1

Where are all the adrenoceptors?

EYE

Mydriasis - contracts pupillary and radia dilator muscles (1)

HEART

SA Node - HR (1 > 2)

Atria - contractility and conduction velocity (1, 2)

AV Node - conduction velocity (1, 2)

His-Purkinje fibers - contractility and conduction velocity (1,2)

Ventricles - contractility, conduction velocity, (1, 2)

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Where are all the adrenoceptors?

LUNG Bronchial Smooth Muscle - Relaxation, airway diameter (2)

Bronchiole glands - secretion (1); secretion (2)

URINARY Detrusor muscle - contractility, relaxation (2)

Bladder sphincter (trigone) - tone, closure (1)

GI GI tract (general) - tone and motility (gastric, intestinal) (1,2; () )

GI sphincters - tone, contraction (1)

GI secretions - secretions; 2 can secretions

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Where are all the adrenoceptors?

BLOOD VESSELS

Skeletal Muscles - 1 = constriction; 2 = strong vasodilation

Skin and mucosa - 1,2 = constriction

Abdominal Cavity - 1,2 = constriction; = dilation in liver

Salivary glands - 1,2 = constriction

Renal - 1,2 = constriction

ReproductiveUTERUS

Contraction = 1 (pregnancy); 2 = relaxation (ritodrine)

Penis

Ejaculation =

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Where are all the adrenoceptors?

• LIVER

Glucose (Gluconeogenesis) via 1,2

Glucose (Glycogenolysis) via 1,2

• PANCREAS

Insulin release via Beta cells (2)

• LIPOLYSIS

TG levels via 2,1,2

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In recent years ephedra products have been extensively promoted to aid weight loss, enhance sports performance, and increase energy.

But FDA has determined that ephedra presents an unreasonable risk of illness or injury. It has been linked to significant adverse health effects, including heart attack and stroke. From http://www.fda.gov

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DIRECT-ACTING ADRENERGIC AGONISTSPhenylephrine*Direct-acting adrenergic agent that primarily binds to alpha receptors and favors alpha1.

*Not a catechol derivative

Physiological effects:Raises systolic and diastolic blood pressures byVasoconstriction (nasal decongestant, and in opthalmic solutions for mydriasis)

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DIRECT-ACTING ADRENERGIC AGONISTSTerbutaline*Direct-acting adrenergic agent that primarily binds to beta2 receptors.

*Not a catechol derivative

Physiological effects:BronchodilatorReduce uterine contractions in premature labor

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DIRECT-ACTING ADRENERGIC AGONISTSAlbuterol*Direct-acting adrenergic agent that primarily binds to beta2 receptors.

*Not a catechol derivative

Physiological effects:Bronchodilator

Widely used as an inhalant to relieve bronchospasm.

Compliments of Byron Yoburn, Ph.D. 9

AntagonistsOverview

• Basic pharmacology of alpha blockers• Basic pharmacology of ß blockers• Clinical uses• Discussion is focused on autonomic and

peripheral effects

You should know the profile of effects that occur from using alpha, ß and ß specific blockers

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Adrenoreceptor Antagonists

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Alpha Blockers• Reversible • Phentolamine, tolazoline, prazosin, labetolol*

(*=beta-blocking too)– duration of action is typically related to kinetics

– What would concentration-effect curve for an alpha agonist look like in the absence (A) or presence of increasing concentrations (B, C) of a reversible antagonist ?

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Alpha Blockers• Irreversible/noncompetitive– Phenoxybenzamine

• binds covalently to alpha receptors– irreversible blockade of long duration (14-48hr)

– somewhat selective for alpha1

– duration of action is typically independent of kinetics

– the pharmacologic actions of phenoxybenzamine are primarily related to antagonism of alpha-receptor mediated-events.

– Most importantly, phenoxybenzamine attenuates catecholamine-induced vasoconstriction (pheochromocytoma).

– Low bioavailability/ side effects? Postural hypotension and tachycardia

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Alpha Blockers

Pharmacologic effects• CV are of most interest

– arterial and venous tone are a function of alpha receptor activity, what does this mean for BP and vascular resistance?

– therefore, what is the effect of block? Why reflexive tachycardia?

– What will happen to the pressor response in the presence of an alpha antagonist? (prevent the pressor effects of usual doses of alpha agonists).

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Alpha BlockersPharmacologic effects

– Other effects• nasal stuffiness• Miosis (alpha receptors which play a role in

mydriasis are blocked)• may be used in patients to decrease difficulty in

urination, reduces resistance to flow at the prostate and base of bladder (the bladder base, urethral sphincter and prostate contain alpha receptors that mediate contraction and therefore promote urinary continence when activated)

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Alpha Blockers• Specific Agents

– prazosin, terazosin, doxazosin (competitive antagonists)• useful in hypertension• all tend to have rel selective alpha 1 effects

– tamsulosin (competitive antagonists)• used in prostatic hyperplasia• may have some selectivity for prostatic alpha 1 receptors

– Phentolamine (competitive antagonists)• mostly of experimental and historical interest• blocks alpha 1 and 2, complex effects• also blocks H1 and H2; and 5HT responses

– Phenoxybenzamine• irreversible; somewhat selective for alpha1• also has action at H1, AcH, and 5HT• used primarily for pheochromocytoma

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Alpha BlockersClinical Uses

– Pheochromocytoma– Hypertensive emergency– Chronic Hypertension (typically alpha 1 blockers used)– Peripheral vascular disease (Raynaud’s)– Local vasoconstrictor excess (to reverse local vasoconstrictor effects of

administered drugs, e.g., NE); inadvertent infiltration of agonist into subcutaneous tissue during intended I.v. administration.

– Urinary obstruction: Benign prostatic hyperplasia.– Male sexual dysfunction (local injection, long-term consequences

unclear)

What is orthostatic hypotension? What might it have to do with alpha What is orthostatic hypotension? What might it have to do with alpha blockers??blockers??

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Adrenoreceptor AntagonistsAdrenoreceptor Antagonists• Used for hypertension, arrhythmias, angina and infarction

• Antihypertensive action depends upon:

–Reduced cardiac output–CNS action, reduced sympathetic activity –Reduction of renin release (What’s this??)

• angiotensin produced through action of renin

• angiotensin is a potent pressor agent

Receptors:Receptors:

1 found in heart muscle

2 found in vasculature, bronchi; produces smooth muscle relaxation

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Adrenoreceptor Adrenoreceptor AntagonistsAntagonists

Metoprolol is metabolizedby CYP IID6.

What might that mean?

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ß Blockers

• Kinetics– typically well-absorbed– Bioavailablity varies (see Table 10-2)– typically well-distributed (Vd)– Interestingly clinical effect may extend beyond that

predicted from half-life (Lipid storage?)• Dynamics

– CV, Respiratory tract, eye, metabolic and endocrine• Clinical uses

– hypertension, ischemic heart disease, arrhythmias, glaucoma, hyperthyroidism, headache, anxiety, alcohol withdrawal, CHF

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How does a Beta Blocker alter E action?

This is primarily alphaThis is primarily beta

Blood pressure is still elevatedby epinephrine because vasoconstriction is not blocked.

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ß Blockers• Membrane stabilizing actions

– unrelated to ß effects– some ß blockers have Na+ channel blocking activity– This results in a “anesthetic-like” action

• effect on heart, neurons and skeletal muscle

– unlikely that this effect is important after systemic administration of these drugs, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident.

– This effect is probably not important for the CV actions of these drugs, but should be avoided if the drug is used locally in the eye-- local anasthesia of the cornea is undesirable.

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Beta Blockers Improve Survival

Pederson, NEJM, 1985, 313:1055 in patients post MI

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Drugs with Drugs with Adrenoreceptor AntagonistAdrenoreceptor AntagonistActionAction

• Propanolol**• Metoprolol• Nadolol• Atenolol• Carteolol• Betaxolol• Bisoprolol• Pindolol• Acebutolol• Penbutolol

• Labetolol• Carvedilol• Levobunonol• Celiprolol

** prototype

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AntihypertensivesSympatholytics

ß-blockersSympathetic

Nonselective: Activity• Propranolol no PROTOTYPEPROTOTYPE• Nadolol no• Timolol noSelective (ß1):• Metoprolol no PROTOTYPEPROTOTYPE• Atenolol no• Esmolol noMixed action• Pindolol + ß2 partial agonist• Acebutalol + ß2 partial agonist• Labetolol ß2 stim / ß1 and 1 block• Carvedilol nonselective ß block / 1 block

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ß Blocker Toxicity issues

• Rash, fever (minor;rare)• CNS effects:

– sedation, sleep disturbance, depression (may need to discontinue)• Effects in asthma patients

– beta receptor blockade may precipitate attacks, even in mild asthmatics

• CV issues– reduction in heart function (rate, contractility)– use cautiously in MI and CHF patients

• Discontinuation problems– requires dose tapering; may be due to upregulation of ß R

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ß Blocker Therapeutics

• Arrhythmias– these drugs slow ventricular response rates in atrial flutter and

fibrillation• sotalol has additional antiarrhythmic effects involving ion channel blockade

• Ischemic Heart Disease– these drugs reduce the frequency of anginal episodes– these drugs may reduce the size of myocardial infarctions

• Hypertension– unclear– mechanism may include effects on the heart and blood vessels,

suppression of the renin-angiotensin system and quite possibly effects in the CNS.

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ß Blocker Therapeutics

• Glaucoma

– topical administration (timolol lacks local anesthetic properties)

– inhibition of aqueous humor production mediated by beta-adrenergic receptors on the ciliary epithelium.

• Reduces secretory activity and intraocular pressure

• other beta blockers used to treat glaucoma– betaxolol, carteolol, levobunolol, metipranolol

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ß Blocker Therapeutics

• Hyperthyroidism

– excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart.

– Blockade of adrenergic receptors

– inhibition of the peripheral conversion of thyroxine to triiodothyronine??? Perhaps also contributing to anti-hyperthyroidism action

– propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism)

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ß Blocker Therapeutics

• Neurologic diseases– several studies show a beneficial effect of propranolol in

reducing the frequency and intensity of migraine headache• other beta blockers with this action include:

– metoprolol

– atenolol

– timolol

– nadolol

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ß Blocker Therapeutics

• Cirrhosis– beta receptor antagonists have been found to diminish

portal vein pressure in patients with cirrhosis.

– there is evidence that both propranolol and nadolol decrease the incidence of the first episode of bleeding from esophageal varices and decrease the mortality rate associated with bleeding in patients with cirrhosis.

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ß Blocker: Propranolol

• Nonselective -antagonist• Therapeutic Effects

– Lowers blood pressure by decreasing cardiac output

– Diminish intraocular pressure in glaucoma (decreased aqueous humor secretion)

– Effective in reducing migrane episodes (may block catecholamine-induced vasodilation in the brain vasculature.

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ß Blocker: Propranolol

• Therapeutic Effects (continued)– Angina pectoris (decreases the oxygen

requirements of heart muscle); does not allow for strenous exercise– tennis

– Myocardial infarction (propranolol has a protective effect on the myocardium– patients appear to be protected against a 2nd heart attack)

– Hyperthyroidism• Effective at blunting the widespread stimulation that

occurs in hypothyroidism

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ß Blocker: Adverse Effects

• Adverse effects– Bronchoconstriction (beta2 is blocked;

contraindicated in patients with obstructive pulmonary disease).

– Arrhythmias (DRUG MUST BE TAPERED OFF GRADUALLY)

– Impaired sexual functioning in men (mechanism unclear)

– Altered metabolism (impaired glycogenolysis and decreased glucagon sectrion– fasting hypoglycemia)

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ß Blocker: Adverse Effects

• Drug InteractionsInhibitors of propranolol metabolism

cimetidine (inhibitor of gastric acid secretion)furosemide (diuretic)

chlorpromazine (anti-schizophrenia)

Inducers of propranolol metabolismbarbituratesphenytoinrifampin