Agrenergic Pharmacology

2) The alterations in the cardiac beta₁ receptor system that occur in heart failure

3) The pharmacologic actions, pharmacokinetics and therapeutic effects of dobutamine and dopamine.

6) The effects and therapeutic uses of drugs that can activate the alpha1 adrenergic receptors.

Amphetamine-Adderall - 42^nd leading prescription drug in the US in 2007- source- rxlist.com

Methylphenidate - Ritalin- Focalin 176th leading prescription drug in the US in 2007- source- rxlist.com

Phenylephrine - Neosynephrine and numerous over the counter cough and cold preparations

The objective of these presentations is to facilitate the understanding of sympathomimetics and sympatholytics and the adrenergic receptors at which these drugs interact to produce their therapeutic effects.

Sympathomimetics: Synthetic analogs of naturally occurring catecholamines that bind to beta or alpha receptors and mimic the actions of the endogenous neurotransmitters. These agents can be divided into direct and indirect acting sympathomimetics.

Sympatholytics: Synthetic analogs that bind to beta or alpha receptors and block the actions of endogenous neurotransmitters or other sympathomimetics.

In addition to interacting with receptors, adrenergic agonists and antagonists can interact at sites on the nerve terminal to produce sympathomimetic or sympatholytic effects. These potential sites are indicated by the numbers. A majority of drugs are direct acting agonists or antagonists. Only a small number of drugs work through the other listed mechanisms.

1) Direct acting agonists or antagonists can act at postsynaptic receptors.

2) Indirect acting agonists release neurotransmitters from presynaptic nerve terminals to produce a sympathomimetic effect.

3) ***FYI, historical interest only**** Guanethidine can inhibit the Ca²⁺-dependent release of norepinephrine and thus have a sympatholytic effect.

4) ***FYI, historical interest only**** Reserpine causes the destruction of storage granules, and as a result, depletion of the synaptic terminal of norepinephrine which is also a sympatholytic action.

5) Blockade of monoamine transporters (SERT, DAT, NET) by drugs such as cocaine, amphetamine, tricyclic antidepressants and serotonin reuptake inhibitors (SSRIs).

These agents have a higher affinity for beta₂ receptors when compared to beta₁ and activate cellular processes via cAMP as previously discussed.

These agents are used in situations that call for the relaxation of smooth muscle, specifically the smooth muscle associated with airways or uterus such as:

The specific use of beta₂ receptor agonists in these conditions will be discussed at relevant section of PHA 824.

The Involvment of the Sympathetic Nervous System and the Beta1-Receptor in Congestive Heart Failure

In congestive heart failure, the heart is not able to eject blood efficiently. As a result there is a decrease in cardiac output which triggers a series of compensatory actions mediated by the sympathetic nervous system including maladaptive changes in the beta1-receptor system. Overall these changes include;

1) Fluid retention-mediated in part by the renal beta₁ receptor promoting renin release.

2) Vasoconstriction and an increase in peripheral vascular resistance-mediated by vascular alpha₁receptors.

4) The excess stimulation of myocardial beta₁ receptors promotes several maladaptive changes including activation of hypertrophic growth and generation of reactive oxygen species.

5) The excess stimulation of myocardial beta₁ receptors caused by the increase in sympathetic tone actually promotes the desensitization and down regulation of these receptors by the pathways previously described.

Because of maladaptive changes in its regulatory functions, the beta1-receptor is a therapeutic target in heart failure. The idea is to provide additional positive inotropic support via agonists at this receptor. While seemingly conceptually sound, agonists at the beta1-receptor are not used in the long term treatment of heart failure. Rather they are reserved for acute inotropic support. As will be discussed later, blockade of the beta1-receptor is now used in the therapy of heart failure.

Dopamine can activate at least 4 different receptors: the beta₁, dopamine₁ (DA₁), alpha₁ and alpha₂. DA₁ receptors exist in the renal vascular bed. Activation of these receptors produces a decrease in renal vascular resistance and an increase in renal blood flow. Activation of the beta₁ receptor increases the force of myocardial contraction. Dopamine has a very unusual action on the heart in that it selectively increases the force of myocardial contraction without a significant effect on heart rate. However, high doses of dopamine, like all catecholamines which activate the beta₁ system, can induce rhythm disturbances. Activation of the alpha₁ and alpha₂ receptor results in vasoconstriction.

1) Activates myocardial beta₁ receptors to increase the force of myocardial contraction.

2) Little effect on heart rate at therapeutic doses - high doses can induce arrhythmias.

Similar to epinephrine and norepinephrine, dopamine and dobutamine have short plasma half lives and can only be used intravenously in constant or intermittent infusions.

Both dobutamine and dopamine have the potential for improving the negative circulatory events associated with heart failure. For example, by increasing the force of myocardial contraction, cardiac output could increase. In addition, dopamine by inducing renal vasodilation (via DA₁ receptors), can increase renal blood flow and urine output. Dobutamine and dopamine can be used in home health situations to treat congestive heart failure.

THE ALPHA1 ADRENERGIC RECEPTOR AS A THERAPEUTIC TARGET

Direct Acting Agents

These directly activate the alpha₁ -adrenergic receptor. They are less potent than the endogenous agonists epinephrine or norepinephrine. However, because of structural

modifications they are orally active and have longer plasma half-lives. There are 2 structural classes of alpha₁ agonists-the phenylethylamines which are close structural analogs of epinephrine and norepinephrine and the structurally unrelated imidazolines. The major action of these agents is to produce alpha₁-receptor mediated vasoconstriction.

4) Ophthalmic preparations - to induce mydriasis (phenylephrine) and topically for symptomatic relief of irritation (many of the above agents).

5) Cough and cold preparations and nasal decongestants - Many of the above phenethylamines and imidazolines.

6) Alpha₁- adrenergic receptor agonists were once used to slow heart rate in patients with atrial tachycardia - Can you reason why this would be so?

THE CENTRAL NERVOUS SYSTEM AS A SITE OF DRUG ACTION-INDIRECT SYMPATHOMIMETICS

These agents require the presence of endogenous monoamine neurotransmitters (norepinephrine, epinephrine, dopamine, serotonin) to produce their effects. Indirect acting agonists work at the nerve terminal to promote the release and/or block the reuptake of endogenous neurotransmitters. Because they are indirect acting agonists, these drugs have little activity if these neurotransmitters are depleted. Cocaine and amphetamine interact with cell surface monoamine transporters for dopamine (DAT), serotonin (SERT) and norepipephrine (NET). These transporters are expressed peripherally and in specific brain loci. As will be discussed in other lectures, the transporters are the site of action of psychostimulants and antidepressant drugs (tricyclic antidepressants, MAO inhibitors and SSRIs).

Amphetamine: Promotes the release of monoamines from nerve endings from the terminal cytoplasm. Amphetamine also blocks the reuptake of monoamines. Several structural analogs of amphetamine are available for clinical use. These include:

Dexamphetamine-This drug is the resolved and more potent d-isomer of amphetamine)

Methylphenidate.-Is also a mixture of isomers that is marketed as Ritalin. Recently, the more potent isomer has been marketed under the trade name of Focalin.

Because of the actions in the CNS these agents produce a feeling of well being and euphoria and have a significant abuse potential due to these mood enhancing effects. As a result these drugs carry a significant abuse liability. Both cocaine and amphetamine are classified by the FDA as schedule 2. Tolerance to the stimulating actions of these agents can develop.

1) Because of its local anesthetic activity, cocaine has some limited uses as an oral, nasal and ophthalmic local anesthetic.

4) Attention deficient disorder with hyperactivity (ADHD) - methylphenidate, amphetamine and analogs.

The toxicity of CNS active sympathomimetics affects multiple organ systems and can result in arrhythmias, hypertension, psychosis and convulsions. Obviously the likelihood of toxicity depends on the dose and the actual blood levels achieved. Toxicity is more apparent in drug abuse situations. The local anesthetic activity of cocaine can also contribute to cardiac arrhythmias. Cocaine is often vaporized and then inhaled. This can result in very high blood levels increasing the likelihood of toxicity. An analog of amphetamine, methamphetamine, is produced illegally and is a widely abused substance. Methamphetamine can be produced from over the counter cough and cold medications such as pseudoephedrine. Lithium, muriatic acid, sulfuric acid, red phosphorus and lye are used in this preparation. When smoked these highly corrosive agents are vaporized resulting in significant damage to teeth and gums.

Receptor	Result of Receptor Activation	Contribution to Therapeutic Effect
DA₁	The renal vasodilation will improve renal blood flow and increase GFR.	This will increase urine output and decrease fluid retention and edema.
beta₁	Produces a positive inotropic effect.	Increase in cardiac output. This is beneficial in CHF.
alpha₁and alpha₂	Vasoconstriction is not a desired effect.	This will counteract the beneficial effects on renal blood flow. In addition, increases in TPR will negatively affect cardiac output.