Autonomic Nervous System--Adrenergic Pharmacology-Lecture I, slide 2

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Table of Contents

  • Introduction

  • Adrenergic Agonists

  • Comparative pharmacology

  • Categories of Actions

    • Smooth Muscle Effects

    • Cardiac Effects

    • Metabolic Effects

    • Endocrine

    • CNS Effects

    • Presynaptic Effects

  • Epinephrine

    • Blood Pressure

    • Vascular Effects

    • Cardiac Effects

    • Smooth Muscle

    • Metabolic

    • Electrolytes

    • Toxicities

    • Therapeutic Use

  • Norepinephrine  (Levophed)

    • Blood Pressure

    • Vascular Effects

    • Therapeutic Use

  • Dopamine  (Intropin)

    • Cardiovascular Effects

    • Therapeutic Use

  • Dopexamine dopexamine

  • Isoproterenol (Isuprel)

    • Adverse Effects

    • Therapeutic Use

  • Dobutamine  (Dobutrex)

    • Adverse Effects

    • Therapeutic Use

  • ß2 selective adrenergic agonists

    • Metaproterenol (Alupent)

    • Terbutaline  (Brethine)

    • Albuterol (Ventolin,Proventil)

    • Ritodrine  (Yutopar)

    • Adverse Effects

  • a-Selective Adrenergic Agonists

    • Methoxamine  (Vasoxyl)

    • Phenylephrine  (Neo-Synephrine)

  • a2 Selective Adrenergic Agonists

    • Introduction

    • Clonidine  (Catapres)

    • Guanfacine  (Tenex)

    • Guanabenz  (Wytensin)

    • a-methyl DOPA  (Aldomet)

    • Miscellaneous

      Amphetamine

      • Methylphenidate  (Ritalin)

      • Ephedrine

      • Vasoconstrictors

  • Clinical Use of Sympathomimetic Agents

 

  • Amphetamines

  • Adrenergic Neuronal Blocking Drugs

  • Classification of adrenoceptors ( a1, a21, ß2 and D1), molecular consequences of their activation, and their important locations.

    • ß  Receptors

    • a Receptors

    • "Desensitization" as it applies to adrenoceptor regulation

  • Catecholamine Metabolic Transformations

  • Pulmonary Uptake

  • Adrenergic and Cholinergic Effects on End Organs

  • Clinical Uses: Sympathomimetic Drugs: a/b Adrenergic Agonists

    • Overview

    • Shock

    • a agonists

    • Drugs Used in Treating Shock

    • Hypertension

    • Cardiac Arrhythmias

    • Congestive Heart Failure

    • Vascular Effects: a Adrenergic Agonists

    • Nasal Decongestion

    • Asthma

    • Allergic Reactions

  • Therapeutic Uses of Indirect-Acting Adrenergic Agonists

  • Adverse Effects: b Adrenergic Antagonists

  • a-Adrenergic Antagonists

    • Introduction

      • a1-adrenergic receptor antagonists

      • a2-adrenergic receptor antagonists

      • Phenoxybenzamine (Dibenzyline)

      • Phentolamine(Regitine) and tolazoline (Priscoline)

      • Prazosin  (Minipress) and Terazosin (Hytrin)

      • Others

  • b Adrenergic Antagonists

    • Introduction

    • ß receptor blockers: Effects on the heart

    • ß receptor blockers: Antihypertensive Effects

    • Pulmonary Effects

    • Metabolic Actions

    • Nonselective-ß adrenergic receptor antagonists

      • propranolol

      • nadolol

      • timolol

      • labetalol

    • Cardioselective ß1 adrenergic receptor antagonists

      • metoprolol

      • esmolol

      • atenolol

    • Adverse Effects of ß adrenergic receptor antagonists

    • Therapeutic Uses

 

 

 

 

Epinephrine

 

  • Epinephrine is a potent activator of alpha and ß adrenergic receptors

  • Prominent Cardiovascular Effects

 Blood Pressure

  • Potent vasopressor

    • Systolic pressure increases to a greater extent than diastolic (diastolic pressure may decrease)

      • pulse pressure widens

    • Epinephrine increases blood pressure by:

      1. enhancing cardiac contractility (positive inotropic effect): ß1-receptor effects

      2. increasing heart rate (positive chronotropic effect): ß1-receptor effects.

      3. vasoconstriction a1 receptor effects

        • precapillary resistance vessels of the skin, kidney, and mucosa

        • veins

    • If epinphrine is administered relatively rapidly, the elevation of systolic pressure is likely to activate the baroreceptor system resulting in a reflex-mediated decrease in heart rate.

  • A principal mechanism for arterial blood pressure control is the baroreceptor reflex.

  • The reflex is initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck.

  • A high density of baroreceptors is found in the wall of each internal carotid artery (just above the carotid bifurcation i.e. carotid sinus) and in the wall of the aortic arch.

As pressure rises and especially for rapid increases in pressure:

  • baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in:

  1. a vasodilatation of the veins and arterioles in the peripheral vascular beds.

  2. negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction)

 

 

Adrenergic

Cholinergic

Sino-atrial (SA) Node

beta1; beta2

increased rate

decreased rate (vagal)

Atrial muscle

beta1; beta 2

increased: contractility, conduction velocity

decreased: contractility, action potential duration

Atrio-ventricular (AV) node

beta1; beta 2

increased: automaticity, conduction velocity

decreased conduction velocity; AV block

His-Purkinje System

beta1; beta 2

increased: automaticity, conduction velocity

------

Ventricles

beta1; beta 2

increased: contractility, conduction velocity, automaticity, ectopic pacemaker

small decrease in contractility

  • At lower epinephrine doses:

    • a lessened effect on systolic pressure occurs

    • diastolic pressures may decrease as peripheral resistance is reduced.

    • Peripheral resistance decreased due to ß2-receptor effects

    Summary

Blood Pressure

Blood Pressure Effects

Epinephrine

Norepinephrine

Systolic

Mean Pressure

Diastolic

variable

Mean Pulmonary

0.1-0.4 ug/kg/min infusion rate

Adaptation of Table 10-2 from: Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.199-242

 

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 Vascular Effects

  • Epinephrine has significant effects on smaller arteriolar and precapilliary smooth muscle.

    Acting through alpha1 receptors, vasocontrictor effects decrease blood flow through skin and kidney.

    • Even at doses of epinephrine that do not affect mean blood pressure, substantially increases renal vascular resistance and reduces blood flow (40%).

    • Renin release increases due to epinephrine effects mediated by ß1-receptors associated with juxtaglomerular cells.

  • Acting through ß2-receptors, epinephrine causes significant vasodilation which increases blood flow through skeletal muscle and splanchnic vascular beds.

  • If an a receptor blocker is administered, epinephrine ß2-receptor effects dominate and total peripheral resistance falls as does mean blood pressure--this phenomenon is termed "epinephrine reversal".

Cardiac Effects

  • Epinephrine exerts most of its effects effects on the heart through activation of ß1-adrenergic receptors.

    • ß2- and a receptors are also present.

    • Heart rate increases

    • Cardiac output increases

    • Oxygen consumption increases

Direct Responses to Epinephrine

  • increased contractility

  • increased rate of isometric tension development

  • increased rate of relaxation

  • increased slope of phase-4 depolarization

  • increased automaticity (predisposes to ectopic foci

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Smooth Muscle

  • Epinephrine has variable effects on smooth muscle depending on the adrenergic subtype present.

    •  GI smooth muscle is relaxed through activation of both alpha and ß -receptor effects.

    •  In some cases the preexisting smooth muscle tone will influence whether contraction or relaxation results following epinephrine.

    •  During the last month of pregnancy, epinephrine reduces uterine tone and contractions by means of ß2-receptor activation.

      • This effect provides the rationale for the clinical use of ß2-selective receptor agonists: ritodrine and terbutaline to delay premature labor.

 

Uterus

alpha1; beta2

Pregnant: contraction (alpha1); relaxation (beta2); Non-pregnant: relaxation (beta2)

variable

  • Epinephrine is a significant respiratory tract bronchodilator. Bronchodilation is caused by ß2-receptor activation mediated smooth muscle relaxation.

    •  This action can antagonize other agents that promote bronchoconstriction.

    •  ß2-receptor activation also decreases mast cell secretion. This decrease may be beneficial is management of asthma also.

Pulmonary
 

Adrenergic 

Effects

Cholinergic
Tracheal and bronchial muscle beta 2 Relaxation contraction
Bronchial glands alpha1, beta2 decrease secretion;increased secretion stimulation

 

Metabolic Effects

  • Insulin secretion: inhibited by a2 adrenergic receptor activation (dominant)

  • Insulin secretion: enhanced by ß2 adrenergic receptor activation

Pancreas 
 

Adrenergic

Effects Cholinergic
Acini alpha decreased secretion secretion
Islets (beta cells) alpha2 decreased secretion ---------
Islets (beta cells) beta2 increased secretion ---------
  • Glucagon secretion: enhanced by ß adrenergic receptor activation of pancreatic islet alpha cells.

  • Glycolysis- stimulated: by ß adrenergic receptor activation

Liver
 

Adrenergic 

Effects Cholinergic
Liver alpha1; beta2 glycogenolysis and gluconeogenesis -----------
  • Free fatty acids, increased: by ß adrenergic receptor activation on adipocytes--activation of triglyceride lipase

Adipose Tissue

Adrenergic

Cholinergic

Fat Cells

alpha2; beta3  

lipolysis (thermogenesis)

---------

  • Calorigenic effect (20% - 30% increase in O2 consumption): caused by triglyceride breakdown in brown adipose tissue.

Electrolytes

  • Epinephrine may activate Na+-K+ skeletal muscle pumps leading to K+ transport into cells.

  • Stress-induced epinephrine release may be responsible for relatively lower serum K+ levels preoperatively compared postoperatively.

  •  Mechanistic basis: "Preoperative hypokalemia" can be prevented by nonselective beta-adrenergic receptor antagonists {but not by cardio-selective beta1 antagonists}.

  • Possible "preoperative hypokalemia" may be associated with preoperative anxiety which promotes epinephrine release-- therapeutic decisions based on preinduction serum potassium levels to take into account this possible explanation

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