Autonomic Pharmacology Part II Flashcards
What neurotransmitter is released at target organs in the sympathetic nervous system?
Norepinephrine - activates alpha and beta receptors
or
circulating epinephrine from adrenal gland
All adrenergic receptors are
G protein-coupled receptors that work by activating secondary messengers within the cell
Alpha receptors
Alpha 1 = causes calcium release inside the cell
- Smooth muscle contraction
- Stimulates “tone” on the postsynaptic side
Alpha 2 = presynaptic; inhibits neurotransmitter release
- Works via negative feedback
Beta Receptors
-
Beta 1 = increases HR
- Both beta 1 and 2 are found on the heart but Beta 1 is the most important for HR increase
-
Beta 2 = triggers relaxation of smooth muscles along respiratory tract and certain blood vessels
- found in airways and BV that cause relaxation, particularly BV in skeletal muscles
-
Beta 3 = leads to lipolysis, breakdown of triglycerides in adipocytes (releases energy reserves)
- This is about getting more fuel, this releases more energy into the blood for more movement and fuel the fight or flight response, glucose and adipose mobilization
Dopamine, norepinephrine and epinephrine are all derived from?
Tyrosine
How does the catecholamines differ?
by functional group
How do norepinephrine and epinephrine differ?
Where they are released
NE - sympathetic neurons
Epi - adrenal gland when SNS is activated
Are Ne and Epi equivalent?
Relatively
The exception is that NE has a low potency at beta 2 receptors
Epi activates all alpha and betas; however, NE doesn’t activate beta 2
Draw the diagram showing epinephrine and norepinephrine actions on receptors
Epinephrine: agonist at ALL ANDROGENIC RECEPTORS
- little change in blood pressure due to the fact that it activates a wide range of areas
Norepinephrine: Minimal activity at Beta 2 adrenergic receptors
- Large increase in Blood pressure because it acts on specifically beta 1 receptors
Blood pressure =
cardiac output x vascular resistance (TPR)
Does epinephrine cause a large change in blood pressure?
No, but norepinephrine has a large increase (doesn’t activate Beta 2 for vasodilation)
Enhancing/decreasing sympathetic NS is known as
Increase = sympathomimetic
Decrease = sympatholytic
What are the drug mechanisms?
- Block adrenergic receptors - using antagonist
- Activate adrenergic receptors - using agonists
- Block uptake transporters
- Increase release of neurotransmitters - increase NE
What is known as the prototypical adrenergic agonist since it activates all receptors?
Epinephrine
What are the main effects of SNS activation?
Vasoconstriction in most tissues - alpha 1
Vasodilation in skeletal muscles - Beta 2
Increase HR and contractility - Beta 1
Dilate/relax bronchial smooth muscle - beta 2
Mydriasis - dilate pupil - alpha 1
What system is responsible for attention, arousal, wakefulness, anxiety, memory formation/ retention and vigor?
Noradrenergic system in the brainstem
T/F peripheral norepinephrine and epinephrine can cross the blood-brain barrier
FALSE but many adrenergic drugs do and can regulate brain adrenergic receptors to produce therapeutic or side effects
Cardiac output =
stroke volume x HR
Mean arterial pressure =
cardiac output x total peripheral resistance
Alpha 1 adrenergic agonists are used clinically for
vasoconstriction - increasing TPR (CO goes down to maintain MAP)
mydriasis for eye exam
Alpha 2 adrenergic agonist are used to
reduce blood pressure
location is usually presynaptic; inhibits neurotransmitter release (works via negative feedback)
if vasodilation, TPR goes down; then the CO goes up (SNS activates increasing CO, maintaining MAP)
Phenylephrine
Alpha 1 selective - activation
used as a decongestant
reflex response - decreases SNS and increases PSNS - vagus nerve activity
Reflex bradycardia = reflex that is happening due to vasoconstriction that is occurring
Histamine does what to the body
Blood pressure
Sympathetic nerve activity
Vagus nerve activity
Heart rate
Causes vasodilation
Alpha antagonist - or alpha-blocker would give a similar but milder effect
Blood pressure - decreases BP
Sympathetic nerve activity - increased activity
Vagus nerve activity - decreased activity
Heart rate - increase HR
Reflex tachycardia
Alpha-adrenergic agonists
Major Uses
-
Alpha 1 - selective
- Vasoconstriction
- To cause mydriasis for eye exam
- Alpha 2 - selective: reduce blood pressure
Drugs:
-
Epinephrine
- used as vasoconstriction in combination with local anesthetics (also levonordefrin)
-
Phenylephrine (PE) - another vasoconstrictor
- Alpha 1 - selective - sometimes used as a local vasoconstrictor
- Used as a decongestant - PE is Sudafed
- Causes vasoconstriction in the nose
-
Oxymetazoline
- Somewhat alpha 1 - selective, primarily acts on alpha 1 because it is applied directly to tissue
- Decongestant nasal spray - vasoconstriction
-
Clonidine
- Alpha 2 selective
- Decreases sympathetic outflow, reduces blood pressure
- still in use but not a first line agent
- Sometimes used for hypertension
- used when someone is resistant to other hypertension medication
- Sometimes used for hypertension
Oxymetazoline
somewhat alpha - 1 selective
primarily acts on alpha 1 because it is applied directly to tissue
Decongestant nasal spray - vasoconstriction
Clonidine
Alpha 2 selective
Decreases sympathetic outflow, reduces blood pressure
Prazosin
Alpha 1 selective antagonist
Antihypertensive
Tamsulosin
Alpha 1 selective antagonist
Relaxes prostatic smooth muscle in benign
Prostatic hyperplasia (BPH)
What could be the consequence of an alpha-blocker that is non-selective
Can cause tachycardia by blocking presynaptic alpha 2 receptors
leads to increased NE release which can then stimulate beta receptors
Alpha blocker side effects
Orthostatic hypotension (decreases in BP due to changes in body position - sit to stand, common for people taking alpha blockers)
Reflex tachycardia (less prevalent with alpha-1 selective drugs, drop in TPR and therefore body would try and increase CO)
Nasal congestion (like phenylephrine - opposite of this)
What are the major uses of beta-adrenergic agonists?
Beta 1 - stimulate cardiac output (rarely used)
Beta 2 - relax bronchial smooth muscle (very commonly used) = used primarily in asthma
Which drug works by activating alpha - 1 receptors?
oxymetazoline
Albuterol
Beta 2 selective agonist for acute asthma exacerbations (rescue inhaler)
Short-acting drug, reacts quickly and lasts for a few hours
Salmeterol
Long-acting beta 2 selective agonist used for asthma
lasts for 12-24 hours
Major uses of “beta blockers” = beta adrenergic receptor antagonists
-
Nonselective or beta 1 selective agents
-
Decrease cardiac work (rate, force of contraction)
- Anti-arrhythmic - decrease excitability of the myocytes of the heart
- Antihypertensive (cardiac effect plus reduced renin)
- Anti-angina - reduces the workload of the heart, decreases the O2 requirement of the heart
- Treatment of heart failure
- Decrease intraocular pressure (glaucoma)
-
Decrease cardiac work (rate, force of contraction)
-
Beta 2 - selective: none in clinical use, although nonselective drugs do block beta 2
- causes constriction of the airways, opposite of albuterol inhalers for asthma
Beta-blocker (beta-adrenergic receptor antagonists) major side effects
Related to Beta 1 blockade: hypotension, heart failure
Related to Beta 2 blockade: hypoglycemia, bronchoconstriction
Propranolol
Non-selective beta blockers (-olol)
- Decreased cardiac output by blocking beta 1 receptors in the heart
- May produce bronchoconstriction by blocking beta 2 receptors in the lungs
- contraindicated in asthmatics - inhaler will not work
-
May impair glucose mobilization by blocking Beta 2 receptors in the liver
- impairs recovery from hypoglycemia in diabetics on insulin
-
Inexpensive
- lots of history of use and therefore predictable, commonly used beta blocker
Metoprolol
Beta 1 selective (cardioselective) beta blockers
- Similar usage and effects compared to propranolol
- Avoids bronchoconstriction and hypoglycemia
- Maybe more expensive
Acebutolol
Other beta blockers
- Has intrinsic sympatheticmimetic activity (ISA)
- Functions as partial agonist
-
Avoids bradycardia that occurs in some patients
- this drug still gives heart SNS but also blocks the full agonist effects of EPI and NE, not as strong as an effect as a full beta blocker
- on their own they can act as a weak agonist but can also block the receptor site
Labetalol
other beta blockers
-
Blocks beta 1 , beta 2 and alpha 1
- Neat thing is that this also blocks alpha 1
-
Useful in hypertension
- affects both CO and peripheral resistance and therefore can treat hypertension - not a common drug
Unopposed alpha stimulation
Beta receptors blocked while alpha are being stimulated
Leads to large increase in vascular resistance; reflex bradycardia
This is why the use of EPI is contraindicated for people on beta blockers
How does cocaine act on receptors?
Indirect or mixed acting Sympathomimetics (indirect because they do not directly activate NE) they enhance sympathetic effects - sympathomimetrics
inhibits NET and NE reuptake
NET = NE reuptake terminal raise NE levels in the synapse
How does amphetamine act on receptors?
Enhances NE release and blocks reuptake
How does ephedrine/pseudoephedrine act?
Enhances NE release and has direct agonist activity
Agonist on alpha and beta receptors
Abuse potential is increased in drugs that
readily enter the CNS
block dopamine reuptake
Risk is highest with (direct/indirect) sympathomimetic drugs since adrenergic receptors are non-selectively activated
indirect
Sympathomimetic toxidrome
MATHS
Mydriasis
Agitation, arrhythmia, angia
Tachycardia
Hypertension, hyperthermia
Seizure, sweating
Sympathomimetic drugs should be avoided or used only with extreme caution in individuals with pre-existing cardiovascular disease: such as
hypertension
angina pectoralis (coronary heart disease)
History of myocardial infarction (MI; heart attacks)
Cardiac arrhythmias
