Sympathomimetics I: Receptors and Endogenous Agonists Flashcards
What is purpose of SNS?
- controlling heart rate
- contractility
- blood pressure
- vasomotor tone
- carbohydrate
- fatty acid metabolism
How does stimulation of the SNS occur?
- in response to physical activity
- psychological stress
- allergies
How are drugs used to influence the SNS?
- treatment of hypertension
- shock
- cardiac failure and arrhythmias
- asthma
- emphysema
- allergies and anaphylaxis
What are sympathomimetics?
- compounds that mimic the endogenous catecholamines (norepinephrine, epinephrine, and dopamine)
- from the sympathetic post ganglionic axon terminal
How can you determine effect of a particular sympathomimetic agent?
- action depends on adrenergic receptor subtype expressed by the organ
- know receptor subtypes and characteristics
Know the basic chemical structures of direct acting agonist
see page 2
What is the parent sturcure of sympathmimetics?
- phenylethylamine is the parent structure
- all synthetic dervative have basic core structure
Describe the structure of endogenous neurotransmitters such as NE, Epi, and DA and what is the importance of different substiutents.
- they all have -OH substituents atthe 3 and 4 position of pheny ring;
- lose of these -OH groups = loss of direct receptors activation
- the -OH groups, prevent access to the CNS (polar)
What sturcute is best for activitiy of sympathomimetics?
- 2 carbons between the phenyl ring and the amine= best for activity
What does increasing the size of the alkyl group do to activity?
- increasing the size of the alkyl group on the amine increases activity at the beta receptors
- why Epi has the highest affinity
How does the lack of -OH affect metabolism and duration of action?
- absence of -OH groups stops metabolism by COMT
- loss of direct sympathomimetic activity
- enhance oral availability and duration of actions
what are some example of sympathmimetics that lack -OH?
- amphetamine
- methamphetamine
- ephedrine
- phendimetrazine
What other substitution effect MAO metabolism?
- substitution on alpha carbon prevents metabolism by MAO
What are the rank order of potency for alpha receptors?
epi> NE>> >>Isoproteranol
What are the two alpha receptors activated by therapeutic levels of epi and NE?
alpha 1 & alpha 2
How does the alpha-1 receptor activation impact the vasculature?
its on smooth muscle:
- surrounding arterioles
- supplying the skin
- kidney
- intestinal mucosa
- veins
Ex. activated on arterioles—–> vasoconstriction—->>increase in blood presure
How does alpha 1 receptor activation impact the heart?
- no direct affect on heart;
- reflex bradycardia may occur in response to increased blood pressure
How does alpha 1 receptor activation activate the eye?
the eye-mydriasis (dilation)
How does alpha-1 receptor activation impact the GI tract?
contraction of the sphincters; inhibits movement
How does alpha-1 activation impact the sex organs?
it promotes ejaculation
How does alpha-1 receptor activation impact the urinary tract?
- contraction of the trigone and sphincter
- decreases voiding
How does alpha-1 receptor activation impact secretion?
- it stimulates salivation and sweating
- inhibiting nasal mucous producation (blood vessel constriction)
- stimulation pilerection
How does the alpha-2 receptor activation affect the vasculature?
- activation of post-synaptic alpha 2 receptors on the veins and the arterioles cause contraction of the smooth muscle
How does alpha-2 receptor activation impact the pancreas?
- decreases insulin—-> elevating glucose levels in the blood
How does alpha-2 receptor activation impact the nose?
- decreases mucous secretion
How can presynaptic activation of alpha-2 receptors be considered sympatholytic?
- amount NE release from terminals is lowerd by via inhibitory autoreceptors (an adrenergic neuron)
How can alpha-2 receptor activation also inhibit ACh?
- block ACh via alpha 2 receptors—-> inhibitory heteroreceptor (cholinergic neuron)
What is the rank order of potency for beta receptors?
isoproteranol> Epi>>>>NE
How do the actions of NE compare to Epi on beta receptors?
- NE and Epi stimulate equally
- NE has little effect on beta-2 receptors @ normal doses
What is beta-1 receptor activation on the heart?
- Epi and NE increase the force of myocardial cells and the rate sinoatrial cells
- the rhythm of the contraction:: increasing the rate of relaxation—->shortens systole, fraction in diastole is increased—> increased filling of the ventricles= overall output is increase
- response is followed by reflex bradycardia
How does beta-1 receptor activation impact the kidneys?
- increases renin secretion—> increase of angiotensin—->vasoconstriction
How does activation of beta-1 impact fat cells?
enhance lipolysis
How does beta-2 activation impact vasculature?
- activation of beta-2 receptors (blood vessels supplying the skeletal muscle, liver, and gut )—–> vasodilaiton of vessels—> increased blood flow to regions
What does beta-2 receptor activation impact the lungs?
bronchodilation
How does beta-2 receptor activation impact the GI system?
- lowers frequency and amplitude of contractions
How does beta-2 receptor activation impact the uterus?
decreases the tone and contractions during preganacy
How does beta-2 receptor activation impact the bladder?
relaxes the detrosor muscle
How does beta-2 activation impact the eye?
- elaxes the ciliary muscle (distance vision)
- lowers aqueous humor formation with an increase in outflow
How does activation of beta-2 receptors impact the metabolism?
stimulated glucagon secretion (results in increased glucose output) and an increased in blood glucose, lactic acid and free fatty acid. Activation of lipase (increas in cAMP levels and PKA activation) results in a break down of triglycerides to free fatty caids. In liver cells activation of phosphorylase catalyzes the breakdone of glycogen to glucose.
What is another commerical name for epiephrine?
Adrenaline
What are some names of the form of epinephrine that can be inhaled and what are they used to treat?
1) bronkaid Mist
2) Primatene Mist
3) Asthma Haler
and they are used to treat
1) asthma
2) pulmonary obstructive diseases: bronchospasms, emphysema, and bronchitis
How does epinephrine work?
its a selective beta2 agonist primiarily used in the chronic treatment of asthma.
its has a longer duration of action and minimal cardiac stimulatory effects
What is the mechanism of action for epinephrine in the inhalation form?
it involves the stimulation of beta-2 receptors which results in tralazation of bronchial smooth muscle.
Epi also inhibits the release of mediators from mast cells that produce bronchial constriction
decrease bronchial secretion and this relieves congestion
What are the names of epinephrine in the parenteral form and and is the use?
1) adrenaline
2) EpiPen
3) Sus-phrine
used for emergency treatment of allergic reactions
Drugs of choice:
acute hypotension
cardiac arrest and syncope
ocular surgery
superfical hemorrhage
its short acting (minutes in duration)
What is the mechanism of action of epinephrine in the parenteral form in regards to acute hypotension, cardiac arrest,
activation of alpha-1 receptors: vasoconstriction in the vessels of the skin, mucosa, and vascular beds of the kidney
activation of beta-1 receptors: the heart increase cardiac output
stimulation of beta-1 receptors: on the heart increase cardiac output
activation of beta-1 receptors in the heart: increase in heart rate and force of contraction
activation of B2 receptors: result in dilation of blood vessels supplying the skeletal muscle
What is the correlation between epinephrine and blood presure?
it differs with the dose of epinephrine
What happens to epinephrine when given at low doses?
at low doses decrease peripheral resistance occurs along with a decrease in diastolic pressure and a small increase in the systolic pressure
What are the effects of epinephrine at high doses?
at high doses an increas in peripheral resistance occurs with an elevation in both systolic and diastolic pressure
Compared to…..
the decrease in blood pressure at low doses is a result of greater sensitvity to vasodilating beta-2 receptors than vasoconstricing alpha receptors to the effects of epi at that dose
What is can be epinephrine be given as an adjunct with?
its an adjunct to local anesthetic
How should local anesthetic be dosed?
give local anesthetic with very diluted epinephrine (1:1000,000)
How does local anesthetic and epinephrine work together?
the epinephrine greatly increase the duraton of the local anesthetic
this allows the local anesthetic to remain in the area for a longer period of time to exert an effect; if epinephrine was not present would be absorbed quickly from site of administration and degraded
more important for short acting and intermediate acting local anesthetic such as procaine and lidocaine
What does epinephrine + local anesthetic do at injection?
vasoconstricts blood vessels–at the site of local injection
What is the mechanism of action for epinephrine in allergic recations?
mechanism of action involves the stimulation of beta-2 receptors, resuling in the relaxation of bronchial smooth muscle
epinephrine also inhibits the release of mediators form mast cells that produce bronchial constriction
due to powerful bronchodilator effects, relieves all known histamine or allergic bronchoconstriction
What is the mechanism of action when epinephrine is used for surgical aid and control peripheral resistance?
it activates the alpha-1 receptors to constrict blood vessels of the skin; reduces bleeding in eye surgery via alpha-1 action and mydriasis
What concentration of epinephrine should be used for surgical aid and to control peripheral resistance?
a very diluted soultion (1: 100,000)
What is the diluted epinephrine 1:100,000 also used for?
used in the past as an opthalmic agent to treat open angle glaucoma to increase outflow of aqueous humor and or desensitization of beta-2 receptors
What are the side effects of epinephrine?
tachycardia, hypertension, anxiety fear, tension, headahe and nervousness
What are the contraindication of epinephrine?
most forms of hypertension and most forms of shock
How fast does epinephrine work and how long does it last?
it has a rapid onset of action and brief duration of action–rapid degradation
How can epinephrine be given in emergency situations?
it can be given intravenously, subcutaneously, by endotracheal tube, or by inhalation
Why is oral adminstration of epinephrine not good?
its ineffective-because its inactivated by intestinal enzymes
How is epinephrine metabolized and how does the body get rid of it?
its metabolized by COMT and MAO; only the metabolites are excrited in the urine
What are the drug interactions with epinephrine?
the alpha blockers block the effects of epi
inhalation anesthetic + epi?
increase risk of arrhythmias and sensitization of the myocardium
local anesthetics + epi?
may cut off blood flow to the skin
TCA + Epi?
increase the risk of hypertension and tachycardia (block uptake)
insulin + Epi?
effect of insulin is reduced b/c more glucose is liberated; diabetes may need to increase insulin
Beta-blockers + Epi?
inhibition of Epi’s effects; hypertension could result due to the loss of beta-mediated vasodilation and alpha-1 receptor effects
Cocaine + Epi?
potentiation of cardiovascular effects and potential for hypertensive crisis
Epi + digitalis ?
increased risk for arrhythmias
Epi + ergot derivatives?
hypertension (sertonin agonist-constric vessels)
Xanthines + Epi?
increased CNS stimulation-additive toxic effects
What happens when epinephrine is used too often?
potential for tolerance to develop
Whats another name for norepinephrine?
levophed
what is norepinephrine mostly used for?
its used for restoration of blood pressure in acute hypotensive states
how is norepinephrine administered, how fast does it act, and what is the duration of its action?
its given IV with a rapid onset of action; the duration of action is 1-2 minutes following the end of infusion
In what case would norepinephrine be poorly absorbed?
if its given by SC injection
How is the action of norepinephrine terminated?
it is destroyed in the gut if given orally and it is metabolized by COMT and MAO; reuptake is also possible for termination of action
What is norepinephrine effect on the activation of alpha-1 receptors and how does this impact blood presure ?
lead to vasconstriction, increased blood pressure, and an increase in total peripheral resistance.
Note- NE has little effect at beta-2 receptors which vasodilates skeletal muscle vessels.
therefore increases in blood pressure is higher for NE than Epi
What are some other actions of norepinephrine?
other actions results in reduction in blood flow to the SKM and skin
some decrease in insulin secretion which can result in hyperglycemia
What are the side effects of norepinephrine?
sympathetic effects at other organs
blandhing and sloughing of skin along injected vein (etravasation and produced by extreme vasoconstriction)
irregular heart beat–arhythmias more likely with large dose
reflex slowing of the heart
anxiety and CNS stimulation
What are the conindications with norepinephrine?
1) sympathomimetics
2) local anesthetics
3) TCA
4) beta blockers
5) digitalis
6) ergot alkalodis
7) methyldopa
What is the contraindication of norepinephrine and sympathomimetics?
amphetamines/cocaine-potentiation of NE effects- especially CNS stimulation
What is the contraindication of norepinephrine with local anesthetics?
sensitization of the myocardium to sympathomimetics
What is the contraindication of norepinephrine to TCA?
it potentiates the cardiovascular effects, resulting in tachycardia and arrhythmias
What is the contraindication of beta-blockers with norepinephrine?
blockade of beta mediated therapeutic effects; unopposed alpha-receptor stimulation resulting in hypertension and bradycardia
What is the contraindication of digitalis to norepinephrine?
can cause arrhythmias
What is the contraindication of ergot alkaloids to norepinephrine?
causes hypertension
What is the contraindication of methyldopa to norepinephrine?
enhanced increase in blood pressure
What is dopamine?
its the immediate precursor of NE and Epi
What is the function of dopamine?
it acts centrally in the regulation of movement
How is dompamine administered?
its administered orally- a substrate for both MAO and COMT
What are the effects of distinct receptor subtypes?
effects are mediated by distinct receptor subtypes; at low concentration the primary effect is on D1 receptors which leads to vasodilation
What is dopamine used to treat?
used in the management of states of low cardiac output such as severe congestive heart failure- it dilates renal and splanchnic beds
used to treat cardiogenic and septic shock
What are some related drugs to dopamine?
related drugs include fenoldopam (corlolpam)- selective D1 receptor agonist which is used to lower blood pressure in severe hypertension
dopexamine (dopacard) is a synthetic analog of dopamine with intrinsic activity at both dopamine and beta2 receptors
In what type of patients does dopamine produce favorable hemodynamic actions?
in patients with severe congestive heart failure, sepsis, and shock
What is concept behind reflex bradycardia?
all systems have a set point–if the system deviates it tries to make up for that to return to the poin
What system is the blood presure important to and what is blood pressure?
its very important to the vasculature
blood pressure is cardiac output X total peripheral resistance
What things can sympathomimetics increase? and how does this impact the baroreceptor?
they can increase the cardiac output and the total peripheral resistance;
the increased BP sensed by baroreceptors—-> the baroreceptor signal to the PSNS neurons of the vagus to fire and release ACh into the heart—> the ACh release causes the heart to slow down ande decrease the cardiac output—> decreases the BP
the TPR does not change because the vasculature is not enervated by PSNS
Name the catecholamines and their receptors
1) epinephrine- alpha1 & 2, beta-1 & 2
2) norepinephrine- alpha 1& 2, beta-1
3) isoproterenol- beta 1 & 2
4) dopamine- beta -1
5) dobutamine- beta-1
Name the catecholamines and what are their receptors.
1) phenylepherine- alpha-1
2) clonidine- alpha-1
3) metaproterenol- beta-2 > beta-1
4) terbutaline, ritrodrine, albuterol- beta-2
5) amphetamine- alpha, beta, and central nervous system
6) ephedrine- alpha, beta, and central nervous system
What are the major effects of the alpha-1 receptors?
vasoconstriction; increased PR; increased blood pressure; mydriasis; increased closure of internal bladder sphincter
What are the major effects of alpha 2 recepectors?
inhibition of NE, inhibition of insulin release
What are the major effects of beta-1 receptors?
tachycardia, increased lipolysis, increase myocardial contractility, increase renin release
What are the major effects of beta-2 receptors?
