Nursing:  Autonomic Pharmacology--Adrenergic Drugs

Introduction

• Distribution of adrenergic receptor subtypes and adrenergic receptor number are important factors in organ or cellular responses to adrenergic input.

  • Adrenergic receptor type in bronchiolar smooth muscle is principally ß₂: epinephrine and isoproterenol might be expected to be effective bronchodilators because of their activity at ß₂ receptors.

    • Norepinphrine is unlikely to have this same effect due to its relative lack of activity at ß₂ sites.

  • α receptor dominate in the cutaneous vascular beds.

    • Norepinephrine and epinephrine cause constriction.

    • Isoproterenol with limited activity at alpha recetors has little effect.

  • Both α and β adrenergic receptor are present in skeletal muscle vascular beds.

    • α receptor activation causes vasoconstriction.

    • β receptor activation promotes vasodilatation.

    • Since ß₂ receptors are activated at lower, physiological concentrations, vasodilation results.

• Physiological effects caused by sympathomimetcs are due not only to direct effects, but also to indirect or reflex effects.

  • α receptor agonist causes an increase in blood pressure.

  • Carotid/aortic baroreceptors activations initiates a compensatory reflex.

  • Sympathetic tone is reduced (decreases heart rate)

  • Parasympathetic tone is increased (decreases heart rate)

  • Blood pressure tends to return to lower levels

Adrenergic Agonists

--increased effect; --decreased effect

(adapted from: Table 12-1 Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p. 260)

Categories of Action

•  Smooth Muscle Effects

  • Smooth muscle activation, including activation of blood vessel vasculature (skin, kidney).

  • Activation of glands (salivary and sweat).

  • Smooth muscle inhibition, including inhibition of smooth muscle of the gut, bronchioles, and skeletal muscle vascular smooth muscle.

•  Cardiac Effects

  • increased heart rate (positive chronotropic effect)

  • increased contractility (positive inotropic effect)

• Metabolic Effects

  • increase in rate of muscle and liver glycogenolysis

  • increase in free-fatty acid release from fat

•  Endocrine

  • Regulation/modulation of insulin, pituitary, and renin secretion

•  Central Nervous System Effects

  • Respiratory stimulation

  • CNS stimulation

  • Appetite attenuation

• Presynaptic Effects

  • Presynaptic effects: modulation of  release of norepinephrine or acetylcholine

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) TheMcGraw-Hill Companies, Inc.,1996, pp.199-242

Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p. 260

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.

• 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

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 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

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 a₂ 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.

Norepinephrine (Levophed)

• Norepinephrine is the primary neurotransmitter released by postganglionic neurons of the autonomic sympathetic system.

  • Norepinephrine (Levophed) is a potent activator of a and ß₁ adrenergic receptors.

• Blood Pressure Effects

  • Norepinephrine is a potent vasopressor

    • Systolic and diastolic pressure increase

      • pulse pressure widens

    • Norepinephrine (Levophed) increases blood pressure by:

      1. vasoconstriction α₁ receptor effects

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

         • veins

    •  Elevation of systolic pressure following norepinephrine is likely to activate the baroreceptor system resulting in a reflex-mediated decrease in heart 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

 

                Norepinephrine Effects on Vascular Tone of Arterioles  (Sympathetic Nervous System Effects)          

Coronary	α1,2; β2	constriction; dilatation
Skin/Mucosa	α1,2	constriction
Skeletal Muscle	α; β2	constriction; dilatation
Cerebral	α1	slight constriction
Pulmonary	α1 , β2	constriction; dilatation
Abdominal viscera	α1, β2	constriction; dilatation
Salivary glands	α1,2	constriction
Renal	α1,2;β1,2	constriction; dilatation

Based on Table 6-1: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, 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.110-111.

Vascular Effects

• Norepinephrine significantly increases total peripheral resistance, often inducing reflex cardiac slowing.

• Norepinephrine (Levophed) causes vasoconstriction in most vascular beds.

• Blood flow is reduced to the kidney, liver and skeletal muscle.

• Glomerular filtration rates are usually maintained.

• Norepinephrine may increase coronary blood flow (secondary to increased blood pressure and reflex activity)

• Norepinephrine (Levophed) may induce variant (Prinzmetal's) angina.

  •  

    "Microvascular Angina and Coronary Artery Spasm"

    "Professor Juan Carlos Kaski, Head of the Cardiovascular Sciences Research Centre, St. George's University of London, UD discusses Microvascular Angina for this Expert Opinion interview." CVSRCVideos https://www.youtube.com/watch?v=3TmUvQJ0hr4 .

     

• Pressor effects of norepinephrine (Levophed) are blocked by α-receptor blockers.

• ECG changes following norepinephrine (Levophed) are variable, depending on the extent of reflex vagal effects.

increase, decrease

0.1-0.4 ug/kg/min IV infusion

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

• Therapeutic use: Norepinephrine

  • Norepinephrine may be used in some circumstances in treatment of shock

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) TheMcGraw-Hill Companies, Inc.,1996, pp.204-213.

Dopamine (Intropin)

• Dopamine is the immediate precursor of norepinephrine.

• Dopamine is a CNS neurotransmitter associated with the basal ganglia and motor control.

• Cardiovascular Effects (Dopamine)

  • Vasodilator:

    • At low doses, dopamine (Intropin) interactions with D₁ receptor subtype result in renal, mesenteric and coronary vasodilation.

      • This effect is mediated by an increase in intracellular cyclic AMP

    • Low doses result in enhancing glomerular filtration rates (GFR), renal blood flow, and sodium excretion.

  • Positive inotropism:

    • At higher doses, dopamine increase myocardial contractility through activation of ß₁ adrenergic receptors

    • Dopamine (Intropin) also promotes release of myocardial norepinephrine.

    • Dopamine (Intropin) at these higher dosages causes an increase in systolic blood and pulse pressure with little effect on diastolic pressures.

  • Vasopressor:

    • At high doses dopamine (Intropin) causes vasoconstriction by activating a₁ adrenergic receptors

• Therapeutic use (Dopamine)

  •  Dopamine may be helpful in managing both cardiogenic and hypovolemic shock

    • Dopamine also may improve kidney function by enhancing renal blood perfusion despite low cardiac output.

      • Oligouria (low urine output) may be an indication of inadequate renal perfusion.

    • Example: dopamine may be used, in postoperative cardiopulmonary bypass patients who exhibit:

      • low systemic blood-pressure

      • increased atrial filling pressures

      • low urinary output

    • Unique among catecholamines in that dopamine can simultaneously increase:

      • myocardial contractility

      • glomerular filtration rate

      • sodium excretion

      • urine output

      • renal blood flow

• Increased sodium excretion following dopamine may be due to inhibition of aldosterone secretion.

  • Dopamine may inhibit renal tubular solute reabsorption (suggesting that natriuresis & diuresis may occur by different mechanisms.)

• Fenoldopam and dopexamine are examples of  newer drugs that may be useful in treating heart failure by improving myocardial contractility.

• Dopamine (Intropin) at higher doses increases myocardial contractility by ß₁ - adrenergic receptor activation.

• Ventilation effects: -- dopamine IV infusion interferes with ventilatory responses to arterial hypoxemia

  Dopamine (Intropin) acts as inhibitory neurotransmitter at carotid bodies and as a result one may observe an unexpected ventilation depression in patients treated with IV dopamine (Intropin), for example, to enhance myocardial contractility.

   

• Dopexamine (Dopacard)

  • Dopexamine is a synthetic catecholamine that activates both dopaminergic and β₂-adrenergic receptors.

  • Administration of dopexamine may result in a slight positive inotropic effect due to β₂-adrenergic agonist activity; furthermore, this drug may potentiate effects of endogenous norepinephrine, secondary to reuptake blockade.

  • Dopexamine enhances creatinine clearance

Isoproterenol (Isuprel)

• Isoproterenol activates ß adrenergic receptors (both ß₁ - and ß₂ -receptor subtypes)

  • Isoproterenol exhibits limited action at α adrenergic receptors

• i.v. influsion of isoproterenol results in a slight decrease in mean blood pressure with a marked drop in diastolic pressure.

• ß₂-adrenergic receptor-mediated reduction in peripheral resistance (reflected in the diastolic pressure effects) is primarily due to vasodilation of skeletal muscle vasculature.

  • Renal and mesenteric vascular beds are also dilated.

• Activation of cardiac ß₁-adrenergic receptors by isoproterenol cause an increase in both contractility and heart rate.

• Activation of ß₂-adrenergic receptors by isoproterenol result in both bronchial and gastrointestinal (GI) smooth muscle relaxation.

• Isoproterenol and ß₂-selective adrenergic agonists inhibit antigen-mediated histamine release.

  Isoproterenol: Limited therapeutic uses include:

  • Emergency settings to treat heart block or severe bradycardia

  • Management of torsades de pointes (a ventricular arrhythmia)

• Isoproterenol (Isuprel) adverse effects include:

  • palpitations

  • tachycardia

  • arrhythmias

  • coronary insufficiency

Dobutamine (Dobutrex)

• Structurally similar to dopamine (Intropin).

  Pharmacological effects exerted through interaction with a and ß adrenergic receptor interactions

  • no effect on release

  • no action through dopamine receptors

   

• Pharmacological effects are due to complex interactions of (-) and (+) enantiometic forms present in the clinically used racemate with a and ß adrenergic receptors.

• Dobutamine (Dobutrex) is a positive inotropic agent usually causing limited increase in heart rate.

  • Positive inotropism is mediated through ß adrenergic receptor activation. Some peripheral a₁ activity causes modest vasoconstriction, an effect opposed by dobutamines ß₂ effects.

•  Dobutamine (Dobutrex): Adverse Effects

  • Significant blood pressure and heart rate increases may occur.

  • Ventricular ectopy

  • Increased ventricular following rate in patient with atrial fibrillation.

  • Increased myocardial oxygen demand that may worsen post-infarct myocardial damage

• Dobutamine (Dobutrex): Therapeutic Use

  • Short-term management of pump failure following surgery, during acute congestive heart failure, or post-myocardial infarction.

  • Uncertain long-term efficacy.

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) TheMcGraw-Hill Companies, Inc.,1996, pp.199-242

ß₂ Selective Adrenergic Agonists

• At low concentration ß₂ selective adrenergic agonists have relatively minor ß₁ cardiac receptor-mediated effects.

• Effective in managing asthma, ß₂ selective adrenergic agonists are orally active and metabolized more slowly compared to catecholamines

• ß₂ selective adrenergic agonists examples include: 

  • Metaproterenol (Alupent)

  • Terbutaline (Brethine)

  • Albuterol (Ventolin,Proventil)

• In asthma, pulmonary ß₂ receptors are targeted by drug administration by inhalation.

  • This route of administration results in lower systemic drug concerntration, an effect which reduces the likelihood of cardioacceleration ( ß₁) or skeletal muscle tremor (ß₂ ).

• Activation of pulmonary ß₂ adrenergic receptors results in smooth-muscle relation and bronchodilation.

• ß adrenergic receptor agonists also decrease histamine and leukotriene release from lung mast cells.

  • Recalling that asthma is first and foremost an inflammatory disease, reduction in histamine and leukotriene release would be beneficial.

• ß adrenergic receptor agonists enhance mucociliary activity and diminish microvascular permeabilty.

• Metaproterenol (Alupent)

  • ß₂ adrenergic receptor-selective and is resistant to COMT (catechol-O-methyl transferase) metabolism in the body.

  • Metaproterenol is less ß₂ selective, compared to terbutaline (Brethine) and albuterol (Ventolin,Proventil).

  • Metaproterenol may be used for long-term and acute treatment of bronchospasm

• Terbutaline [Brethine]

  • This agent is ß₂ adrenergic receptor-selective and is also resistant to COMT (see above).

  • Terbutaline is active after oral, subcutaneous, or administration by inhalation and typically shows a rapid onset of action.

  • This agent may be used for management of chronic obstructive lung disease and for treatment of acute bronchospasm (smooth muscle bronchoconstriction), including status asthmaticus

  Albuterol [Ventolin]

  • Albuterol is another ß₂ adrenergic receptor-selective drug.

  • This agent is effective following inhalation or oral administration and may be commonly used in chronic and acute asthma management.

  Ritodrine (Yutopar)

  • Ritrodrine, a ß₂ adrenergic receptor-selective drug was developed for use as a uterine relaxant.

  • This agent may be administered by i.v. in certain patients for arresting premature labor; if successful, oral therapy may be started.

  • ß₂ adrenergic receptor-selective agonists may not improve perinatal mortality and may increase maternal morbidity.

  • In women being treated for premature labor, ritodrine (Yutopar) or terbutaline (Brethine) may cause pulmonary edema .

  Adverse Effects associated with adrenergic agonists

• Excessive cardiovascular stimulation

• Skeletal muscle tremor (tolerance develops, unknown mechanism) due to ß₂ adrenergic receptor activation

• Overusage may be a factor in morbidity and mortality in asthmatics.

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) TheMcGraw-Hill Companies, Inc.,1996, pp.213-216.

α₁ Selective Adrenergic Agonists

• α₁ selective adrenergic agonists activate α adrenergic receptors in vascular smooth muscle producing vasoconstriction.

  • Peripheral vascular resistance is increased.

  • Blood pressure may be increased, causing a reflex reduction heart rate

  • α₁ adrenergic agonists are used clinically in management of hypotension and shock.

  • Phenylephrine (Neo-Synephrine) and methoxamine (Vasoxyl) are direct-acting vasoconstrictors.

  • Mephentermine (Wyamine) and metaraminol (Aramine) act both by direct receptor activation and by promoting epinephrine release (indirect activity).

• Methoxamine (Vasoxyl)

  • Methoxamine is a specific α₁ receptor agonist and as such both:

    • increases peripheral resistance and

    • causes an increase in blood pressure that precipitates sinus bradycardia (decreased heart rate) due to vagal reflex.

  • Reflex bradycardia may be blocked by atropine (muscarinic antagonist)

  • Clinical uses include management of hypotensive states and termination (by vagal reflex) of paroxysmal atrial tachycardia (adenosine or other agents may be preferable)

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) TheMcGraw-Hill Companies, Inc.,1996, pp.216-219.

α₂ Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists

Introduction

• α₂ selective adrenergic agonists are used to treat essential hypertension.

• Their mechanism of action involves:

  • (1) activation of central α₂ adrenergic receptors at cardiovascular control centers

  • (2) this central activation decreases sympathetic outflow thereby reducing sympathetic vascular tone and blood pressure.

   

• Clonidine (Catapres):

  • Clonidine (Catapres) is primarily used in treating essential hypertension.

  • A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.

  • This response is due to α₂ selective adrenergic receptor activation.

  • Adverse Effects:

    • dry mouth

    • sedation

    • sexual dysfuction

  • Clonidine's α₂ selective adrenergic receptor activation of vascular smooth muscle may increase blood pressure in patients with severe autonomic dysfunction with profound orthostatic hypotension (in these patients the reduction of central sympathetic outflow in not clinically important.

   

• Guanabenz Wytensin)

  • Guanabenz (Wytensin)is primarily used in treating essential hypertension.

  • A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.

  • This response is due to a₂ selective adrenergic receptor activation.

  • Adverse Effects:

    • dry mouth

    • sedation

• Guanfacine

  • Guanfacine is used for treating essential hypertension.

  •  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.

  • This response is due to a₂ selective adrenergic receptor activation. a₂ receptor selectivity is greater than that observed with clonidine despite similar efficacy in treating hypertension.

  • Adverse Effects:

    • dry mouth

    • sedation

     

• α-methyl DOPA-- (methyldopa (Aldomet))

  • α-methyl DOPA (methyldopa (Aldomet)), metabolically converted to α-methyl norepinephrine, is used for treating essential hypertension.

  • A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.

  • This response is due to a₂ selective adrenergic receptor activation.

  • Adverse Effects:

    • dry mouth

    • sedation

     

• Amphetamine

  • CNS stimulant (releasing biogenic nerve terminal amines):

    • respiratory center

    • mood elevation

    • decreased perception of fatigue

  • Other effects: headache, palpitations, dysphoria

    • Appetite suppression

    • Weight loss due to decrease food intake

    • psychological tolerance/dependence

  • Indirect acting sympathomimetic

  •  Toxicity:

    • CNS: restlessness, tremor, irritablity, insomnia, aggressiveness, anxiety, panic, suicidal ideation, etc.

    • Cardiovascular: arrhythmias, hypertension or hypotension, angina

    • GI: dry mouth, anorexia, vomiting, diarrhea, cramping

    • Treatment:

      • urinary acidification by ammonium chloride

      • hypertension: nitroprusside or α adrenergic receptor antagonist

      • CNS: sedative-hypnotic drugs

  • Therapeutic Use:

    • Narcolepsy

    • Obesity

    • Attention-deficit hyperactivity disorder

     

• Methylphenidate (Ritalin)

  • Mild CNS stimulant, chemically related to amphetamine

  • Effects more prevalent on mental than motor activities

  • General pharmacological profile similar to amphetamine

  • Major Therapeutic Use:

    • Narcolepsy

    • Attention-deficit hyperactivity disorder

• Ephedrine

  • α and ß adrenergic receptor agonist

  • Indirect sympathomimetic also, promoting norepinephrine release

  • non-catechol structure, orally active

  • Pharmacological effects:

    • increases heart rate, cardiac output

    • usually increases blood pressure

    • may cause uriniary hesitancy due to stimulation of a smooth muscle receptors in bladder base.

    • bronchodilation: ß adrenergic receptor response

  • Limited Clinical Use due to better pharmacological alternatives (asthma, heart block, CNS stimulation)

   

• Vasoconstrictors for Nasal Mucosal Membranes and for the Eye

  • propylhexedrine

  • naphazoline (Privine)

  • tetrahydrozoline (Visine)

  • oxymetazoline (Afrin)

  • phenylpropanolamine (Propagest)

  • pseudoephedrine (Sudafed)

  • ethylnorepinephrine (Brokephrine)

  • xylometzoline (Otrivin)

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) TheMcGraw-Hill Companies, Inc.,1996, pp.216-219

Amphetamine & related drugs

•  use (very limited) as appetite suppressant with high abuse potential

•  Fenfluramine: appetite suppressant; cardiotoxic (withdrawn from market)

• Methylphenidate (Ritalin) similar but with fewer peripheral effects, useful in Attention Deficit Disorder

.

Drug Lists