Systemically absorbed epinephrine could also increase heart rate and exacerbate cardiac rhythm disturbances or myocardial ischemia. Learning Objectives Lecture II 1. Understand the potential sites of action for sympathomimetics and the difference between a direct and indirect acting agonist.
Understand the pharmacologic actions and therapeutic actions of drugs that act at the beta 1 and beta 2 -adrenergic receptors as well as the alpha 1 -adrenergic receptor.
Know the mechanism of action and effects of amphetamine and cocaine. Understand how the pressure of sympathomimetics alters the dental management of patients. Sympathomimetics: synthetic analogs of naturally occurring catecholamines that mimic the actions of the endogenous neurotransmitters.
These agents can be divided into direct and indirect acting sympathomimetics. Direct acting agonists or antagonists can act at postsynaptic receptors. Indirect acting agonists release neurotransmitters from presynaptic nerve terminals to produce a sympathomimetic effect. Inhibition of the membrane uptake of catecholamines by drugs such as cocaine and tricyclic antidepressants produce a sympathomimetic effect.
Inhibition of monoamine oxidase by drugs such as Tranylcypromine. In congestive heart failure, the failing heart is not able to eject blood as efficiently as the normal heart. As a result there is a decrease in cardiac output which triggers a host of compensatory actions.
These include fluid retention, vasoconstriction, an increase in peripheral vascular resistance, an increase in the levels of circulating catecholamines and tissue hypoxia. Dopamine and dobutamine activate the myocardial beta 1 receptor and thus increase the force of contraction of the failing heart. This will result in an increase in cardiac output. These drugs are reserved for use in the acute management of heart failure.
These agents have a higher affinity lower equilibrium dissociation constant for beta 2 receptors when compared to beta 1. Therefore, they selectively activate beta 2 receptors when compared to beta 1. Uses 1. Airways dysfunction; bronchial asthma, chronic bronchitis, emphysema In airways dysfunction, beta 2 selective agonists relax airways thus decreasing airways resistance.
Premature labor In premature labor, the beta 2 selective agonists relax uterine smooth muscle. Drugs that relax uterine smooth muscle are referred to as tocolytic agents. Side effects related to dental practice 1. Xerostomia, with inhaler usage. These structural modifications of the parent catecholamine nucleus result in drugs that are orally active and have longer plasma half-lives. However, these same modifications result in lower affinity for the receptor than do the endogenous agonists epinephrine or norepinephrine.
There are two structural classes of alpha 1 agonists phenethylamines which are closely aligned in structure to epinephrine and the imidazolines, compounds structurally unrelated to epinephrine. Levonordeferin is a phenyethylamine that has been used in dental practice in combination with local anesthetics.
Hypotension-to increase blood pressure during a surgical procedure where a general anesthetic has induced hypotension 2. Ophthalmic preparations-to induce mydrasis also in topical preparations for symptomatic release of eye irritation.
Cough and cold preparations-Induces constriction of nasal mucosa decreases resistance to air flow. Indirect Acting Sympathomimetics These agents require the presence of endogenous catecholamines to produce their effects. They have little activity if catecholamines are depleted.
Cocaine: Blocks reuptake of monoamines into nerve endings. Cocaine also has local anesthetic activity. Amphetamine: Promotes the release of NE from nerve endings. Amphetamine can also block the reuptake of norepinephrine.
Amphetamine-like compounds 1. Methylphenidate A major site action of cocaine, amphetamine and amphetamine-like agents is in the CNS.
These drugs produce a feeling of well being and euphoria. As a result the drugs carry a significant abuse liability. Both cocaine and amphetamine are on the FDA schedule 2. Uses of Cocaine 1 below , Amphetamine and Amphetamine-like agents below 1. Cocaine has limited use as a local anesthesic and vasoconstrictor in surgical procedures involving oral, laryngeal or nasal cavities. Appetite suppression 3.
Hyperactivity in children 4. Recall that epinephrine can be absorbed systemically after intraoral administration. This epinephrine can be taken up by nerve terminals and this uptake contributes to the the termination of the actions of epinephrine. These actions are summarized in the table below:. As a consequence of the baroreceptor reflex, a drug that acts on adrenergic receptors can precipitate changes in sympathetic and parasympathetic nervous system activity that tends to offset the effects of the drug.
Although such a drug would decrease total peripheral resistance and lower blood pressure, its administration also results in reflex-mediated increases in heart rate and contractility, as shown below. To review the synthesis, release, and actions of norepinephrine and epinephrine, watch this movie. If the movie does not play in this window, or you would like to see it in a window of alternate size, download it from this link. Introduction If you need a refresher on the process of synaptic transmission, please review the following Neurophysiology Modules you completed in the spring: Module 2: Membrane potentials Module 3: Action potentials Module 4: Synaptic transmission Norepinephrine and Epinephrine Norepinephrine is synthesized from the amino acid tyrosine through by a series of enzymatic steps in particular cells in the central nervous system, as well as by most postganglionic neurons of the sympathetic nervous system.
Norepinephrine is released like most neurotransmitters: when an action potential invades a nerve terminal, voltage-gated calcium channels typically N-type open, and the entry of calcium causes fusion of the norepinephrine-containing vesicles with the membrane, thereby releasing norepinephrine into the synaptic cleft.
A few neurons in the central nervous system also contain PNMT. Interestingly, many of these neurons are located in the rostral ventrolateral medulla RVLM , the brainstem area that plays a primary role in controlling blood pressure by regulating the activity of sympathetic preganglionic neurons. The axons of RVLM neurons project to the thoracic and lumbar spinal cord, and make synaptic connections with sympathetic preganglionic neurons. This diagram shows the locations of PNMT-containing neurons in a section through the human brainstem.
Presumably the stained neurons are located in the RVLM. These actions are summarized in the table below: Change in Blood Pressure Change in Baroreceptor Afferent Activity Change in Activity of Sympathetic Efferents to Heart and Blood Vessels Change in Activity of Parasympathetic Efferents to Heart Increase Increase Decrease Increase Decrease Decrease Increase Decrease As a consequence of the baroreceptor reflex, a drug that acts on adrenergic receptors can precipitate changes in sympathetic and parasympathetic nervous system activity that tends to offset the effects of the drug.
For instance, the heart rate will increase, pupils will dilate, energy will be mobilized, and blood flow will be diverted from non-essential organs to skeletal muscle. Adrenaline epinephrine : The 2D structure of adrenaline epinephrine is illustrated. Noradrenaline norepinephrine : The 2D structure of noradrenaline norepinephrine is illustrated here. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP.
Isoprenaline is a nonselective agonist. Adrenergic signal transduction : This schematic shows the mechanism of adrenergic receptors. The result is that high levels of circulating epinephrine cause vasoconstriction. Smooth muscle behavior is variable depending on anatomical location. One important note is the differential effects of increased cAMP in smooth muscle compared to cardiac muscle. Increased cAMP will promote relaxation in smooth muscle, while promoting increased contractility and pulse rate in cardiac muscle.
Common or still unspecified effects include: vasoconstriction of cardiac arteries coronary artery , vasoconstriction of veins, and decreased motility of smooth muscle in the gastrointestinal tract. The former interacts with calcium channels of the endoplasmic and sarcoplasmic reticulum, thus changing the calcium content in a cell.
This triggers all other effects. It causes vasoconstriction in many blood vessels, including those of the skin, gastrointestinal system, kidney renal artery , and brain. Other areas of smooth muscle contraction are:. Antagonists may be used in hypertension.
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