Adrenergic Flashcards
NE synthesis rate limiting step
Tyrosine to DOPA via Tyrosine Hydroxylase
VMAT
Vesicular Monoamine Transporter:
Transports dopamine into vesicle
Which receptor type is primarily associated with autoreceptor feedback
Alpha2 adnrenergic
Autoregulation process
Alpha2 coupled to Gi gprotein, decreases cGMP, decreases calcium, decreased vesicular release
L-DOPA to Dopamine
Dopa decarboxylase
Dopamine to Noradtrenaline
Dopamine beta hydroxylase (DBH)
Noradrenaline to Adrenaline
Phenylethanolamine-N-methyltransferase (PNMT)
NE to Epi
- Some NE diffuses out of vesicle,
- is methylated by PHMT to Epi
- Epi diffuses back into vessicle
Why can’t pt on MAOI have smoked meat, wine, and fermented cheese?
Contains tyramine; A MAO-A inhibitor
Which MAO is more selective and what for?
MAO-B ; Dopamine
Reserpine (Serpasil)
MAO and Use
Blocks VMAT-2
Previously; CNS-dystonias
previously; anti-hypertensive
Carbidopa (Lodosyn)
MOA
Use
Distribution
- Inhibits Dopa Decarboxylase
- Adjunctive PD treatment
- Prevents peripheral conversion of L-Dopa to dopamine
Alpha1
Type
Location
Response
Gq
Vascular Smooth Muscle
Glandular Smooth Muscle
Contraction
Alpha2
Type
Location
Response
Gi
- Presynaptic Nerve Terminals
- Decrease NE release
Beta1
Type
Location
Response
- Gs
- Cardiac Muscle
- Increase HR and FOC
Beta 2
Type
Location
Response
-Gs
-Vascular Smooth Muscle - Relaxation
Bronchiole Smooth Muscle - Relaxation
Skeletal Muscle - Glycogenolysis
Liver -Glycogenolysis and Gluconeogenesis
Beta 3
Type
Location
Response
Gs
Adipose - lipolysis
Bladder SM - Relaxation
Atomoxetine (Strattera)
MOA
Selective NERI;
Indirect Agonism
Methylphenidate (Ritalin)
MAO
NET, DAT inhibitor;
Indirect Agonism;
Stimulant
COMT
Catecol-o-methyltranferase
MAO-A inhibitors consideration,
On-target ADR
MAO-A found in gut, dietary restriction may be necessary
Mechanisms to increase presynaptic release of NE and DA
- Alter VMAT function (direction)
- Displace NE from vessicles
- Reverse ditrection of NET/DAT
Pseudoephedrine MOA
Indirect Agonist + Direct Agonist
a) Displaces vesicles, increases NE/DA presynaptic release in CNS and PNS
b) Direct agonism on both A and B adrenergic receptors
Ephedrine t1/2 compared to NE
10X longer, not a substrate for MAO or COMT
Ephedrine Actions A1 B1 B2 B2/3
A1 - Vasoconstriction, increased TPR, decreased pulmonary secretions
+B1 - Increased FOC
+B2 - Bronchiole SM relaxation
+B2/3 - Thermogenesis
Phentermine (Fastin; Qsymia phentermine/topiramate)
MOA
Increase presynaptic release of NE and DA
Phenteramine ADR
Increased BP, Tachycardia, heart palpitations, HA, insomnia. Any surprises here?
Amphetamine (Dexedrine, Adderol)
MOA
Increases presynaptic release of NE and DA by Reversing direction of DAT
-Also weak inhibitor of MAO
Amphetamine therapeutic use
ADHD, Narcolepsy, short term appetite suppression
Methamphetamine (Desoxyn)
MOA
Meth significance
FDA approved indication
MOA similar to amphetamine,
- Methyl group extends half life
- Narcolepsy
Modafinil (Provigil)
MOA
Similar to amphetamines, more selective for DA (+) Neurons in Wakefullness areas of hypothalamus
Modafinil approved uses
- Shift-work disorder
- Off label: excessive fatigue, anti depressant, adhd, bipolar, militarty
Modafinil ADRs
Rash
Modafinil selling point over methamphetamine
Equivalent wakefulness, no hyperactivity
Phenylephrine
MOA
Selective Alpha-1 Agonist
Phenylephrine Use and PK
Not as potent as NE
Longer t1/2
Nasal decongestant
Phenylephrine 10% opthalmic solution
Mydriatic
Extended use of phenylephrine
rhinitis medicomentosa, “afrin addiction”
Other Alpha-1 agonist uses
- Orthostatic Hypotention
- Surgical bleeding control
- Allergic reaction: decrease secretion of mediators (histamine)
- STRESS INCONTINENCE
Clonidine (Catapres)
MOA
Selective Alpha-2 agonist
Reduces sympathetic outflow @CNS (Locus Ceruleus) and locally
Clonidine most common use
HTN secondary to increased SNS outflow
Alpha-2 agonist common use
HTN secondary to increased SNS outflow
Indirect skeletal muscle relaxant (CNS level)
Alpha - 2 (Clonidine) agonist ADRs
- Anticholinergic - like
- sedation,
- hypotension
Selective Alpha -1 ANTagonist Drugs
Doxazosin (Cardura)
Terazosin
Tamsulosin (Flomax)
Doxazosin Selectivity
1000x higher for Alpha - 1 verses Alpha - 2
Non-selective among blocking A1a, A1b, A1c
Alpha blockers and HTN
Decrease TPR by blockade of A1b and A1c on VSM
Tamsulosin (Flowmax)
Selective for A1a receptors
-Located in the trigone muscle –> relaxation of internal urinary sphincter
Rx for Pt with HTN and BPH
Use non-selective Alpha blocker such as Doxazosin or Terazosin
Rx for pt w/ Orthostatic Hypotension and BPH
Use Tamsulosin (Flowmax) to avoid dangerously low hypotension
What happened with 5alpha reductase inhibitors and BPH
Turned off effects of testosterone, caused ED. ED still an issue after therapy d/c
Alpha1 blocker ADRs
- Orthostatic hypotension
- Nocturia
- Runny nose
A1a and eye surgery
Intra-operative floppy iris syndrome
Tamsulosin only –>A1a
Selective Alpha -2 antagonists
Eg, Yohimbine
Increase sympathetic outflow through a central mechanism
Selective Beta -2 Agonists
Use
Overuse
SYMPTOMATIC treatment of asthma and COPD
Over use - status asthmaticus
–>pharmacodynamic tolerance by down regulation of Beta2
Eg, Beta2 Agonists:
Albuterol (Proventil, Ventolin)
Metaproterenol (Alupent) Concerns
Has some Beta1 affinity –> Cardio ADRs –> Avoid in pt at risk for MI
Why not use Long Acting Beta Agonists alone?
Only treats symptoms. Doesn’t address underlying cause of inflammation
LABA use
12 h half life,
Good for pt w/ problems at night or when exercising
NOT for acute attacks
Mirabegron (Myrbetriq)
MOA
Selective Beta-3 Agonist
Mirabegron effect
Relaxes Detrusor muscle;
Mirabegron Metabolism
CYP3A4 and CYP2D6
Mirabegron ADRs
Increased HR and BP
Mirabegron is 2-3x more expensive than Muscarinic antagonists. Why use Mirabegron?
Preferred for use in pt with comorbid dementia or on cusp of dementia
Muscarinic antagonist inhibit congative function
Pt with stage fright. How to choose a Beta blocker
Choose one that does not cross the BBB.
Beta antagonist therapeutic uses
- Hypertension
- Angina
- Cardiac Arrhythmias
- Ischemic Heart diseases
- Hyperthyroidism
- Prophylaxis for migraine
- Acute panic attack
Beta antagonist Cardio Actions
Reduced HG, FOC, BP
Slowed Conduction at AV
Beta Antagonist ADRs
- Bradycardia
- Increased bronchoconstriction
- Cold extremities
- Hypoglycemia
- Weight Gain
- Fatigue, insomnia, depression, nightmares, fever
Beta Blocker Rebound Hypersensitivity
- HTN
- Angina
- MI
- Fatal Arrhythmias
ISA beta blockers and rebound hypersensitivity
Less common. Partial agonist does not cause upregulation in receptor density
Carvediol (Coreg)
A competative antagonist of alpha1 and beta2 receptors
ISA and partial agonist to Beta1
- Vasodiation
- Contraindicated in asthmatitics
Selective Beta1 ANTagonist
Eg
Metoprolol (Lopressor)
Metoprolol Fun Facts
No ISA
Extensive first pass metabolism
BEST CHOICE FOR ASTHMATICS
But watch out for rebound hypersensitivity
Onobotulinum Toxin Type A (Botox)
Cleaves SNAP-25
Indirect nicotinic and muscarinic receptor antagonist
Rimabotulinum Toxin Type B (Myobloc)
Cleaves VAMP/Synaptobrevin (vesicular associated protein)
Indirectly cause relaxation of skeletal and smooth muscle
Treatments repeated every 2-3 months
Muscarinic Agonists:
Common uses
+Non-obstructive gastrointestinal disorders with immobility
+Non-obstructive urinary bladder disorders with immobility
+Xerostomia
+Miosis: iris constriction
Atropine and Mycetism
In Mushroom poinsoning use Non-selective, competitive mAChr antagonist (Atropine)
mACh Agonist contraindications
\+PUD \+Asthma \+Recovering from MI \+BPH \+PD
mACh ANTagonists:
Common Uses
GI antispasmotic - relaxes GI and decreases secretions
+IBS
+PUD
+Overactive Bladder/Nocturnal enuresis
+Sinus Bradycardia (IV atropine following MI
+Opthamoology - Mydriasis
Additional mAChR Antagonist uses
+Adjunctive therapy in PD
+Asthma: Decreased secretions and slight bronchodilation. Ajunct to Beta2 agonists
+Surgery: decrease secretions
Bethanachol (Urecholine)
MOA
M3 mACh agonist with poor GI absorption –> Slows GI motility and Decreased secretions
Bethanachol uses:
GI/Bladder emptying disorder in Spinal chord injury patients
*Doesn’t cross BBB FYI
Propranolol MOA
Non-selective beta-blocker
Competitive Antagonist (No ISA)
Propranolol use
Anti-hypertensive, anti-arrythmic
