrowing pulse pressure early, and very quickly will see widening of pulse pressure
If doing IV at high dose, the diastolic pressure will stay high

-Low dose, see much more affect of 2causing vasodilation

-Affect on heart is variable depending on the amount of vasoconstriction and vasodilation, is there a net decrease in TPR or net increase

-The reflex of heart depends absolutely on the dose (if you increased or decreased the mean blood pressure)

-Can affect 2 receptor of the lung to cause bronchiodilation

Used in emergency situation

-Affects on eye

Can be used topically to decrease optical pressure in the treatment of glaucoma
Utilizing smooth muscle to cause an increase in outflow of aqueous humor and decreasing humor production thus decreasing eye pressure

-Metabolic affects

Increase blood glucose levels and fatty acid levels

-Redistribution of blood flow is dose dependent

At high dose, don’t see redistribution
At lower dose, see it because of 2 response

Epinephrine Clinical Use

-Not used in treatment of asthma much anymore because of not as selective as 2 agents

-Used to general surgery to restrict blood flow to a particular organ

-If used with local anesthetic, will hold the anesthetic at the site of injection because of vasoconstriction (does not get into systemic circulation much

-Can be used to get heart started

-Used to treat glaucoma, applied topically

-Adverse affects

1 affects conductivity of heart and can cause spontaneous firing of the heart muscles
Any stimulation by any agents of 1 can cause arrhythmias
Increase force of contraction and increase force of the heart, you increase the oxygen demand of the heart
Any ischemic affect, like coronary artery disease, of heart will be intensified
If have weak area of vasculature in cerebrum, intense acute vasoconstriction can cause rupture
Vasoconstriction can cause headaches
Symptoms of anxiety not because of epinephrine getting into brain, but because of affects on cerebral vasculature

Question from student, why epinephrine doesn’t cause stimulation of 2 receptors in eye so that the stimulation of 2 will cancel out

-Stimulate 2 cause increase of humor production of the eye

-2 causes decrease in humor production of eye

-Explanation is that 2 gets desensitized

Norepinephrine Clinical Use

-Can be used in a hypotensive type of situation like cardiogenic shock

-Has lots of adverse affects

-Not used a lot

Isoproterenol Clinical Use

-Not used a lot

-Prototype for  agonists

-Can be used in selective stimulation for heart blocks depending on level of heart block

Dobutamine Clinical Use

-Used in only acute heart failure not in chronic treatment of heart failure

-Biggest problem is arrhythmias

-Cardiogenic shock

Low blood pressure and poor perfusion throughout the body that is initiated by the heart (ex. cardiogenic shock due to MI)

Dopamine Clinical Use

-Used in more general cases of shock including cardiogenic shock

-Big advantage is that it keeps renal blood flowing

Contraindications

-Hypertension especially if have 1 component or if you have a strong increase in cardiac output (more in NE)

-Co-administration of anything that increase norepinephrine levels (cocaine)

-Atrial fibrillation is not lethal situation by itself but the possibility of it becoming a ventricular fibrillation is real if you give a 1 agonists