Sympathomimetics Flashcards
Sympathomimetic
mimics activation of the sympathetic nervous system.
Direct vs indirect acting sympathomimetics
Direct-acting sympathomimetics
- Receptor agonists at alpha or beta adrenergic receptors
Indirect-acting sympathomimetics
- Agents that cause the release of NE
- Agents that block the reuptake of NE
Stuff in the eye
alpha one receptor causes constriction of the radial muscle causing dilation (mydriasis)
Parasympathetic causes contraction of the circular muscle (miosis) and contraction of the ciliary mucsle (accommodation)
adrenoreceptor on bronchial smooth muscle
beta 2 –> relaxation
adrenoreceptors on GI tract
alpha 2, beta 2
Think number 2s when you gotta go number 2.
remember that you’re holding it– this is sympathetic, after all
adrenoreceptors on the urinary bladder
detrusor muscle- beta
trigone/ sphincter- alpha 2
adrenoreceptors on the uterus
alpha 1, beta 2
causes contraction-relaxation
adrenergic receptors for glycogenolysis
skeletal muscle- beta
liver- alpha 1 and beta 1
Think “L-1-ver”
adrenergic receptors for lipolysis
beta 2 and 3 (increase)
adrenergic receptors for renin secretion
beta 1, increases
adrenergic receptor for insulin secretion
alpha 2, beta 2
The 2s. There are 2 “i”s in “insulin”
Rules of thumb for smooth muscle
Alpha1 (a1) Receptors
Stimulate contraction of all smooth muscle
Vascular smooth muscle Vasoconstriction
Glandular smooth muscle
Beta2 (b2) Receptors
Relax smooth muscle (e.g., lungs; arterioles)
Muscarinic Cholinergic Receptors
Contract smooth muscle
Apparent discrepancy – ACh & muscarinic agonists given IV cause vasodilation, due to release of nitric oxide (NO)
Different intracellular signal than a1 receptors
Modes of action for direct, indirect, and mixed-acting agents
Direct Receptor Agonists
directly stimulate receptor
epinephrine, NE, etc.
Indirect Acting Agents
release NE or block reuptake
amphetamines, tyramine
Mixed Acting Agents
both NE release and receptor activation
alpha 1 adrenergic effects
vasoconstriction
contraction of vascular smooth muscle
a1 vasoconstriction a1mydriasis (dilates pupil) contraction of iris radial muscle a1 contraction of spleen a1 contraction of uterus a1 contraction of pilomotor muscle (erects hair) a1 increases force of contraction in heart less important than b1 effect
Metabolic
a1 stimulates glycogenolysis
a2 Adrenergic Effects
CNS
- Postsynaptic receptors –multiple effects
Platelets
- Stimulate platelet aggregation
Nerve terminals
- Adrenergic and cholinergic nerve terminals
- Auto-receptors inhibit neurotransmitter release
Some vascular smooth muscle - contraction
Metabolic
- inhibit insulin release
- Fat cells – inhibit lipolysis
Beta 1 adrenergic effects
b1 Heart stimulation of heart rate - chronotropic effect stimulation of force of contraction - inotropic effect
stimulate renin release
Beta 2 adrenergic effects
Smooth Muscle Relaxation b2
relaxation of bronchioles b2
relaxation of uterus b2
relaxation of vascular smooth muscle b2 (vasodilation, certain vascular beds only)
relaxation of detrusor (bladder) b2
relaxation of intestinal smooth muscle b2
Skeletal Muscle
b2 – stimulates potassium uptake
glycogenolysis in the liver
stimulates insulin release
Beta adrenergic effects: metabolic and hormonal
glycogenolysis b2 (liver)
lipolysis b3 (fat cells)
stimulation of insulin release b2
stimulation of renin release b1
Dopamine Effects
CNS
D1, D2, D3, D4, D5
Essential neurotransmitter in many different neural circuits
*** Renal Afferent Blood Vessels
D1 – Dilation
Increase blood flow to kidney
Nerve Endings
D2 – Modulate neurotransmitter release
mechanism of action for beta and alpha 2 receptors
GDP exchanged to GTP, adenylyl cyclase increases cAMP –> protein kinase, enzymes
alpha-1 receptor signaling
Gq
Phospholipase C–> IP3 –> calcium freed
Rank Order of Potency at Receptors
a1- Epi > NE » Iso Phenylephrine a2- Epi > NE » Iso Clonidine b1- Iso > Epi = NE Dobutamine b2- Iso > Epi >>NE Albuterol b3- Iso = NE > Epi No selective agonist clinically available
Baroreceptor Reflex Control of Heart Rate and Blood Pressure
Beta 1- stimulation of heart rate and force
muscarinic- decrease in heart rate
alpha 1- vasoconstriction
beta 2- vasodilation
Epinephrine and the heart
positive chronotropic effect
positive inotropic effect
increased conduction in atria, A-V nodes & purkinje fibers
increased oxygen consumption
the work of the heart is increased substantially
Epi - Blood Vessels
Epinephrine stimulates both
a1 vasoconstriction
b2 vasodilation
Epinephrine is more potent at b2 than a1
NE = Epi at b1; Epi>NE at a1, Epi»_space;NE at b2 ***
At high doses, a1 vasoconstriction predominates
Distribution and density of a & b receptors differs in different vascular beds
skeletal muscle both b2 and a1 present
dose-dependent vasodilation (b2) or vasoconstriction (a1)
coronaries vasodilation due to both b2 and metabolic
(NO, adenosine)
kidney, skin, mucosa, primarily a1 vasoconstriction
mesenteric beds, both b2 and a1, density varies
cerebral unchanged
pulmonary vasoconstriction a1
Epi - Smooth Muscle
Bronchial relaxation b2 GI-relaxation; slight decrease in muscle tone Bladder relax detrusor b2 contract sphincter a1 Spleen contraction Eye - mydriasis, lowers IOP Uterus - relax (b2)during last month of pregnancy
Epi - Glands
Lacrimation (a1 secretion)
Sweating (palms) and piloerection (a1)
Salivation - scant, mucous secretion
Pancreas - blocks insulin release (a2 inhibit > b2 stimulate)
Epi - Metabolic Effects
Calorigenic effect
Glycogenolysis and gluconeogenesis by liver (a1, b2)
Lipolysis - increased free fatty acids (a1, b1, b2, b3) (a2 inhibit)
Epi - Clinical Uses
Anaphylaxis (drug of choice)
- bronchodilation b2
- vasoconstriction a1
- maintains BP, prevents spread of antigen
- inhibits release of histamine and other allergic mediators from mast cells (b2)
- reduced edema
Epi - Other Uses
Asthma (pediatrics) Racemic Epi delivered by nebulizer is used for bronchodilation Glaucoma – rarely used *** Infiltration with local anesthetics for vasoconstriction to keep anesthetic local Cardiac resuscitation Topical hemostatic arterioles and capillaries ineffective for large blood vessels
Epi - Adverse Effects
Arrythmias
especially with certain gaseous anesthetic agents
Cerebral hemorrhage from elevated blood pressure when given high dose i.v.
Tissue necrosis from vasoconstriction at site of injection
CNS - fear, anxiety, headache
Epi- Contraindications
Hypertension
Shock (hypovolemic) - further compromised blood flow
Hyperthyroidism
Angina pectoris - increases O2 demand
Asthmatics with degenerative heart disease
Norepinephrine (Levophed)
Natural sympathetic and CNS neurotransmitter
Agonist at alpha 1, alpha 2, beta 1 receptors
** very weak (low potency) at beta 2 receptors
Heart:
direct: positive inotropic and chronotropic (1)
indirect: reflex bradycardia (blocked by atropine)
net effect: increase force; decreased rate
slow, forceful heartbeat
Blood vessels: alpha1-mediated vasoconstriction; BP
Norepinephrine administration and side effects
Administration: IV infusion to maintain blood pressure during spinal anesthesia or hypotensive shock.
Side Effects: anxiety, slow forceful heart beat; headache
Isoproternol (Isuprel)
Synthetic catecholamine
** Potent agonist at all beta receptors; no alpha effects
Heart beta 1 increased heart rate and force
Blood vessels:
beta 2 vasodilation in skeletal muscle & mesentery
decreased diastolic BP
increased systolic BP
no change or decreased mean BP
Other isoproternol effects
Smooth muscle: relaxes bronchial and uterine
Metabolic: increases free fatty acids
stimulates insulin release & glycogenolysis
Clinical Uses: can be used (not 1st choice) in cardiac arrest, MI, cardiogenic shock to increase cardiac output
Side Effects: tachycardia, headache, flushing, arrhythmias, anginal pain
Dopamine (Intropin)
Important neurotransmitter in CNS
CNS receptors: D1, D2, D3, D4, D5
Peripheral receptors: D1, beta 1, alpha
Pharmacological effects
blood vessels: *** vasodilates renal and mesenteric (D1 receptors) increase blood flow to kidney
heart: mild increase in rate and force (partial agonist beta 1)
blood vessels: high doses cause vasoconstriction & increased BP (alpha 1)
Dopamine Clinical uses
Cardiogenic Shock
Increases cardiac output and enhances perfusion of kidney
Must monitor BP carefully because higher infusion rate or dose causes vasoconstriction and decreased tissue perfusion
Sometimes used in chronic CHF
Dobutamine (Dobutrex)
Beta 1-selective agonist
actually complicated beta 1 agonist, alpha 1 agonist/antagonist
Clinically mostly 1-effects
positive inotropic & some increase in rate
Cardia output increases
little vascular effect
Clinical Use: MI, CHF, cardiogenic shock
Adverse effects: may increase size of infarct
potential arrhythmias
alpha 1 -Adrenergic Agonists and mixed-acting alpha agonists
= Pressor Agents
Phenylephrine (Neosynephrine) Prototype
Methoxamine (Vasoxyl)
Midodrine (Pro Amatine)
Mixed Acting Alpha agonists
Mephentermine (Wyamine sulfate)
Metaraminol (Aramine)
Phenylephrine
prototype alpha-1 agonist
Effects:
vasoconstriction
increase peripheral resistance; increase BP
increased blood pressure causes reflex bradycardia (blocked by atropine)
Phenylephrine uses
Uses: to maintain BP in hypotensive states
– spinal anesthesia
paroxysmal atrial tachycardia
– induces baroreceptor reflex slowing of rate
Nasal decongestant
Glaucoma: decreases IOP
– deceases aqueous humor production
Infiltration with local anesthetic (usually epi)
beta-2 selective agonists
About 10 -fold more potent for beta 2 over beta 1
primarily greater selectivity for lung over heart
Synthetic agents that are more resistance to metabolism than catecholamines
- longer acting
- some orally effective
Albuterol (Proventil, Ventolin)
relatively selective beta 2 (10x)
** bronchodilation **
used for treated bronchospams in asthma
- aerosol delivery - restricts to lungs, decreases systemic absorption and side effects
- p.o. - sometimes used, more side effects when oral
Side effects:
muscle tremors, tachycardia (1 and reflex), anxiety, restlessness, headache, hypoglycemia, hypokalemia
Other beta2 selective agonists
Metaproterenol (Metaprel, Alupent)
Terbutaline (Brethine)
inhaled, PO or SC - asthma; delay delivery
Isoetharine (generic)
Ritodrine (Yutopar)
i.v.; relax uterine muscle; delay premature delivery
*** Salmeterol (Serevent)
long-acting bronchodilator for nighttime asthma
*** Formoterol (Foradil) – like salmeterol
Bitolterol (Tornalate) - prodrug; asthma
Indirectly Acting Sympathomimetics
Release of NE from nerve terminals results in sympathomimetic effects
- primarily a1 and b1 receptor
Some drugs can both release NE and also directly activate receptors and thus are called mixed-acting sympathomimetics
– notably ephedrine also stimulates b2
Tyramine
Tyramine is found in high levels in certain foods: beer, red wine, cheese.
Normally rapidly degraded by MAO in GI tract and liver
Patients taking MAO inhibitor (for depression) get high level of tyramine
Tyramine displaces NE from nerve terminal - causes hypertensive crisis, MI, stroke.
Cocaine
Cocaine, tricyclic antidepressants (TCAs), and SNRIs competitively block NE reuptake into nerve terminal
NE levels in synapse higher for longer periods
Amphetamines
Mechanism:
cause release of NE from adrenergic nerve endings and inhibit net NE reuptake by competing with NE binding to uptake transporter
result more NE in synapse and at receptor sites for a longer period; i.e., sympathomimetic
*** Relatively hydrophobic and readily enter CNS
Effective orally Less metabolized than catecholamines Effects last for several hours Effects from both peripheral and CNS Many different amphetamines: d and l isomers, dextroamphetamine, methamphetamine [Tradename=Adderal]
related drugs: methylphenidate (Ritalin),
(fenfluramine, phenylpropanolamine, phenmetrazine, diethylpropion, mazindol)
Amphetamines in the CNS
increase NE, DA and 5-HT
increase alertness, decrease fatigue, increase mood
increase amount of work but also number of errors
physical performance improved acutely
rebound fatigue and depression
potential for dependence, schedule II controlled substances
Amphetamines - cardiovascular effects
vasoconstriction, increased heart rate
effects vary with dose and drug
clinical uses of amphetamines
Narcolepsy
ADHD
Obesity
- depress appetite not metabolism; tolerance develops, usefulness is questionable
amphetamine toxicity
acute overdose: signs and symptoms are extensions of therapeutic effects
CNS: restlessness, dizziness, tremor, talkative
Paranoid delusions, panic, psychosis
Cardiovascular: palpitations, headache, arrhythmias, anginal pain, circulatory collapse,
Death, convulsions, coma, cerebral hemorrhage
acidify urine, enhance urinary excretion, give sedative, sodium nitroprusside or alpha-blocker
Ephedrine
Mixed acting agonist (direct and indirect)
direct: Beta-receptor agonist
indirect: releases NE
Not substrate for COMT or MAO
orally active and long-acting
CNS - stimulant
CV - mild increase force and rate, weak vasoconstriction
Lungs - mild bronchodilation
Uses: pressor agent, bronchospasm, nasal decongestant
Nasal Decongestants
Local vasoconstrictors ( agonists)
Vasoconstriction in nasal mucosal edema (runny nose) or in eyedrops redness
rebound congestion a problem with overuse
Found widely in OTC cold & flu medications
** Phenylephrine – main ingredient used in OTC meds
- Pseudoephedrine (Sudafed) (access restricted) ***
Used illegally to synthesize methamphetamine
- Naphazoline
- Tetrahydrozoline (Tyzine, Visine)
- Xylometazoline (Otrivin), Oxymetazoline (Afrin)
