7-30 Sympathomimetics - Physiology Flashcards
Name 5 major catecholamines. What is the prototype catecholamine?
Prototype: Epinephrine (Epi)
Norepinephrine (NE)
Isoproterenol
Dopamine
Dobutamine
What are some major pharmacokinetic features of catecholamines?
Metabolized rapidly
Not effective orally
Do not penetrate CNS readily
What are the direct actions of the drugs that act on catecholamine R?
agonist at alpha and beta adrenergic receptors
What are the indirect actions of the drugs that act on adrenergic receptors?
release norepinephrine from adrenergic nerve endings; i.e. amphetamines, tyramine;
or block norepinephrine reuptake transporter. e.g., cocaine.
What are the mixed actions of a drug that acts on adrenergic receptors?
Mixed Actions: ephedrine; pseudoephedrine – these compounds can release NE and also have direct agonist activity at receptors
Stimulation of alpha adrenergic receptors will result in what 9 effects?
- Constriction of blood vessels a1 (to lesser extent a2)
- mydriasis a1 (contraction of iris radial muscle = pupil dilation)
- contraction of the spleen a1
- contraction of the uterus a1
- constrict sphincter of bladder a1
- glycogenolysis, ‑ liver a1 (relatively weak compared to b2)
- ejaculation, vas deferens a1
- inhibit release of insulin a2
- relaxation of intestinal smooth muscle a2
Stimulation of alpha 1 adrenergic receptors will result in what 7 effects? Which effect is weak? (Yes, it’s repetition, deal with it.)
- Constriction of blood vessels
- Mydriasis (pupil dilation via iris radial mm contracting)
- Contraction of the spleen
- Contraction of the uterus
- Constrict sphincter of the bladder
- glycogenolysis from the liver (weak compared to beta 2)
- Ejaculation (vas deferens)
Stimulation of the alpha 2 adrenergic receptor will result in what 3 effects? Which one is weak?
- Constriction of blood vessels - less than alpha one though
- Inhibits release of insulin
- Relaxation of intestinal smooth mm
Stimulation of beta adrenergic receptors results in what nine effects?
positive inotropic and chronotropic effects on the heart b1
- stimulates release of renin b1
- relaxation of bronchioles b2
- relaxation of the uterus b2
- relaxation of vascular smooth muscle in certain blood vessels (skeletal muscle coronaries, some mesenteric) b2
- metabolic effects (glycogenolysis, b2) (Lipolysis, b3)
- stimulates release of insulin b2
- relaxation of detrusor muscle (bladder) b2
- relaxation of Intestinal smooth muscle b2
Stimulation of the beta 1 adrenergic receptor results in what 2 effects?
Positive inotropic and chronotropic effects on the heart
Stimulates release of renin
(Increases heart rate, heart contractility, BP)
Stimulation of the beta 2 adrenergic receptor results in what 7 effects?
Relaxes 5 things, and makes replenish energy in all your cells:
- Relaxation of bronchioles
- Relaxation of the uterus
- Relaxation of vascular smooth mm in certain blood vessels (skeletal mm, coronaries, some mesenteric)
- Metabolic effects - glycogenolysis (Beta 3 also does lipolysis
- Stimulates release of insulin
- Relaxation of bladder detrussor mm
- Relaxation of intestinal smooth mm
What would be the vasopressor response to a dose of tyramine? Norepinephrine? Why?
(Hint: tyramine is a derivative of tyrosine that acts as a catecholamine releasing agent.)
Both would increase blood pressure via release of norepinephrine onto alpha 1 receptors.
What would be the vasopressor response to a dose of tyramine or norepinephrine after taking cocaine? Why?
Cocaine blocks NET
This prevents any released NE from being taken up, functionally increasing the relative concentration of NE to stimulate alpha 1 receptors and thus increasing BP
Cocaine blocks uptake of tyramine into adrenergic nerve terminal, preventing release of NE and increase in BP
What is the second messenger cascade associated with beta receptors?
GPCR - G stim
Increases adenylyl cyclase, cAMP, enzyme phosphorylation
What is the second messenger cascade associated with alpha 2 receptors?
GPCR - G inhib
Inihibition of adenylyl cyclase
What are the pharmacological effects of epinephrine on the heart?
Heart:
positive chronotropic effect
positive inotropic effect
increased conduction in atria, A‑V nodes and Purkinje fibers
increased oxygen consumption
increased work of the heart
What are the effects of epinephrine on blood vessels?
skeletal muscle (alpha1, and beta2) Epi has greater affinity for beta2, so at low doses Epi activates beta2 causing relaxation; at high doses, alpha1 effect predominates and blood vessels constrict.
coronaries; vasodilation (beta2 and metabolic)
kidney, skin, mucosa; vasoconstriction (alpha1)
cerebral; unchanged
Pulmonary: Vasoconstriction (alpha1)
capacitance vessels; vasoconstriction (alpha1)
What is the effect of a low dose of epinephrine on skeletal mm blood vessels?
Epinephrine has greater affinity for beta 2
- low dose will activate beta 2 receptors and cause relaxation
What is the effect of a high dose of epinephrine on the blood vessels?
Epi binds both alpha 1 and beta 2, but alpha 1 predominates at high doses
causes blood vessel constriction, increased BP
What would happen to BP if you gave someone an alpha blocker and steadily increasing concentration/dose of Epi?
BP would fall and stay at a low level due to max’ed out beta 2 signalling
What is the net effect of a low dose of Epi (10 mcg/mL) on BP?
Slight decrease diastolic pressure
increased systolic pressure
Overall/mean blood pressure should then be the same, maybe slightly increased
What are the effects of epinephrine on smooth muscle?
bronchial; relaxation
gastrointestinal; slight decrease in tone
bladder; relaxation of detrusor beta2 and contraction of sphincter alpha1
spleen; contraction
eye; mydriasis lowers intraocular pressure
uterus; relaxation during last month of pregnancy and at parturition
What are the effects of Epi on glands?
sweat; paracrine glands in palms have a1 adrenoceptors
salivary: secrete amylase and H2O
pancreas; blocks release of insulin (alpha2> beta2 effect).
What are the metabolic effects of Epi?
a) Calorigenic Effect
b) Tremors, skeletal muscle, b2 receptor mediates K+ uptake
What are the pharmacological effects of NE?
Agonist at:
alpha 1
alpha 2
beta 2 - very weak though
What effect (direct and indirect) does NE have on the heart?
direct; positive inotropic and chronotropic effects
indirect: reflex bradycardia (blocked by atropine) - secondary to vasoconstriction
Net effect: positive inotropic and negative chronotropic effects.
What effect does NE have on blood vessels? What receptor does it work through?
Blood Vessels: only an alpha1 effect (no Beta2 effect because of low potency)
Vasoconstriction:
Net Effect on Blood Pressure: always increased
What are the metabolic effects of NE?
alpha1, weak glycogenolysis and beta3, lipolysis
What does isoproterenol do? What receptors does it work on?
Synthetic agent,
Receptor selectivity; agonist at Beta1, Beta2 and Beta3 receptors
What is the effect of isoproterenol on the heart?
Increased HR and force of contraction
What is the effect of isoproterenol on the blood vessels? BP?
Vasodilation of blood vessels in skeletal muscle
BP:
increased systolic
decreased diastolic
no change or slight decrease in mean atrial BP
What is the effect of isoproterenol on smooth muscle?
Relaxes bronchial and uterine smooth muscle
What is the effect of isoproterenol on metabolism? How is this different from Epi?
Increases FFA`s
Effects on blood glucose less than Epi because this agent releases insulin (b2) and thus opposes the b2 effect (glycogenolysis) in the liver.
What effect does dopamine have on adrenergic receptors?
agonist at Beta1 adrenergic and D1 dopaminergic receptors at low and high doses.
higher doses stimulate alpha1 adrenergic receptors which will override the dopaminergic effect.
What effect does dopamine have on the heart?
Mild positive inotropic and chronotropic effects, compared to isoproterenol
What effect does dopamine have on blood vessels?
vasodilation of mesenteric and renal vascular beds (dopamine receptors)
Higher doses stimulate alpha adrenergic receptors and overcome the vasodilatory effects
What can block the effect that dopamine has on blood vessels?
dopamine receptor antagonists
- i.e. chlorpromazine, FYI
What kind of drug is dobutamine? What receptor does it work on?
Selective beta 1 adrenergic agonist
What is the efficacy of dobutamine compared to NE?
dobutamine is partial agonist, NE is full beta 1 agonist
- less efficacious
What are the pharmacological effects of dobutamine?
Pharmacological Effects; Primarily induces mild stimulation of the pump with little vascular effects. Observe a weak positive inotropic effect with lesser positive chronotropic effects
Name 2 alpha adrenergic receptor agonist that are non-catecholamines.
- Phenyephrine - alpha 1 agonist
- Methoxamine - alpha 1 agonist
What is the mechanism of amphetamines?
mainly indirect;
releases NE from adrenergic nerve endings and will inhibit net NE reuptake by competition.
Amphetamines comprise a large group of drugs.
What are the CNS effects of amphetamines?
CNS; stimulation results in increased alertness, confidence, ability to concentrate and a decreased sense of fatigue
What are the cardiovascular effects of amphetamines?
Cardiovascular;
vasoconstriction,
positive inotropic effect
negative chronotropic effect.
Effects are usually small and vary with drugs.
What are the smooth muscle effects of amphetamines?
mild constriction of sphincter of the bladder
What receptors does ephedrine work on?
mixed action - direct beta receptor effects
indirect actions - releases NE
What effect does ephedrine have on the CNS?
Some stimulatory effects
What effects does ephedrine have on the cardiovascular system?
mild positive inotropic effect, heart rate unchanged, weak vasoconstriction
What effects does ephedrine have on the bronchioles?
Bronchioles; sustained but moderate relaxation
What is the main alpha agonist in OTC meds? Why?
Pseudoephedrine was widely used in over-the-counter cough & cold remedies. Now over-the-counter sales restricted in most states because pseudoephedrine can be used to make illegal methamphetamine. Increasing diversion to illegal drug trade forced removal. Now, phenylephrine is the main alpha agonist used in over the counter preparations.
How do nasal decongestants work?
Through alpha 1 vasoconstrictor action
How do you terminate the signal of a SNS nerve that’s releasing NE?
Use NET, or a reuptake pump
- blocking this creates higher levels of NE
- indirect agents - ie cocaine, tricyclic antidepressants
Sympathetic nerves have what little endings?
Boutons, where NTs are released
- different from NMJ, NTs released far away from receptors, which allow NTs to diffuse away for a bit - doesn’t reach blood stream
How can NE be taken up again and metabolized, outside of NET?
With COMT or MOA enzymes
2 degradative enzymes
In the heart, what is the predominant receptor type? What does it affect?
Beta 1
Controls:
rate/chronotropy
contractility/inotropy
Conduction velocity
In the heart, what is the sympathetic response?
Mediated through beta 1
Increases:
rate
contractility
conduction velocity
What is the cholinergic/muscarinic receptor response in the heart?
M2
Decreased rate and conduction velocity
No effect on contractile force
What is the primary adrenergic response in the eye? What receptor is it mediated through?
Mydriasis - pupil dilation via contraction of radial ciliary mm
Mediated through alpha 1 stimulation
What is the effect of cholinergic stimulation to the eye?
Contraction of circular muscle miosis
How is accommodation in the eye accomplished?
Cholinergic stimulation causing contraction of the ciliary muscle producing accommodation for near vision
What is the predominant adrenergic receptor type in the GI tract? Response?
alpha 2
beta 1
decreased response
What is the primary adrenergic response in sphincters in the GI tract?
contraction, mediated via alpha receptors
What is the rule of thumb in regards to alpha 1 receptors?
Stimulates contraction of all smooth muscle
- vascular and glandular smooth muscle
What is the rule of thumb in regards to beta 2 receptors?
Relaxes smooth muscle - lungs, arterioles
Cardiovascular response to isoproterenol is?
Pure beta agonist
increase pulse rate
decreases peripheral vascular resistance
increases systolic pressure, decrease diastolic pressure
Infusion of NE has what physiological effects of the CV system?
potent alpha 1 agonist
peripheral vascular resistance goes way up, vasoconstriction
Mean BP goes up - systolic and diastolic
Heart rate goes down, stimulation of arterial baroreceptors causes stimulation of vagal nerve baroreceptor reflex, causing drop in HR due to vagal nerve stimulation
Epinephrine at a low dose would cause what effects in the CV system?
alpha 1 agonist
Drop in blood pressure, at low levels of Epi BP drops due to beta 2 agonism, vasodilation
Heart contractility stimulated through beta 1, increase in systolic pressure but mean BP doesn’t change, doesn’t stimulate baroreceptor reflex that would decrease heart rate
Why are responses in the CV system so different between NE and Epi?
Different binding of receptors due to methyl group on Epi.
NE - drop in heart rate, increase in BP
Epi - increase in HR, decrease/no change in BP
