Adrenergic agents- 9 Flashcards
Fight verse flight
allows you to predict changes based upon what is or is not necessary for “survival”.
Essential function- enhanced by sympathetic input.
Unnecessary function- shut down by sympathetic input.
In most cases parasympathetic control is the opposite of sympathetic control.
Sympathetic responses- more detail
pic pg.2
Adrenergic agents
drugs that mimic or enhance the actions of endogenous catecholamines EP or NE.
Direct acting agents- activate adrenergic receptors (alpha 1, 2, beta 1, 2 agonists).
Indirect acting agents- cause receptor activation by indirect means, but exert no direct receptor actions (catecholamine transport inhibitors, monoamine oxidase inhibitors)
Adrenolytic agents
drugs that block (attenuate) actions of EP/NE.
Adrenoceptor blockers- adrenergic receptor antagonists.
Adrenergic neuron blockers- have non-receptor actions (reserpine).
Teminology
EP and NE and the adrenergic receptors that mediate their actions are located in CNS and ANS. Sometimes these drugs are referred to as sympathomimetic or sympatholytic- this is misleading because they don’t act selectively on ANS. Terms adrenergic and adrenolytic are more appropriate.
Two types of adrenergic receptors
Alpha adrenergic receptors- alpha 1 and 2.
Beta adrenergic receptors- beta 1 and 2.
Relative affinities of endogenous catecholamines at adrenergic receptor types
Epinephrine- best at beta 1 and 2, good at alpha 1 and 2.
Norepinephrine- best at alpha 1 and 2, medium at beta 1.
Dopamine- best at beta 1, no others.
Alpha 1 and 2 agents- location
present in visceral organs as well as the CNS.
Alpha 1 coupled to phospholipase C.
Alpha 2 coupled to adenyl cyclase.
Subtype-selective drugs have distinct therapeutic applications.
Agonist- Phenylephrine (mixed), Xylazine (alpha 2).
Antagonist- Phentolamine (mixed), Prazosin (alpha 1), Yohimbine (alpha 2).
Beta 1 and 2 agents- location
present in visceral organs as well as the CNS.
Beta 1 mainly in heart.
Beta 2 non-cardiac tissues.
Both increase cAMP. Subtype-selective drugs have multiple therapeutic applications.
Agonist- isopreoterenol (mixed), dobutamine (B1), terbutaline (B2).
Antagonist- propranolol (mixed), atenolol (B1).
Cardiac tissues (response to sympathetic stim)
effects of EP and NE are mediated primarily by B1 receptors in cardiac tissues. Sympathetic stimulation all aspects of cardiac function.
Sinoatrial node- increase rate.
Ventricles (myocytes) atria- increase contractility.
A-V node tissue/ Atria & ventricles- increased conduction velocity.
Cardiac responses to B1 receptor stimulation
response to sympathetic stim
via G-protein mediated activation of adenyl cyclase with increased production of intracellular cAMP.
B1 activation increases the rate of depolarization in pacemaker cells of the SA node (increase inactivation of K channels). Catecholamines also increase myocardial O2 use and increase the risk of arrhythmias.
Blood vessels (response to sympathetic stim)
primary target is vascular smooth muscle cell. While the overall response is typically a pressor response, perfusion within different vascular beds may be increased or decreased. Responses are mediated by opposing actions of alpha and beta receptors.
A1= contraction- inc. resistance.
B2=relaxation- dec. resistance.
Alpha effect predominates in most tissue.
Cardiovascular actions of norepinephrine
response to sympathetic stim
A1 stimulation= increase pressure.
mAChR stimulation= decreased HR
Cardiovascular actions of isoproterenol
response to sympathetic stim
B1 stimulation= increase HR, increase systolic.
B2 stimulation= decreased diastolic (vasodilation).
Cardiovascular actions of epinephrine- low dose
response to sympathetic stim
B1 stimulation= increased HR.
B1 +- A1 stimulation= maybe systolic, increase CO.
B2 stimulation= decreased diastolic (vasodilation).
Cardiovascular actions of epinephrine- high dose
response to sympathetic stim
B1 stimulation= increased HR.
B1 + A1 stimulation= increased systolic (inc. CO + vasoconstriction).
A1 stimulation= increased diastolic (vasoconstriction).
Epinephrine “reversal”
response to sympathetic stim
situation in which the normal pressure effect of epinephrine is reversed in the presence of an A1 receptor antagonist. Can produce profound hypotension.
Acepromazine maleate (PROMACE)
CNS depressent, used as a tranquilizer. Acts as a antagonist at A1 adrenergic recceptors, including VSM.
Administration of acepromazine causes a modest to large decrease in mean arterial pressure.
Hypotension can occur after rapid IV injection causing cardiovascular collapse.
Phenylephrine
a postsynaptic alpha receptor stimulator with strong peripheral vasoconstrictive action, used as a second line treatment for equine hypotension. Infusion by effect. Ophthalmic solution- treatment of horner’s syndrome.
Human product.
Eye (response to sympathetic stim)
A1- contracts radial muscle= mydriasis (pupil dilation). Indirectly opposed by parasympathetic- induced contraction of sphincter muscle.
B2- relaxes ciliary muscle= flattening of lens. Directly opposed by parasympathetics.
Lungs (response to sympathetic stim)
major effect is relaxation of bronchial smooth muscle via B2 receptor activation. Regulation of bronchial glandular secretions is species-dependent and variable.
B2= enhanced secretion.
A1= reduced secretion.
Gastrointestinal tract (response to sympathetic stim)
generally inhibited by increased sympathetic tone.
B1or2- reduced motility and secretion.
A1- constricts sphincters.
NE can directly inhibit ACh release from parasympathetic terminals- mediated by presynaptic receptors.
Urinary bladder (response to sympathetic stim)
complimentary effects lead to reduced urination.
B1- relaxes fundus (smooth muscle).
A1- constricts spincter.
Sweat glands (response to sympathetic stim)
with the exception of horses, sympathetic postganglionic neurons are atypical insofar as they are cholinergic.
Release ACh onto mSChR.
Dogs exhibit localized sweating in foot pads.
Horses exhibit “adrenergic sweating”.
Endogenous catecholamines
catecholamines are synthesized in sequential steps within a singular biosynthetic pathway. Different neurons synthesize and release DA, NE, or EP preferentially. Sympathetic neurons release NE and EP. Many CNS neurons release DA.
3 naturally occurring agents are used therapeutically.
Chemical properties of catecholamine agents
all contain a catechol ring.
Readily oxidized in room air (turns colors). Many adrenergic drugs are NOT catecholamines. DA, EP, NE are natural catechols, isoproterneol is synthetic.
Phenylephrine is NOT a catecholamine.
General PK properties of catecholamines
not well absorbed from the GI tract nor from SC injection- so give IV. Typically rapid onset and short duration of action due to efficient inactivation processes.
Uptake- active process mediated by CATS, isoproterenol is not a substrate, inhibited by many drugs (cocaine, ketamine).
Enzymatic degradation- monoamine oxidase (MAO) enzymes, catechol-o-methyltransferase (COMT).
Therapeutic uses of alpha adrenergic agonists
Maintain blood pressure: “pressor agents”, EP, NE and phenylephrine most common. Used to reverse hypotension from many causes. Caution to hypovolemic shock or generalized sympathetic discharge.
Reduce localized bleeding: topical EP is used most frequently. Most effective for damage to small vessels, minor abrasions, ect.
Nasal decongestants.
Emetic effect: in cats.
Catecholamine formulations
Epinephrine: available in solutions and suspensions, supplied in single use ampules or multi-dose vials.
Norepinephrine:
Isopreterenol: human product, parenteral solution is 1mg/5ml ampule, also available as an oral elixir.
Dopamine: human product, parenteral solution is 200mg/5ml.
Phenylephrine (neosynephrine)
mixed alpha 1 and 2 adrenergic agonist. Primarily used for its acute pressor action, especially for management of acute shock. Human formations only, IM or IV. Synthetic drug (non-catecholamine) with prolonged action- IM (10-15 min delay with 1 hr duration).
Eliminated by hepatic metabolism & CAT.
Adverse effects: bradycardia, CNS stuff.
Contraindications: patients with severe hypertension or V tachycardia.
Acute treatment of cardiac failure
therapeutic uses of B-adrenergic agonists
used to treat ventricular bradyarrhythmias, B1 activation -> inc. conduction velocity. Temporary treatment of atrio-ventricular block- dobutamine is drug of choice, isopreterenol is limited. Contraindicated in congestive heart failure- inc. O2 consumption.
Respiratory difficulty and bronchial asthma
therapeutic uses of B-adrenergic agonists
B2 receptor stimulation is used for short term therapy of bronchitis, respiratory distress and bronchial asthma- B2 relaxes bronchial smooth muscle. Commonly used drugs administered via different routes: EP- IM, IV. terbutaline- IM, inhalation. Clenbuterol (horses)- prohibited in food animals.
Allergic or hypersensitivity reactions
therapeutic uses of B-adrenergic agonists
EP is the drug of choice for acute treatments. It is a physiological antagonist of histamine and certain other autacoids in key tissues- bronchial SM in lungs and vascular SM in blood vessels.
Delay parturition
therapeutic uses of B-adrenergic agonists
B2 agonists relax uterine smooth muscle and can dely or prevent premature delivery. Tocolytic effect (horses, cows, sheep).
Isoproterenol (ISUPREL)
non-selective beta agonist. Parenteral 1mg/5ml. No oral formulations- IV only. Administered by short IV infusions primarily for cardiac stimulation. Undergoes rapid hepatic elimination in most species. Human product.
Terbutaline (BRETHINE)
prototype B2 selective agonist. Parenteral and oral formulas. Given BID (cats) or TID (dogs) for acute asthma. Intradermal sweat test in horses with possible anhydrosis -> ARCI class 3 agent.
Pre-existing level of sympathetic activity
Relaxed patient- low sympathetic tone. Less effect by adrenergic blocker.
Excited patient- high sympathetic tone. Large effect by adrenergic blocker.
Acute reduction in BP
therapeutic uses of A adrenergic antagonists
Blockade of A1 receptors causes VSM relaxation.
Essential hypertension, vasospasm, pheochromocytoma.
Urinary tract disorders
therapeutic uses of A adrenergic antagonists
Relaxes urethral smooth muscle. Urethral obstruction (cats), detrusor sphincter dyssynergia.
Reversal of xylazine-induced depression
therapeutic uses of A adrenergic antagonists
Reversal agents. Involved action on CNS A2 receptors. Can also be used for other A2 agonists- yohimbine and atipamezole are drugs of choice.
phenoxybenzamine (DIBENZYLINE)
Compound product. Alpha adrenergic antagonist. Noncompetitive mixed alpha antagonist. Administered orally or IV. Little PK imformation.
Yohimbine (YOBINE)
Alpha adrenergic antagonist. Older A2 selective blocker. Natural plant alkaloid. Less selective. Crosses BBB.
Atopamezole (ANTISEDAN)
Alpha adrenergic antagonist. Very selective alpha 2 blocker. Injectable is 5mg/ml. Used as reversal agent for medetomidine and xylazine. Crosses BBB.
Common side effects of alpha blockers
mostly due to blackade of A1 receptors.
Postural hypotension, GI irritability, nasal stuffiness, impotence, sedation and depression (CNS).
Therapeutic uses of B adrenergic antagonists
related to cardiac B1 effects- antiarrhythmic, adjuvant for heart failure, obstruction cardiomyopathy, hyperthroidism.
Long term control of systemic hypertension.
Contraindications- associated with B2 bloackade (asthma, diabetes)
Propranolol (Inderal)
non-selective beta blocker (B 1 and 2). Primary use is as anti-arrhythmic agent (class 2). Human formulations only. Must be withdrawn gradually after long-term use.
ADME- good oral absorption- but high first pass. Elimination by hepatic metabolism.
Adverse effects- bradycardia and hypotension, CNS depression.
Contraindications- heart failure and sinus bradycardia, bronchospastic lung disease.
Atenolol (tenormin)
selective beta 1 blocker. Human formulations only. Primary use is as anti-arrhythmic agent 2- cardioprotective in cats with hyperthyroidism or hypertrophic cardiomyopathy, Must be withdrawn gradually after long term use.
Esmolol (Brevibloc, Miniblock)
ultra short acting beta 1 blocker (T1/2=10 min in dogs). Administered IV. Metabolized by plasma esterases.
Adrenergic receptor mediated control of VSM
A1 receptor= vasoconstriction.
B2 receptor= vasodilation.
