Sympathomimetics 6, 7 & 8 Flashcards
What is a monoamine?
Has one amino group connected to aromatic ring by a two carbon chain.
What are examples of monoamines?
Serotonin, dopamine, norepinephrine, epinephrine and histamine
What is a catecholamine?
Monoamine with catechol group.
What are examples of catecholamines?
Norepinephrine, dopamine and epinephrine
Where are catecholamines synthesized come from?
L-tyrosine
What is the rate limiting step for catecholamine synthesis?
The enzyme tyrosine hydroxylase which will make L-tyrosine a catecholamine.
Where is norepinephrine made?
Presynaptic vesicle
Where is epinephrine made?
adrenal medulla by an enzyme found in the kidneys called Phenylethanolamine N-methyltransferase
What are the functional groups of the catecholamine that allow it to bind to the adrenergic receptor?
Catechol, Beta hydroxyl and amine group.
At physiological pH, NE and E are 98% ionized
Of the beta receptors which are the major and minor ones?
Major are B1 and B2.
Minor is B3.
What is the difference between direct acting and indirect acting sympathomimetic agents?
Direct acting bind to the adrenergic receptor and show activity.
-alpha and beta agonist
Indirect acting don’t bind to the adrenergic receptor or show binding.
-amphetamines (releasers) and cocaine (reuptake inhibitors)
What is alpha 1 activity?
Gq - excitatory
Vasoconstriction when activated.
Causes pupillary dilation, midriasis.
Ejaculation
Inhibit urination and GI
What is alpha 2 activity?
Gi/o - inhibitory
Vasoconstriction when activated
Prejunctionally inhibits NE release
In CNS decreases CV SNS input
What is beta 1 activity?
Gs - stimulatory
activation causes cardiac stimulation
Secretion of renin, produced from aldosterone due to decreased salt or low Blood Volume which will help regulate BP.
What is beta 2 activity?
Gs- stimulatory
activation causes cardiac stimulation
Bronchodilation
Relaxation of uterine
GI inhibition
Vasodilation
What receptor activity does NE have?
A1, B1 and A2
can’t bind B2 due to lack of methyl that epinephrine has.
What receptor activity does E have?
A1 + A2, B1 + B2
will favor Beta receptor over alpha
What happens as you add more methyl groups to the amine R1 group?
Receptor selectivity switches from alpha 1 to beta 2.
MAO activity also decreases.
What happens when you modify the catechol ring?
Normal catechol results in beta over alpha selectivity.
Making the 2 hydroxyl groups in the meta position results in B2 selectivity NO COMT
Adding a meta methyl to a hydroxyl group results in B2 selectivity NO COMT
Only meta hydroxyl group results in A1 selectivity.
What is important to know about NE?
Not orally available due to COMT quick metabolism. Parenteral
Can bind A1 (vasoconstriction leads to high BP) A2 and B1 (cardiac stimulation increase force and conduction) as agonist
Used as pressor (treat hypotension)
What is important to know about E?
Binds all 4 adrenergic receptors
A1: (vasoconstriction leads to high BP)
B1: (cardiac stimulation increase force, rate and conduction)
B2: (vasodilation leading to fall in blood pressure and bronoconstrction)
Substrate for MAO and COMT
Many dosage forms.
Used in anaphylaxis with local anesthetics
What is the action and clinical use of E?
Low [] effects B1 and B2
High [] effects a1 predominant
Clinical: acute anaphylaxis and cardiac effect with local anesthetics due to vasoconstriction.
What does NE look like for the heart rate and BP
Increase in BP
Increase in HR
What does E look like for the heart rate and BP
BP remains
Increase in HR
What is important to know about dopamine?
Low dose:
-D1 agonist (vasodilation in renal, mesenteric and coronary arteries increasing blood flow)
-B1 agonist (Cardiac stimulation by increasing force, rate and conduction)
High dose:
-A1 agonist (vasoconstriction leading to increase in BP)
-B1 agonist (Cardiac stimulation leading to increased force, rate and conduction)
What is different about dopamine?
There is no chiral carbon due to lack of Beta hydroxyl group.
Rapid metabolism.
EX: Fenoldopam selective D1 agonist for severe HTN
-vasodilator which will lower HTN
What is the mixed B1, A1 agonist?
Dobutamine (Dobutrex)
Metabolized by COMT but not MAO
B1 agonist - cardiac stimulation leads to increased force, rate and conduction
A1 agonist - vasoconstriction leads to increased BP
Where are A1 receptors found?
Vascular smooth muscle, GI smooth muscle, Intestinal smooth muscle, heart and liver. VASOCONSTRICTION.
Gq is stimulatory mobilizing Ca++ and activating PKC
What are A1 agonist drugs manipulated for?
Nasal decongestant.
Vascular failure in shock and tachycardia
What are A1 antagonist drugs manipulated for?
Hypertension
Benign prostatic hyperplasia
Pheochromocytoma
What are the direct A1 agonist?
Phenylephrine (Neosynephrine)
Methoxamine (Vasoxyl)
Oxymetazoline (Visine)
What should you know about Phenylephrine?
Direct A1 agonist.
Missing hydroxyl group - A1 selective now
Clinical:
Nasal decongestant
Mydriasis without cycloplegia (ciliary paralysis)
Pressor (increase BP) indirect
Vasoconstriction in regional anesthesia
MAO but no COMT
What is the problem with Phenylephrine?
Has high first pass metabolism and broken down in the liver before reaching blood. Does Not reach site of action. No more effective than placebo.
What is important about the imidazoline A1 agonist?
Imidazoline has resonance stability allowing the positive charge to spread over 3 atoms. This makes these molecule more basic (higher pka) than regular aliphatic amines
Partial agonist!
What are the 2-alkyl imidazolines ?
Naphazoline (Privine)
Tetrahydrozoline (Visine)
Oxymetazoline (Afrin, Visine)
Local administration to promote vasoconstriction
-Nasal and ophthalmic decongestants
What should you know about the A2 adrenergic receptor?
Gi/o - inhibitory (inhibit sympathetic activity)
-Inhibit adenylyl cyclase
-activate potassium channels
-inhibit calcium channels
-decrease cAMP
Found presynaptically and function as autoreceptors to inhibit sympathetic output.
-decreased neurotransmitter release
What are A2 receptor agonist manipulated for?
HTN
Pain
Glaucoma
How do A2 agonist reduce BP?
They reduce sympathetic output from the brain.
A2 found on brain stem (cardiovascular control center)
Inhibit NE release, decreasing HR, contractility, renin release and decrease vasoconstriction
What is important about clonidine?
Has imidazoline ring so it can bind to A1.
-dichlorophenyl ring
less charged so CNS access
Many dosage forms
Use: HTN, opiate withdrawal and ADHD
What are the side effects of clonidine?
Hypotension, sedation, dry mouth
Where are B1 receptors found?
Heart
Increases force of contraction
Increases HR
Increases conduction velocity in AV node
Kidney
Increases renin release
Agonist:
For shock and congestive heart failure
Antagonist:
For HTN, angina, arrhythmias, CHF
Where are B2 receptors found?
Smooth muscle
relaxation, especially bronchial smooth muscle
Vasodilation
Agonist
-asthma and premature labor
Antagonist
-Glaucoma (very few)
Where are B3 receptors found?
Urinary bladder
relaxation and prevention of urination
Agonist:
overactive bladder
