Adrenergic Drugs Flashcards
Synthesis of NT in Adrenergic nerve terminal
- tyrpsine is actively transported into nerve endings
- is converted into DOPA by tyrosine hydroxyls (Rate-limiting step)
- DOPA is converted to dopamine by DOPA decarboxylase
- DA is metabolized to NE via Dopamine beta decarboxylase
- NE is taken up & stored in granules; NE not stored in granules is called the mobile pool–this can be inactivated by MAO
During depolarization, Ca2+ enters the presynaptic terminal via the voltage-dependent Ca channels–>degranulation of storage vesicles–>NE released via exocytosis into synaptic junction
Actions:
- NE can activate pre junctional receptors = alpha 2 receptors (feedback regulation system–>inhibition of further release)
- can activate postsynaptic receptors (alpha 1 & beta 1-3 receptors)
Termination of NE action
- mainly by reuptake (via NET= NE transporter)
2. Diffusion away from receptor site with eventual metal by catechol-o-methyl transferase (COMT) in plasma or liver
MAO inhibitors
increase the pre junctional levels of NE
Displacers
indirect acting sympathomimetics displace the stored NE
uptake inhibitors
indirect actinv sympathomimetics inhibit the uptake into nerve cell–>increases post junctional levels/actions of NE
alpha 2 receptor
pre-synaptic autoreceptor
coupled to G2–>inhibition of adenyl cyclase–>decrease cAMP
D1 receptors
activates adenyl cyclase–>increases cAMP
alpha 1 receptors
coupled to Gq–>stimulates PLC–>activates IP3 & DAG pathway
beta receptors
coupled to Gs–>activation of adenyl cyclase–>increased cAMP
Things that affect PVR
alpha 1: vasoconstriction–>increase TPR–>Increase BP
beta 2: vasodilation–>decrease TPR–>decrease diastolic BP
alpha 1 receptor locations & actions
- most vascular smooth muscle–>vasoconstriction–> Increase TPR & Increase BP
- Pupillary dilator muscle–>contraction–>dilates pupil
- Prostate (ductus deferens & seminal vesicles)–> contraction–>ejaculation
alpha 2 receptor locations & actions
- postsynaptic CNS adrenoceptors–>probably multiple
- presynaptic nerve terminals–>inhibition of NT release–> decrease sympathetic outflow
- some vascular smooth muscle (nasal mucosa)–> nasal decongestion
- fat cells–> inhibition of lipolysis
beta 1 receptor locations & actions
- heart–> increase F & rate of contraction
2. juxtaglomerular cells–> increase renin release
beta 2 receptor locations & actions
- bronchial relaxation–>bronchodilation
- uterine relaxation
- vascular bed in skeletal muscle
vasodilation–>decrease TPR
- skeletal muscle–>promotes K uptake
- human liver–>activates glycogenolysis
- increase pancreas insulin secretion
beta 3 receptor locations & actions
Fat cells–>activates lipolysis
D1 receptor locations & actions
dilates renal bv
D2 receptor locations & actions
nerve endings–> modulates NT release
Indirect agonist types:
- act via displacement of stored catecholamines from adrenergic nerve ending
ex) amphetamine & tyramine - act via inhibition of repute of catecholamines already released
ex) cocaine & TCAs
some drugs may have direct & indirect actions
Indirect acting adrenergic agonists
- tyramine
- amphetamine
- ephedrine*
- metaraminol*
1-4 increase release of NE - cocaine (blocks reuptake
Nonspecific Adrenergic Agonists
- NE: a1=a2, B1»B2
- Epi: a1=a2=b1=b2
- Dopamine: D1=D2>B1»a
- Ephedrine: a1=a2=b1=b2
a1=a2=b1=b2
Epi & Ephedrine
alpha 1 agonists
- phenylephrine
- methoxamine
- metaraminol
alpha 2 agonists
clonidine
non-specific beta agonists
isoproterenol; B1=B2
beta 1 agonists
dobutamine
beta 2 agonists
- terbutaline*
- albuterol*
- metaproterenol
- ritodrine*
NE
non-specific adrenergic agonist: a1=a2; B1»B2
Fendolopam
D1 agonist
Adrenergic effect on BV
a1 –>
B2–>
a1–> increases arterial resistance
b2–>promote sm relaxation–>decrease arterial resistance
skin & splanchnic vessels have predominantly alpha receptors & constrict in the presence of Epi & NE
Adrenergic effect on Heart
- direct effects via B1 receptors–>increased Ca influx into cardiac cells = Pacemaker activity increased (+ chronotropic effect)
- conduction velocity in AV node increased
- intrinsic contractility is increased (+ inotropic effect)
Beta & alpha receptors in pancreatic islets
b receptors–>increase insulin secretion
alpha2 receptors–>decrease insulin secretion
Effect of Insulin
- Increased glycogen synthesis: insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; 2. lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood.
+ inotropic effect
intrinsic contractility increased
+ chronotropic effect
pacemaker activity increased
Phenylephrine effect on BP
alpha 1–>increase TPR –> Increase BP
also decreases venous capacitance
this leads to a dose-dependent rise in BP
Stimulation of B1 receptors in heart
increase CO & BP
Affect of stimulation of b2 receptors on BP
decrease peripheral resistance via vasodilation in certain vascular beds
Isoproterenol effect on CO & BP
increase CO; decrease peripheral resistance by activating B2 receptors
lowers BP via B2; raises HR via B1
Phenylephrine effect on BP & HR
raises BP (via alpha 1 receptors) but not HR bc no effect on beta receptors
Epi effect on BP & HR
increases BP & HR
antimuscarinics vs alpha 1 effect on eye
alpha 1–>only mydriasis, no cycloplegia
antimuscarinics–>cycloplegia
increased alertness, reduced fatigue, anorexia, euphoria, insomnia
effect of non-catecholamines (i.e. amphetamines) on CNS
in very high doses: aggressiveness, marked anxiety, convulsions
catecholamines don’t enter CNS
effect of stimulating receptors located on radial pupillary dilator muscle of iris
alpha receptors; stimulation–>mydriasis (dilation)
phenylephrine use
used as mydriatic for retinoscopy
epinephrine use in glaucoma
non-selective agonist used to increase the outflow of aqueous humor via uveocleral veins (obsolete) in treating glaucoma
apraclonidine use
alpha 2 selective agonist used to decrease aqueous secretion in the treatment of glaucoma
brimonidine use
alpha 2 selective agonist used to decrease aqueous secretion in the treatment of glaucoma
timolol
beta antagonist used to treat glaucoma: decrease the production of aqueous humor
(affects beta receptors in ciliary body)
beta 2 receptor stimulation in bronchial smooth muscle:
effect & use
bronchodilation; used to treat bronchial asthma
Adrenergic affects on Respiratory tract
- decongestant action of adrenoreceptor stimulants (via alpha receptors)
- B2–>bronchodilation of bronchial sm
Adrenergic affects on GU tract
- B2 receptors in uterus–>relaxation; used in premature labor
- alpha1A receptors in bladder base, urethral sphincter & prostate mediate contraction–>promotes urinary continence
- B2 receptors in bladder wall–>relaxation
- alpha receptor activation in ductus deferens, seminal vesicles & prostate –>ejaculation
Epi
- very potent vasoconstrictor & cardiac stimulant
- increase in systolic BP due to positive inotropic (Increase FOC) and chronotropic (Increase HR) effects via B1
- effect on skeletal m bv
low-dose epi which receptors predominate
beta 1, 2
high-dose epi which receptors predominate
alpha 1, 2, b1 no beta 2
EPI affect on skeletal m bv
activates B2 receptors–>dilation–>decrease TPR–>decrease diastolic BP
contributes to increased blood flow during exercise
NE
- more alpha action than beta
- relatively little action on b2
- increase TPR & BP (systolic & diastolic) via alpha 1
- compensatory baroreflex activation–>overcomes direct positive chronotropic (increase HR) effects of NE
- positive inotropic (increase FOC or contractility) effects on heart via B1
Isoproterenol
- very potent beta receptor agonist; little effect on alpha
- chronotropic & inotropic actions
- potent vasodilator (bc activates beta receptors almost exclusively)–>increase in CO assoc w fall in diastolic & MAP
Dopamine
- activates D1 receptors in several vascular beds–> vasodilation
2.
Dobutamine
relatively B1 selective synthetic catecholamine
low doses of dopamine (2-5mcg)
acts primarily on dopaminergic receptors–> increased renal, coronary & cerebral blood flow
infusion rate of dopamine above 5mcg
stimulates beta receptors and increases release of NE–> increase in cardiac contractility
high doses of dopamine (infusion rate between 10-20mcg)
begins to act on alpha receptors–>vasoconstriction
amphetamine
indirect acting CNS stimulant; peripheral actions mediated through release of catecholamines
Sx: stimulant effect on mood
methamphetamine
very similar to amphetamine with a higher ration of central to peripheral action
dextroampheramine aka
adderall
methylphenidate aka
ritalin
ephedrine MOA & use
found in various plants i.e. ma huang; mild stimulant in CNS;
MOA= displaces NE from storage vesicles in presynaptic neurons
pseudoephedrine
aka sudafed; narrows bv–>decreases swelling & congestion
phenylephrine
relatively pure alpha agonist
used as nasal decongestant & mydriatic
xylometazoline & oxymetazoline
direct acting alpha agonists
used as topical decongestants bc promote constriction of nasal mucosa
Clonidine
- receptor type
- use
- side effects
- warnings/special uses
- alpha 2 selective agonist
- used in HTN, diabetic diarrhea, narcotic addicts & to treat benzodiazepam withdrawals
- postural hypotension, dry mouth, sedation, rebound hypertension
- don’t stop treatment abruptly bc withdrawal & rebound hypertension
methyldopa
- receptor type
- use
- side effects
- warnings/special uses
- alpha 2 selective agonis
- used in HTN, diabetic diarrhea, narcotic addicts & to treat benzodiazepam withdrawals; DOC IN PREGNANCY
- postural hypotension, dry mouth, sedation, rebound hypertension
- DOC in pregnancy
apraclonidine
clonidine derivative used in glaucoma
bromonidine
clonidine derivative used in glaucoma
tyramine
normal byproduct of tyrosine metabolism in the body; has similar effect to NE;
found in high concentrations in fermented foods i.e. cheese & smoked/aged fish
when given parenterally–>indirect sympathomimetic action bc of release of stored catecholamines
Clinical: greatly intensified in patients treated with MAOI–> marked increase in BP, so patients on MAOI should be careful eating tyramine-containing foods i.e. smoked/pickled fish & cheese
example of physical antagonism
activated charcoal–>adsorbs
example of chemical antagonism
antacids
bronchospasm, mucous membrane congestion, angioedema & severe hypotension
anaphylaxis
Tx: IM epinephrine .3-.5mg; supplemented by glucocorticoids & antihistamines
anaphylaxis is mediated by
Type 1 immune reaction; IgE-mediated reaction
Tx of acute hypotension
usually of short duration while giving IV fluids
NE, Phenylephrine when vasoconstriction is desired
massive MI can lead to
cardiogenic shock and acute HF;
positive inotropic agents (–>increase FOC) used to avoid this: dopamine or dobutamine
drugs used in emergency management of complete heart block & cardiac arrest
isoproterenol & epi
drugs used to avoid cariogenic shock & acute HF following massive MI
dopamine or dobutamine
modafinil use
new amphetamine substitute used to treat narcolepsy
albuterol uses
beta 2 agonist
used to treat bronchial asthma, premature labor & threatened abortion
salmeterol use
beta 2 agonist used to treat bronchial asthma
phenylephrine use
used for fundus exam
clonidine use
moderate to severe hypertension
epinephrine use
to prolong duration of local anesthetics (i.e. lidocaine) & reduce systemic toxicity
alpha 1 receptor agonist effects on BP & HR
i.e. phenylephrine, methoxamine
increase BP
decrease HR
alpha 2 receptor agonist use
ie clonidine, alpha-methyl dopa
decrease BP, used as anti-hypertensives
beta 1 & beta 2 agonist use
increase HR, SV, CO
ie isoproterenol, dobutamine (b1>b2)
beta 2 agonist use
decrease TPR, bronchodilation
ie salmeterol, albuterol, terbutaline
Dobutamine
beta 1 stimulator
alpha 1 effect in the prostate
contraction of the ductus deferens & seminal vesicles (resulting in ejaculation)
alpha 2 affect on fat cells
inhibition of lipolysis
alpha 2 affect on some vascular smooth muscle cells in the nasal mucosa
nasal decongestion
beta 2 affect on skeleton muscle
promotes K+ uptake
beta 2 affect on the human liver
activates glycogenolysis
increases pancreas insulin secretion
D1 affect on smooth muscle
dilates renal blood vessels
D2 affect on nerve endings
modulates NT release
alpha 1 increases PVR by affecting arterial or venous resistance
ARTERIAL (it increases arterial resistance!!!)
beta 2 affects PVR by?
promotes smooth muscle relaxation–> decreases arterial resistance
beta 1 affects the heart BY
increasing calcium influx into cardiac cells
the skin & splanchnic vessels are predominantly _____ receptors and _____ in the presence of NE & E
- alpha 1 receptors
2. constrict
NE acts best on
alpha 1 = alpha 2 = beta 1; VERY LITTLE effect on beta 2!
_____ receptors result in increased insulin secretion
beta receptors
______ receptors result in decreased insulin secretion
alpha 2
phenylephrine’s effect on BP
phenylephrine = alpha 1 –> increases TPR–> increase BP
it also DECREASES venous capacitance
this leads to a dose-dependent rise in BP
stimulation of beta 1 receptors in the heart–>
increases HR & CO–> increases BP
stimulation of beta 2 receptors in the heart–>
decreased peripheral resistance (via vasodilation in certain vascular beds)
a nonselective agonist like isoproterenol will—>
- increase in CO (by activating beta 1 receptors) but also
2. decreases peripheral resistance by activating beta 2 receptors
phenylephrine use
mydriatic for retinoscopy
epinephrine use
glaucoma bc increases outflow of aqueous humor via uveocleral veins (obsolete)
remember mystics also increase outflow (i.e. pilocarpine, physostigmine, carbechol)
alpha 2 selective agonist examples and uses in treating glaucoma
- apraclonidine & brimonidine
2. decrease aqueous secretion
beta antagonists ie timolol use in treating glaucoma
decrease the production of aqueous humor (affects bet ain ciliary)
useful in premature labor
beta 2 receptors in uterus mediate relaxation
receptors stimulated to promote urinary continence
- alpha 1a: located in bladder base, urethral sphincter & prostate
- beta 1 receptors in the bladder wall also mediate relaxation
receptor in the bladder wall that mediates relaxation and is use??
- beta 2
2. used to promote urinary continence
stimulation of _____ receptor stimulates renin secretion
beta 1
what will happen to systolic & diastolic BP with epinephrine use
- systolic BP increases: vasoconstriction from alpha 1 stimulation
- diastolic BP may decrease: beta 2 receptors in skeletal muscles–> dilation of vessels
remember #2 promotes blood flow to muscles during exercise
High dose of epinepherine
NO beta 2 just alpha 1= alpha 2 = beta 1 –>high dose Epi = NE
low dose epinephrine
beta 1 & beta 2 & alpha 1 & alpha 2; so low dose epinephrine = same beta effects as isoproterenol
how does dopamine affect BP
D1 in vascular beds–> vasodilation
Does methamphetamine has a higher ratio of central or peripheral actions
central
low doses of dopamine (2-5 mug)
act primarily on dopaminergic receptors–>increased renal, coronary and cerebral blood flow
doses of dopamine above 5mcg/min
dopamine stimulates beta receptors and increases release of NE–> increase cardiac contractility
doses of dopamine between 10-20mcg/min
dopamine acts at alpha receptors–>vasoconstriction
