Autonomic Pharmacology - continued

b. General scheme of autonomic function

i.e.) heart - drug that causes drop in blood pressure - ie. nitroglycerin, histamine

these drugs produce vasodilation

a. decrease in arterial pressure sensed by receptors (baroreceptors) -carotid sinus, aortic arch

b. afferent (sensory) nerves carry message (decrease firing) to brain (medulla)

c. Medulla -maintain homeostasis (cardiovascular center) - increase pressure - stimulates sym. to heart- efferent fibers

d. Spinal cord to ganglion (preganglionic fibers) release Ach - Nic

e. Ach combines with nicotinic receptor

f. AP in post ganglionic fiber

g. Post ganglionic terminal releases NE

h. Combines with

--b1 receptors (increased cAMP)- increased HR, contractility, arterial pressure

-- a1receptors (increased DAG, IP₃, Ca⁺⁺) - blood vessels -vasoconstriction

-drugs can interfere or increase effect at any step

If pressure is too high - must be able to follow it through, in book give NE, which indirectly decreases HR

V. Termination of Transmitter Action

must be terminated or effect would be terminal

1. Acetylcholine- enzyme in receptor region

acetylcholinesterase

ACH è è è acetate + choline

Also enzymes in plasma that hydrolyze Ach "cholinesterases" -ie pseudocholinesterase

ACH when it binds it is split into acetic acid + choline

2) Catecholamines- Norepinephrine, Epinephrine

a. Reuptake into adrenergic nerve terminals

most important-transport back to granules (active transport) (blocked by cocaine)

- if NT is not in granules -- some broken down by MAO monoamineoxidase, -- MAO is in mitochondria

b. Diffuses away

c. Extraneuronal enzymes- outside of neuron -- COMT -catechol-O-methyl-transferase, also some MAO - family of enzymes.

Drugs can interfere with these enzymes

Adrenergic Nervous System

VI. Sympathomimetic (Adrenergic) Agents -- Agonists - drugs which mimic the action of sympathetic nervous system

A. Catecholamines- Epinephrine and Norepinephrine

1. Biosynthesis

start with tyrosine (amino acid)

2. Site of action of drugs affecting above process

3. Pharmacologic effect of EPINEPHRINE

response varies in different organs

constricts blood vessels in the skin -- because primarily a

dilate - muscular arterioles -- both b2 and a

reacts with a1, a2, b1, b2

at low concentration b2 -predominates - dilation

at high conc. a1 predominates - constriction

 

a. Blood pressure

- large dose è increases BP

vasoconstriction a1

increase HR, increase contraction of heart - b1

 

- low dose è decreases BP, or no change

vasodilation b2

increase HR, increase contraction

potent bronchodilator

b. Metabolic effects

1. increase glucose production - energy - b2 - fight or flight (ie. increase glucagon, glycogen to glucose)

2. Inhibition of insulin secretion - a2

3. Increase in oxygen consumption

4. increased renin from juxtaglomerular- b1- renin- angiotensin (vasoconstriction) - aldosterone -Na retention

c. Pharmacologic effect of NOREPINEPHRINE

1. equal to Epin. in b1 action -- ie.) heart

2. slightly less a (ie. constriction)

3. no b2 activity -therefore, no dilation, no bronchodilation

Epinephrine- a1, a2, b1, b2

Norepinephrine- a1, a2, b1

d. Pharmacokinetics of Epinephrine and Norepinephrine

1. Absorption is poor with oral administration because drugs are rapidly conjugated and oxidized in the intestine.

2. Absorption is slow with subcutaneous administration because drugs cause local vasoconstriction.

3. Inhaled solution can be used for their action on respiratory tract (b₂ - epinephrine)

4. Drugs IV-- must be careful so that heart does not fibrillate

5. Liver is important in degradation- COMT, MAO -- metabolites excreted in urine (very short duration of action.)

e. Therapeutic uses

1. Epinephrine

a) Treat bronchospasm b2

b) Primary treatment for anaphylactic shock (allergy- exposure to antigen- bee venom -powerful antibody response Ig E. --- mast cells produce histamine and PG, get leakage of fluid and dilation of blood vessels, also bronchoconstricton ****- can't breath (often injected SC - there is some rapid absorption)

c) Restore cardiac activity in cardiac arrest (in physiology lab--give to animals to restore heart activity

2. Norepinephrine - treating hypotension during anesthesia- not used much (given IV)

f. Untoward effects (troubling)

1. anxiety - stimulus of CNS- later

2. headaches - increase blood flow to brain - b1 (increase heart rate and increase contraction)

3. cerebral hemorrhage- vasopressor effect

4. pulmonary edema- pulmonary hypertension

above are due to alterations in blood flow

g. Prolonged exposure can lead to receptor downregulation -- true for all receptors -- desensitization -- this has been studied for adrenoceptors -- ie. internalization of receptors -- or for b receptors --- bARK - b adrenergic receptor kinase -- phosphorylates/disrupts G protein so no adenylyl cyclase to produce cAMP

B. Other Sympathomimetic Drugs----Isoproterenol b1, b2

1. Pharmacologic effects

a. mostly b effect

b. IV- decreases peripheral resistance- b2 - decreases BP

c. Blood pressure falls slightly- vasodilation, but also increased heart rate, increased contractility b1, thus there is an increased CO

d. Relaxation of bronchial smooth muscle

e. less hyperglycemia (glycogen-glucose) than epinephrine (b2) because isoproterenol directly stimulates insulin secretion from pancreatic islet cells (glucose - to glycogen)

2. Pharmacokinetics

a. oral unreliable

b. good parenteral absorption - bypass GI (ie. SC no vasoconstriction)

c. metabolized by COMT- little by MAO

3. Therapeutic uses

a. bronchodilator

b. cardiac stimulant

4. Untoward effects

similar to epin.

a. New England Journal of Medicine (1992) - if take too much, increase rate of sudden heart failure -- OD of inhalation (aerosol) - fatal ventricular arrhythmias

C. Dopamine (intermediate of NE synthesis) a (high doses), b₁

1. Pharmacologic effects

a. important NT of CNS, also has b₁ effect, and causes release of NE from nerve terminals

b. receptors for dopamine in kidney D₁ (decrease kidney arterial resistance- (vasodilation via increased cAMP) - increase pressure in kidneys - increase glomerular filtration. also D₂ receptors - discuss later

c. at high doses it has an a effect -- vasoconstriction

2. Pharmacokinetics

a. similar to Epinephrine

3.Therapeutic uses

a. shock, cardiogenic- loss of contraction

b. congestive heart failure

4. Untoward effects

a. Heart pain, arrhythmias, hypertension, short lived - because of rapid metabolism

D. Phenylephrine a

1. Pharmacologic effects

a. Direct stimulant of a receptors, less potent than NE but longer lasting because not broken down by COMT

- vasoconstriction

- increased AP (arterial pressure)

- reflex decrease in the heart rate

2. Therapeutic usage

a. nasal decongestant-Neo-Synephrine

b. increases blood pressure

c. to provide local vasoconstriction (As a 10% opthalmic solution for eyes "gets the red out")

3. Untoward effects

a. cardiac irregularities

b. administration to eyes and nose - can be systemically absorbed

E. Ephedrine-occurs in various plants--used in China for 2000 years- in US 70 years ago- first orally active sympathomimetic drug

1. Pharmacologic effects

a. mixed-acting agent - that is both indirect and direct

1) Primary effect is indirect, it causes the release of NE from storage terminals. This is accomplished by displacing NE from storage granules inducing release

2) The direct effect - adrenergic receptors (a, b1, and b2)

b. When administered IV- action similar to Epin. - but less potent, longer lasting.

It does cause central nervous system stimulation- which can result in insomnia, nervousness, nausea, agitation

2. Pharmacokinetics

a. Ephedrine- absorbed when taken orally

b. resistant to COMT and MAO, therefore long lasting.

3. Therapeutic uses

a. Treatment for bronchial asthma

b. nasal decongestant [similar drug pseudoephedrine---Sudafed]

F. Amphetamine

-CNS stimulant-talk about later

-but also sympathomimetic -- mimics the action of the sympathetic nervous system

1. Pharmacologic effects

a. Acts indirectly by releasing norepinephrine

b. amphetamine also CNS stimulant --enters CNS easily

 

1) stimulates respiratory center-medulla

2) wakefulness

3) alertness

4) decreased sense of fatigue

5) elevation of mood

6) physical activity of athletes is improved

7) depresses appetite center in lateral hypothalamus (dextroamphetamine, Dexedrine- you buy dexatrim) (Talk about therapeutic uses later)

Similar Drugs

G. Methyl Phenidate- amphetamine variant (Ritalin -- given for ADD - attention deficit disorder (hyperactivity)-- but also used by people to sharpen their concentration -- yellow pills)

-stabilizing effect in children (increased concentration)-- mechanism may be by increasing NE

H. Methamphetamine - pressor activity---speed----ice-when smoked-----designer-Ecstasy

-similar to ephedrine, also CNS stimulant

I. b2- stimulating Bronchodilators [increase cAMP]

-relax smooth muscle

-little or no effect on the heart

used for treating asthma or bronchospasm

1) Albuterol (Proventil) -- b2 - 12 hour asthma treatment

2) Metaproterenol - b2

3) Terbutaline (Brethine) -- b2

longer duration --- used to suppress labor

J. a2 agonists [decreased cAMP]

-used for treating hypertension

Clonidine and methyl dopa prevent NE release

discuss in greater detail latter 

--------many, many more

VII. Sympathetic Antagonists

-Block adrenergic receptors

-called sympatholytics

-antiadrenergic

A. a Adrenergic blocking agents

-agonists- NE, phenylephrine

1. Phenoxybenzamine - orally - not used much anymore

a. Mechanism of action

1) Binds covalently to the a receptor, producing irreversible blockade (not permanent--14-48 hours)

-also blocks Histamine (H1), Ach. and serotonin receptors, role of these actions is not known.

Non Competitive Inhibition

b. Pharmacologic effects

-antagonizes sympathetic responses mediated by a adrenergic receptors

1) Cardiovascular

A) increases cardiac output - result of decreased TPR

            DP

CO = ---------

            TPR

B) postural hypotension - lack of compensatory symp. vasoconstriction

PA in brain falls - normally sensed by baroreceptors- if phenoxybenzamine, no norepinephrine a receptor response- thus no increased TPR - called orthostatic hypotension

drugs that block both a and b1 would produce even more orthostatic hypotension

2) CNS- stimulates CNS --direct effect -- nausea, hyperventilation

c. Therapeutic uses

1) For acute hypertensive episodes---due to sympathomimetics or MAO inhibitors i.e. tranylcypromine (a MAO inhibitor- derivative of amphetamine)

was once used to reverse vasoconstriction in shock but not anymore -- ie. constriction in gut and kidney- irreversible shock

--Must be careful so that BP does not fall too much

2) To relieve vasospasm in Raynaud's Phenomenon- contraction of blood vessels to digits- results from great increase in sympathetic activity

3) Pheochromocytoma- tumor of adrenal medulla- get excess NE and E

d. Untoward effects

1) Hypotension- reflex tachycardia

2. Phentolamine and tolazoline- slowly absorbed orally reversible a1, a2 adrenergic blockade. structures see text

a. Pharmacologic effects

-lowers blood pressure, reflex cardiac stimulation

-used for acute hypertensive episodes

B. b-adrenergic blocking agents (agonists -- Isoproterenol, Epinephrine)

1. Propranolol- b1 and b2 competitive antagonist

a. Pharmacologic effects

1) Propranolol decreases heart rate, CO

2) Decreases blood flow to most tissues except brain

3) Decreases oxygen consumption in coronary

4) Propranolol inhibits renin secretion (kidney) renin- angiotensinogen- angiotensin I - angiotensin II - aldosterone- (angiotensin is a potent vasoconstrictor - decrease in resistance) b₁

5) Increase airway resistance- b₂ blockade

b. Pharmacokinetics

1) Completely absorbed from GI tract, but large portion is metabolized by liver

2) 90% is bound to plasma proteins

3) Elimination half-time ~ 3 hours - but is much longer in cirrhosis

c. Therapeutic uses

1) Treatment of hypertension

2) Prevention of angina pectoris (heart doesn't work so hard)

3) Prevention of ventricular arrhythmias

4) Long term prevention of sudden death in patients with myocardial infarction

5) Prevention of migraine headaches--excessive pulsation of temporal arteries propranolol decreases HR and BP.

new drugs -- sumatriptan and amitriptyline -- these alter serotonin?

6) Reduces intraoccular pressure (ie. glaucoma)

Other examples

a. Timolol- blocks b1 and b2

b. Metoprolol- blocks b1

c. dozens of others in testing phase

All three are important anti-hypertensive and antiarrhythmic

EXAM - approximately 23 multiple choice, 11 type K questions, 2 short identify the drug, 1 short answer (answer will be a combination of words and figures)

For type K questions - Choose the answer

A if a, b, and c are correct

B if a and c are correct

C if b and d are correct

D if only d is correct

E if a, b, c, and d are correct

you will need a #2 pencil and a calculator - you have from 7:00 - 9:00 to take the exam

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