Block 1 Lecture 6 -- Adrenergics Flashcards
Describe NT affinity for alpha receptors.
EPI ~ NE»_space; ISO
Describe NT affinity for beta receptors.
ISO > EPI > NE
Where are alpha1 receptors located?
vascular, glandular smooth muscle
Where are alpha2 receptors located?
presynaptic nerve terminals
Where are beta1 receptors located?
cardiac muscle
Where are beta2 receptors located?
- vascular, bronchiole smooth muscle
- skeletal muscle
- liver
Where are beta-3 receptors located?
adipose
bladder smooth muscle
What type of GPCR is alpha-1?
Gq
What type of GPCR is alpha-2?
Gi
What type of GPCR are the beta receptors?
Gs
alpha-1 agonists cause:
contraction of vascular and glandular smooth muscle
alpha-2 agonists cause:
decreased NE release from pre-synaptic nerve terminals
beta-1 agonists cause:
increased HR + FOC in cardiac muscle
beta-2 agonists cause:
- relaxation of vascular and bronchiole smooth muscle
- glycogenolysis in skeletal muscle
- glycogenolysis + gluconeogenesis in the liver
beta-3 agonsits cause:
- lipolysis in adipose
- - relaxation of bladder smooth muscle
What do G-alpha-s GPCRs do?
activate adenylyl cyclase
- ++ cAMP
- ++ Ca
- ++ PKA, phosphorylation
What do G-alpha-i GPCRs do?
inhibits adenylyl cyclase
- (–) cAMP
- (++) K efflux
- (–) Ca channels
What do G-alpha-q GPCRs do?
activates PLC-beta
- PIP2 –> IP3 + DAG
- IP3 causes Ca release from ER into cytosol
- DAG activates PKC
What are the G protein receptor subtypes?
alpha-s
alpha-i
alpha-q
What do sympatholytics do?
block synthesis of catecholamines
What is the class and MoA of carbidopa?
Sympatholytic
- inhibits DOPA-decarboxylase in the periphery (prevents L-DOPA dose wasting)
- does not cross BBB (DA does not x either, but L-DOPA does)
What do sympathomimetic drugs do?
increase the activity of the SNS
How do indirect-acting sympathomimetics have effect?
increase [NT] in cleft
1) reuptake transporter inhibitors
2) block catabolism (MAOIs)
3) increase presynaptic NE and DA release
How does Atomoxetine work?
indirect-acting sympathomimetic (reuptake blocker)
- NET blocker
- nonstimulant for ADHD
How does Methylphenidate work?
- indirect-acting sympathomimetic (reuptake blocker)
- - NET, DAT blocker
What makes a drug a stimulant?
blocking DAT (increasing DA)
How does Phentermine work?
indirect-acting sympathomimetic
- increases NE/DA release
- appetite-modulatory hypothalamic effect
When is Phentermine used?
short-term obesity treatment (less than 1 mo.)
– Topiramate added due to subjective evidence of weight loss in epileptics
What are ADRs of Phentermine?
1) HTN
2) tachycardia
3) palpitations
4) H/A
5) insomnia
What are C/Is of Phentermine?
1) HTN
2) CVD
3) hyperthyroidism
4) glaucoma
5) MAOIs
6) drug abusers
How does amphetamine work?
indirect-acting sympathomimetic
- increases presynaptic DA/NE release
- reverses DAT by acting on VMAT to increase cytoplasmic DA
- D-amphetamine also weak MAOI
What is amphetamine used for?
ADHD
narcolepsy
short-term appetite suppression
How does modafinil work?
same as amphetamines…
indirect-acting sympathomimetic
– increases presynaptic DA/NE release
– reverses DAT by acting on VMAT to increase cytoplasmic DA
– more selective for DA neurons in HT areas
What is modafinil used for?
1) narcolepsy
2) shift-work sleep disorder
others…
MS, cognition, anti-depressant, ADHD, bipolar, meth/cocaine addiction
What are ADRs of modafinil?
dermatological
What is the MoA of pseudoephedrine?
sympathomimetic: indirect + direct agonist
- - displaces NE + DA from vesicles in CNS and PNS
- - direct-acting agonist for alpha/beta adrenergic receptors
- - not degraded by MAO/COMT
What is the half-life of pseudoephedrine relative to NE?
10x longer
What are the effects of pseudoephedrine?
1) relax bronchiole sm
2) vasoconstriction for nasal/pulmonary
3) anorexigenic
4) thermogenesis
5) HR, FOC, TPR
What are ADRs of pseudoephedrine?
1) thermogenic effects worse with exercise
What are C/I’s of pseudoephedrine?
1) CVD/HTN, obesity, MAOIs
2) overuse = HTN crisis, arrhythmias, death
3) hyperthyroidism (increased beta1 receptors…CV thyrotoxicosis)
What is the MoA of phenylephrine?
alpha-1 agonist
- mydriatic (dilation) and nasal decongestant
- 1% nasal, 10% ophth solns
What are other uses of alpha-1 agonists?
1) idiopathic orthostatic hypotension
2) alpha-1 mediated vasoconstriction for surgery (less anesthetic and blood loss)
3) allergy (decreases mediators like histamine)
4) stress incontinence
Describe relative potency of NE and phenylephrine?
Phenylephrine less potent but longer t1/2
What is the MoA of doxazosin/terazosin?
alpha-1 antagonist; 1000x more selective for a1 than a2, but non-selective among a1’s
– decrease TPR by blocking a1a, a1c on vsm
What are uses of doxazosin/terazosin?
BPH
HTN
CHF
pheochromocytoma
What is the MoA of Tamsulosin?
alpha-1 antagonist selective for a1a of trigone muscle in bladder
What are ADRs specific to tamsulosin?
associated with intra-operative floppy iris syndrome during surgery
What are ADRs of alpha-1 antagonists?
1) orthostatic hypotension
2) nocturia
3) stuffy/runny nose
What are C/I’s of alpha-1 antagonists?
prostatic carcinoma
What is the MoA of clonidine?
selective alpha2 agonist
– reduces sympathetic CNS outflow (major) and local sympathetic outflow (minor)
What is clonidine used for?
HTN secondary to increased CNS SNS outflow (withdrawal)
– ADHD (sleep), migraine prophylaxis, neuropathic pain, smoking cessation, PMS, PTSD
What are ADRs of Clonidine?
sedation
hypotension
bradycardia
dry mouth
How is clonidine supplied?
oral or TD patch
How does albuterol work?
beta2 agonist
What is albuterol used for?
acute bronchospasm
- rapid onset, short acting
- over use = status asthmaticus (PD tolerance)
What is the MoA for Mirabegron?
b3 agonist
What are the uses of Mirabegron?
OAB
– especially if comorbid dementia when anticholinergics that cross BBB may be C/I
What are the ADRs of Mirabegron?
increased HR and BP
also very expensive
How is Mirabegron metabolized?
CYP3A4 and CYP2D6
moderate inhibitor of 2D6
How do beta antagonists differ?
1) subtype selectivity
2) ISA (partial agonist?)
3) lipid solubility (x BBB)
4) metabolic pathways
Describe ADME of propranolol
75% lost to 1st pass
90% bound in plasma
t1/2 = 3 hours
How does propranolol work?
beta-blocker (b1/cardioselective)
- competitive antagonist
- no ISA or alpha affinity
How does carvedilol work?
beta-blocker
- competitive antagonist of a1 and b2
- moderate ISA of b1
What are the c/i’s of carvedilol?
asthma
Which beta blockers are nonselective?
propranolol
carvedilol
Which beta blockers are selective?
metoprolol
nebivolol (bystolic)
How does metoprolol work?
selective b1 beta blocker
- no ISA
- big 1st pack
- best for asthma pts
What is uptake 1?
presynaptic/primary
What is uptake 2?
postsynaptic/astrocytic – secondary
What are Uptake 1 transporters?
- NET, DAT, SERT (NE transporter, DA transporter, Serotonin transporter)
- MAO
What are uptake 2 transporters?
COMT
Describe NT affinity for uptake 1 vs uptake 2?
Uptake 1 = NE
Uptake 2 = Epi
Where is MAO expressed?
- presynaptic terminals
- astrocytes
- gut lining
Where is COMT expressed?
- pre- and post-synaptic
- astrocytes
- periphery
What NTs are broken down by MAO-A?
NE, Epi, 5-HT
tyramine
Where is NE synthesized in the CNS?
locus coeruleus
What is tyramine?
a toxic dietary substance if absorbed with MAOI
- found in fermented cheeses, etc.
- broken down by MAO
What NTs are broken down by MAO-B?
It’s more selective for DA
In what disease might MAOB-I’s be used?
PD
What is one counseling point for MAO-AI’s?
dietary restrictions! (tyramine)
What are MAO-AI’s used for?
depression
How do drugs that increase NE/DA presynaptic release work? (mechanisms)
1) alter VMAT fx (reverse direction)
2) displace NE from synaptic vesicles
3) reverse NET/DAT
What class of drug is yohimbine?
a2 antagonist
What are LABAs used for?
asthma (not acute) in conjunction with an inhaled steroid
What drugs has an increase in sudden death been correlated to?
LABAs
only when used for asthma; no issues for COPD
What are the uses of beta blockers?
1) HTN, angina, arrhythmias, MI, CHF
2) hyperthyroidism
3) migraine prophylaxis
4) acute panic attack/stage fright
What are ADRs of beta antagonists?
1) bradycardia
2) pulmonary airway resistance
3) cold extremities, rash (vasodilation)
4) hypoglycemia
5) weight gain
6) CNS: fatigue, insomnia, depression, nightmares, fever
7) rebound hypersensitivity
What are the effects of rebound hypersensitivity from b-blocker?
HTN, angina, MI, fatal arrhythmias
