Topic 10: Adrenergic Agonists

Adrenergic receptors are __ transmembrane segment __.

7; GCPRs

Epinephrine and norepinephrine are __ catecholamines, whereas levonordefrin is __.

natural; synthetic

How are catecholamines synthesized?

tyrosine —> L-DOPA —> Dopamine —> norepinephrine —> epinephrine

Which catecholamines are natural? (3)

norepinephrine, epinephrine, dopamine

Which catecholamines are synthetic? (3)

levonordefrin, isoproterenol, dobutamine

What receptors are activated by norepinephrine?

alpha 1, alpha 2, beta 1

What receptors are activated by epinephrine?

alpha 1&2, beta 1&2

What receptors are activated by dopamine?

dopamine, alpha 1, beta 1

What receptors are activated by levonordefrin?

alpha 2, beta 1

What receptors are activated by isoproterenol?

beta 1, beta 2

What receptors are activated by dobutamine?

beta 1

Epinephrine does not discriminate between __.

adrenoceptor subtypes

Where are catecholamines released from?

post-ganglionic sympathetic neuron terminals & adrenal glands (epi and some NE)

What are the 3 classes of non-catecholamines? How do they work?

1. direct acting: act on receptors directly

2. indirect-acting: causes NE release or blocks reuptake of NE

3. mixed-acting: both direct and indirect effects

What are examples of direct-acting non-catecholamines? What receptors do they activate? (3)

albuterol- beta 2

clonidine- alpha 2

phenylephrine- alpha 1

What are examples of indirect-acting non-catecholamines? What receptors do they activate?

tyramine- alpha 1&2, beta 1

amphetamine- alpha in CNS, beta 1; can also cause dopamine and serotonin (5-HT) release centrally

What is an example of mixed-acting non-catecholamines? What does it do?

ephedrine: alpha in CNS, beta, and NE release

Norepinephrine release is dependent on __.

calcium

NE release can have 5 paths. What are they?

1. activation of postjunctional receptor (alpha and beta receptors)

2. extraneuronal uptake

3. diffuse into blood

4. metabolized

5. neuronal reuptake

6. prejunctional receptor (alpha 2): inhibits NE release

What pharmacologic effects do catecholamines have? (3)

no direct central effects (meaning have no effect in CNS)

not effective orally (bc rapidly broken down, don’t usually make it to target area)

short-acting (bc have efficient rapid reuptake and metabolic mechanism)

What pharmacologic effects do non-catecholamines have? (4)

many have central effects

many are effective orally

many are longer acting

many are more selective in action

How do indirect-acting sympathetics have a role on NE?

enhance release of NE, decrease its reuptake, or decrease its metabolism

**NE needs to be present to produce effects

Why do catecholamines have no direct central effects?

they are polar, aqueous, and soluble —> can’t cross the blood brain barrier

Responses to administration of sympathomimetic drugs are influenced by: (5)

influence of route of administration

distribution of drug

receptors activated

autonomic nervous system adjustments

tachyphylaxis with indirect-acting drugs (tachyphylaxis = sudden dec in receptor response)

How does NE affect heart rate, systolic pressure, and diastolic pressure? Why?

decreases heart rate, inc systolic and diastolic pressure

alpha receptors —> increase systolic and diastolic BP

baroreceptor reflex —> bradycardia (decreased heart rate)

• despite beta 1 receptor activation which tends to increase heart rate

• baroreceptor reflex is activated by an increase in BP (it’s the compensatory mechanism for BP increase)

How does epinephrine affect heart rate, systolic pressure, and diastolic pressure? Why?

initially: heart rate dec, systolic and diastolic BP increase

• same initial response as NE bc activation of alpha receptors & baroreceptor reflex

then: heart rate increases, systolic and diastolic bp decrease

• beta 2 receptors causes vasodilation —> decreased diastolic BP

• beta 1 receptors —> increase heart rate

returns back to baseline

Alpha 1 and alpha 2 cause __.

vasoconstriction

How is epinephrine and levonordefrin used in dentistry? Why?

added into local anesthetics

anesthetics on their own cause vasodilation, which increases redistribution away from site of intended action & increases bleeding —> vasoconstrictors like epinephrine & levonordefrin oppose the vasodilation

—> increases duration & efficacy, delayes and reduces blood levels, causes local hemostasis (helps bleeding stop)

In refractory asthma and anaphylactic shock, __ can be used as a treatment.

epinephrine

How do receptors activated in epinephrine relate to CV effects?

alpha 1 & some alpha 2 —> peripheral vasoconstriction —> increases BP

beta 1 —> increased heart rate and force of cardiac contraction

beta 2 —> vasodilation in skeletal muscle —> decreases BP

Epinephrine’s CV effect depends on __.

adrenoreceptor subtype activation

Levonordefrin in the CV system can increase __ due to __ receptors. This causes reflex __.

blood pressure; alpha; bradycardia

Sometimes, __ is preferred over epinephrine because of less changes in __.

levonordefrin; heart rate

What precautions must be considered when using catecholamines, like epinephrine, clinically? (2)

1. if pt has cardiovascular disease, excessive CV stimulation can cause HTN, arrhythmias, stroke, myocardial infarction

2. central acting sympathomimetics can also result in excessive CNS stimulation, causing tremors, seizures, psychotic reactions

What drug interactions are present for catecholamines? (3) What do they do?

1. NE reuptake inhibitors (antidepressants, amphetamines, ADHD meds)

2. COMT (catechol-o-methyl-transferase) inhibitors (common in parkinson’s)

3. adrenergic antagonists

these can make sympathomimetic effects of epi or levonordefrin more enhanced

Antidepressants that inhibit the reuptake of serotonin and norepinephrine can be thought of as __.

indirectly-acting sympathomimetic drugs (enhance actions of epinephrine or levonordefrin by blocking NE)

The metabolic inactivation of most injected catecholamines depends on __.

COMT

What are 5 therapeutic uses for catecholamines?

1. vasoconstriction (alpha receptors)

2. cardiac stimulation (beta receptors)

3. bronchial dilation (beta 2)

4. ocular effects (alpha 1)

5. CNS effects (alpha, D)

Alpha receptors allow for __ in therapeutic uses.

vasoconstriction

Beta receptors allow for __ in therapeutic uses.

cardiac stimulation (in bradycardia, hypotension)

What effect do alpha receptor antagonists have?

vasodilation

What effect do B1 & B2 receptor antagonists have?

decreased HR

When effect do beta 1 receptor antagonists have on the kidney?

decreased renin release

In benign prostatic hyperplasia (BPH), beta 1 blockade leads to__.

relaxation of prostatic smooth muscle

How does beta 1 receptor antagonists affect blood pressure?

decreases BP by decreasing HR & contractility & decreasing renin release

How do nicotinic-receptor antagonists decrease hypertension?

block parasympathetic and sympathetic outflow —> ANS can’t regulate blood pressure —> decreases heart rate & constriction of blood vessels

How do drugs that reduce adrenergic transmission decrease hypertension?

decrease synthesis, prevent release, or deplete norepinephrine from adrenergic terminals

Centrally acting drugs reduce hypertension by:

reducing sympathetic outflow

What are the two classes of alpha receptor antagonists? Give examples of both.

1. nonselective

   • phentolamine (reversible)

   • phenoxybenzamine (irreversable)

2. selective

   • prazin, doxazosin, terazosin

What are potential uses of alpha blockers? (5)

1. hypertension

2. benign prostatic hyperplasia

3. pheochromocytoma

4. male impotence

5. reversal of local anesthesia

Limitations of __ include: orthostatic hypotension, reactive tachycardia, intraoperative floppy iris syndrome.

nonselective alpha blockers

Limitations of __ include orthostatic hypotension in Prazosin and cardiovascular stimulation or anxiety in Yohimbine.

selective alpha blockers

What are the 4 classes of beta receptor antagonists?

1. nonselective (Beta 1&2)

2. cardioselective (mainly beta 1)

3. beta blocker with intrinsic sympathomimetic activity (partial agonists)

4. alpha 1 and beta receptor blockers

What are partial agonists?

drugs taht bind to and activate a given receptor but only have partial efficacy at the receptor compared to a full agonist

When are partial agonists used?

used to activate receptors to give submaximal responses when insufficient endogenous ligand is present or to reduce overstimulation of receptors when excess endogenous ligand are present

__ is used for: hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction, congestive heart failure, glaucoma, migraine headache, thyrotoxicosis, stage fright, or tremors.

beta receptor antagonists

The limitations of __ include: congestive heart failure, bronchial asthma, insulin-dependent diabetes and hypoglycemia, and rebound hypertension.

beta receptor antagonists

What two vasoconstrictors have interactions in dental local anesthetics?

non-selective beta blockers

alpha blockers

In the sympathetic nervous system, alpha 1 and some alpha 2 receptors cause __, which increases __.

vasoconstriction; blood pressure

vasoconstricted blood vessels = narrower = higher pressure and force needed to pump blood

In the sympathetic nervous system, beta 1 receptors increase __.

heart rate and force of contraction

In the sympathetic nervous system, beta 2 receptors cause __ in the skeletal muscle, which decreases __.

vasodilation; blood pressure

What do non-selective beta blockers block? What is an example?

both beta 1 and 2

ex: propranolol, nadolol, timolol

What do cardioselective beta blockers block? What is an example?

beta 1 only

ex: atenolol, metoprolol

What is an example of combined alpha and beta blockers?

labetalol, carvedilol

How is blood pressure or heart rate affected in non-selective beta blocker interactions?

increased blood pressure —> hypertension and reflex bradycardia

beta blocker = blocks beta 1 (increases HR) and beta 2 (decreases BP)

There is likely no __ with cardioselective beta1 agents or combined alpha and beta blockers.

interaction

In an alpha blockade, how is heart rate and blood pressure affected? What is this called?

increased heart rate (from beta1), decreased BP (from beta2) —> hypotension & tachycardia

called epinephrine reversal

What are alpha blockers mainly used for?

BPH (benign prostatic hyperplasia)

What are 3 types of alpha blocking drugs?

alpha blockers (prazosin)

phenothiazines (thorazine)

butyrophenones (Haldol)

What adrenergic agonist is really an antagonist?

alpha-2 agonists (prejunctional receptor)

What do alpha-2 agonists do?

decrease overall sympathetic tone by decreasing release of natural NT from presynaptic terminals

__ is used for hypertension, opioid withdrawal, analgesia/anesthesia, and to counteract amphetamine insomnia.

alpha2 agents

Clonidine, dexmedetomidine, guanfacine, guanabenz, alpha-methyldopa are examples of __ agents.

alpha 2

The limitations of __ agents are cardiovascular depression, somnolence, rebound hypertension with cessation of therapy.

alpha 2