Anesthesia Pharmacology Chapter 6:  Autonomic Adrenergic Pharmacology

 

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.

  • Alpha receptor dominate in the cutaneous vascular beds.

    • Norepinephrine and epinephrine cause constriction.

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

  • Both alpha and beta adrenergic receptor are present in skeletal muscle vascular beds.

    • Alpha receptor activation causes vasoconstriction.

    • Beta 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.

  • Alpha 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 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.

• 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 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

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.

• 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.

Metabolic Effects

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

• Insulin secretion: enhanced by ß₂ adrenergic receptor activation

• Glucagon secretion: enhanced by ß adrenergic receptor activation of pancreatic islet alpha cells.

• Glycolysis- stimulated: by ß adrenergic receptor activation

• Free fatty acids, increased: by ß adrenergic receptor activation on adipocytes--activation of triglyceride lipase

• 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

Norepinephrine

• 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

• Potent vasopressor

  • Systolic and diastolic pressure increase

    • pulse pressure widens

  • Norepinephrine (Levophed) increases blood pressure by:

    1. vasoconstriction alpha₁ 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

 

                  Arterioles            

Coronary	alpha1,2; beta 2	constriction;dilatation	constriction
Skin/Mucosa	alpha1,2	constriction	dilatation
Skeletal Muscle	alpha; beta2	constriction,dilatation	dilatation
Cerebral	alpha1	slight constriction	dilatation
Pulmonary	alpha1 , beta2	constriction; dilatation	dilatation
Abdominal viscera	alpha1, beta2	constriction; dilatation	-------
Salivary glands	alpha1,2	constriction	dilatation
Renal	alpha1,2;beta1,2	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) TheMcGraw-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

• Pressor effects of norepinephrine (Levophed) are blocked by alpha-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

  • may be used 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

• 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 results 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)

  •  Cardiogenic and hypovolemic shock

    • by enhancing renal perfusion despite low cardiac output. Oligouria 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: newer drugs

  • 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)

  •  Consequence: Unexpected ventilation depression in patients treated with IV dopamine (Intropin) to enhance myocardial contractility

• Dopexamine

  • Dopexamine--synthetic catecholamine

  • Activation of dopaminergic and beta₂ receptors

  • Slight positive inotropic effect (beta2-adrenergic agonists activity; potentiation those endogenous norepinephrine secondary to reuptake blockade)

  • Dopexamine enhances creatinine clearance

Isoproterenol (Isuprel)

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

• Has limited action at a 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: increased contractility and heart rate.

• Activation of ß₂ - adrenergic receptors: Bronchial and GI smooth muscle relaxation.

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

  Isoproterenol: Limited therapeutic uses:

  • emergency settings to treat heart block or severe bradycardia

  • management of torsades de pointes (a ventricular arrhythmia)

• Isoproterenol (Isuprel) adverse effects:

  • 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

  • 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 low systemic drug concerntration, reducing likelihood of cardioacceleration ( ß₁) or skeletal muscle tremor (ß₂ ).

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

  • ß₂ receptor-mediated relaxation of vascular smooth muscle may be due to cAMP-dependent kinase phosphorylation of myosin light chain kinase (producing an inactive form)

• 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: resistant to COMT (catechol-O-methyl transferase) metabolism

  • Less ß₂ selective compared to terbutaline (Brethine) and albuterol (Ventolin,Proventil).

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

• Terbutaline [Brethine]

  • ß₂ adrenergic receptor-selective: resistant to COMT

  • Active after oral, subcutaneous, or administration by inhalation

  • Rapid onset of action.

  • Used for management of chronic obstructive lung disease and for treatment of acute bronchospasm (smooth muscle bronchoconstriction), including status asthmaticus

  Albuterol [Ventolin]

  • ß₂ adrenergic receptor-selective

  • Effective following inhalation or oral administration.

  • Commonly used in chronic and acute asthma management.

  Ritodrine (Yutopar)

  • ß₂ adrenergic receptor-selective: developed as a uterine relaxant

  • 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-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.

Alpha₁ Selective Adrenergic Agonists

• Alpha₁ selective adrenergic agonists activate a adrenergic receptors in vascular smooth muscle producing vasoconstriction.

  • Peripheral vascular resistance is increased.

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

  • a₁ 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.

• Smooth muscle tone is determined by modulation of myosin light-chain kinase activation.

  • Myosin light-chain kinase phosphorylates myosin--a step that initiates myosin-actin interaction. (by contrast in skeletal or cardiac muscle Ca²⁺ interaction with troponin is central to initiation of muscle contraction)

  • Increases in intracellular Ca²⁺ with Ca²⁺ calmodulin complex formation results in activation of myosin light-chain kinase.

• Alpha₁ receptor activation causes Ca²⁺ influx

• In some cells, α₁ receptor activation causes IP₃ production, which releases sequested Ca²⁺.

• Methoxamine (Vasoxyl)

  • specific alpha₁ receptor agonist

  • increases peripheral resistance

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

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

  • Clinical use:

    • hypotensive states

    • termination (by vagal reflex) of paroxysmal atrial tachycardia (adenosine may be preferable)

Phenylephrine (Neo-Synephrine)

• Specific alpha₁ receptor agonist

• Increases peripheral resistance

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

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

• Clinical use:

  • hypotensive states

  • mydriatic

  • nasal decongestant

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.

alpha₂ Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists

Introduction

• alpha₂ selective adrenergic agonists are used to treat essential hypertension.

• Mechanism of action:

  • activation of central a₂ adrenergic receptors at cardiovascular control centers

  • activation decreases sympathetic outflow, reducing sympathetic vascular tone.

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 a₂ selective adrenergic receptor activation.{Vertebral arterial or intra cisterna magna injection results in hypotension. This experiment demonstrate clonidine central action.}

  Adverse Effects:

  • dry mouth

  • sedation

  • sexual dysfuction

  Clonidine's a₂ 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

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

  • Alpha-methyl DOPA (methyldopa (Aldomet)), metabolically converted to alpha-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 alpha 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

• alpha 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