Nursing Pharmacology: Adrenergic Pharmacology

Nursing Pharmacology: Autonomic Pharmacology Adrenergic Drugs

Epinephrine

Epinephrine is a potent activator of α 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 α₁ 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:
  - vasodilatation of the veins and arterioles in the peripheral vascular beds and
  - negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction)

Adrenergic

Cholinergic

Sino-atrial (SA) Node

β₁; β₂

increased rate

decreased rate (vagal)

Atrial muscle

β₁; β₂

increased: contractility, conduction velocity

decreased: contractility, action potential duration

Atrio-ventricular (AV) node

β₁; β₂

increased: automaticity, conduction velocity

decreased conduction velocity; AV block

His-Purkinje System

β₁; β₂

increased: automaticity, conduction velocity

------

Ventricles

β₁; β₂

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)

Vascular Effects

Epinephrine has significant effects on smaller arteriolar and precapilliary smooth muscle.
Acting through α₁ 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 areceptor 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 αreceptors 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

Smooth Muscle

Epinephrine has variable effects on smooth muscle depending on the adrenergic subtype present.
- GI smooth muscle is relaxed through activation of both α 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.
- Uterine effects (summary)
  - Uterus
    - α₁-receptor mediated contraction in pregnancy
    - β₂-receptor mediated relaxation in pregnancy
    - In non-pregnant individuals, relaxation occurs via β₂-receptor activation
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 Actions:
  - Tracheal and bronchial muscle
    - β₂-receptor mediated relaxation
    - Cholinergic receptor mediated contraction
  - Bronchial glands
    - α₁-receptor mediated decreased secretion
    - β₂-receptor mediated increased secretion
    - Cholinergic receptor mediated contraction

Metabolic Effects

Insulin secretion is inhibited by α₂ adrenergic receptor activation and is the dominant effect.
Insulin secretion is enhanced by ß₂ adrenergic receptor activation.
- Pancreas
  - Acini cells
    - Adrenergic Effects:
      - α-adrenergic receptor activation results in decreased secretion.
    - Cholinergic effects: increased secretion.
  - Islet cells
    - α₂ adrenergic receptor activation results in decreased secretion.
    - β₂-receptor receptor activation results in increased secretion.
    - Glucagon secretion is increased by β-adrenergic receptor activation of pancreatic islet alpha cells.
    - Glycolysis is stimulated by β-adrenergic receptor activation.
- Liver
  - α₁-adrenergic receptor activation promotes glycogenolysis.
  - β₂-adrenergic receptor activation enhances gluconeogenesis.
  - Free fatty acids are increased by β-adrenergic receptor activation on adipocytes.
    - The mechanism involves activation of the enzyme triglyceride lipase.
- Adipose tissue
  - Fat cells:
    - α₂-adrenergic receptor activation and β₃-adrenergic receptor activation are associated with lipolysis and promote thermogenesis.
      - The calorigenic effect (20% - 30% increase in O₂ consumption is 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 β-adrenergic receptor antagonists {but not by cardio-selective β₁ antagonists}.
- Possible "preoperative hypokalemia" may be associated with preoperative anxiety which promotes epinephrine release.
  - Therapeutic decisions based on preinduction serum potassium levels may be helpful.