Sympathomimetics, adrenergic blockers, and sympatholytics Flashcards Preview

Neuro > Sympathomimetics, adrenergic blockers, and sympatholytics > Flashcards

Flashcards in Sympathomimetics, adrenergic blockers, and sympatholytics Deck (41)
Loading flashcards...

Steps in norepinephrine (catecholamine) synthesis

-Tyr enters cell and is converted into L-DOPA by tyrosine hydroxyls (TH)
-L-DOPA is converted into dopamine by aromatic acid decarboxylase (AADC)
-Dopamine (DA) is packed into storage/NT vesicles and then converted into norepinephrine (NE) by DA-betahydroxylase (occurs within the vesicles



-Direct acting: combine with the receptors and exert an effect. These do not require an intact nerve, only the receptor
-Indirect acting: drugs that require an intact nerve terminal for an effect to occur (do not directly bind to receptor, but rather alter the synaptic process in some way)


Mechanisms of sympathomimetics

-Some examples of mechanisms: cause release of NT, block NT from being metabolized by monoamine oxidase (MAO inhibitors) or block reuptake by NE transporter (NET inhibitor), or prevents the NT from being packaged by vesicular monoamine transporter (VMAT inhibitor)
-All of these examples (except for the last one) cause an increase of NT in the synapse and thus increase their effect
-The last example depletes the synaptic vesicle of NT and thus diminishes the NTs effect in the synapse


Types of adrenergic receptors

-There are 2 forms of alpha receptors a1 and a2, and three forms of beta receptors b1, b2, and b3 (only care about b1 and b2)
-b3 is found in fat and is activated to begin induce lipolysis
-All b receptos stimulate AC while a2 receptors inhibit AC
-a1 receptors usually activate PLC


a1 stimulation

-a1 receptors found on vasculature smooth muscle everywhere but in skeletal muscle (thats b2)
-Stimulation of a1 by a direct sympathomimetic leads to vasoconstriction of the artery or vein
-Phenylephrine binds specifically to a1 only and causes vessel constriction (increases BP)
-a1 receptors also found in eye and cause pupillary dilation (mydriasis)
-Thus a1 blockers (prazosin for short term, phenoxybezamine for long term) will cause vasodilation of vessels and miosis (pupillary constriction)
-Prazosin is specific to a1, phenoxybenzamine is selective for a1 (but also binds to a2)


a2 stimulation

-a2 receptors are found on the presynaptic terminal, and when activated they inhibit the release of NE
-Direct sympathomimetics on a2 causes reduction of NE release and an inhibition of the sympathetic affect
-Clonidine is an a2 agonist and inhibits the release of NE from adrenergic neurons
-Blocking a2 leads to disinhibition of NE release, increasing NE release


b1 stimulation

-b1 receptors are found in the heart (SA and AV nodes)
-Binding of a direct sympathomimetic to the b1 receptors in the SA node cause tachycardia (positive chronotropic effect)
-Binding to the b1 in AV node increases electrical conduction at the node and in the heart
-Binding of b1 in the heart also leads to a positive inotropic effect (larger force of contractions) in both atria and ventricles
-Dobutamine only binds to b1 receptors (agonist)
-Atenolol and metoprolol inhibit b1 receptors causing brachycardia and hypotension, also inhibits cardiac reflex


b2 stimulation

-These are found in the airway smooth muscle (bronchioles) and in vasculature smooth muscle
-Skeletal muscle vasculature contains mostly only b2, where as all other vasculature contains both a1 and b2
-Binding of direct sympathomimetics to b2 causes dilation of both the bronchioles and skeletal muscle vessels
-Dilation of the skeletal muscle vessels causes a drop in BP
-Albuterol binds specifically to the b2 receptors in the bronchioles and causes bronchodilation
-Propanolol binds to and blocks the b2 receptor (and b1), thus causing bronchocontraction and skeletal muscle vasoconstriction (b2), but also induces bradycardia and hypotension (via decreasing HR and force of contraction; b1) to overall cause decrease in HR/BP and cause bronchoconstriction


Example of effects of a sympathomimetic

-Giving phenylephrine will constrict the vessels everywhere but skeletal muscle (used for nasal decongestant)
-This results in an increased peripheral resistance and thus an increase in diastolic BP
-Increasing diastolic BP in turn increases systolic BP, and the cardiac reflex reacts by decreasing HR
-So we see an increase in diastolic pressure and systolic pressure, and a decrease in HR


Affects of NE on adrenergic receptors 1

-NE binds to a1 and b1 receptors, but not to b2
-Therefore NE increases peripheral resistance and thus diastolic BP (action of a1)
-NE also increases HR and force of contractions, which, along w/ increase in diastolic BP, increases systolic BP (b2)


Affects of NE on adrenergic receptors 2

-Due to the combined effect of increased diastolic BP (a1) and b1 direct effect on systolic BP, the increase in systolic BP is greater than the increase in diastolic BP
-The mean BP is increased
-As the BP increases the cardiac reflex will sense it and increase para output to heart, thus decreasing the HR
-Overall effects of giving NE: increased diastolic and systolic BP, but decreased HR (due to cardiac reflex)



-Binds to and activates b1 and b2 receptors
-The b1 activation increases HR and force of contractions, thus increasing systolic pressure
-The b2 activation causes vasodilation in skeletal muscle, thus greatly decreasing resistance and diastolic BP
-Since the decrease in diastolic BP is larger than the increase in systolic BP, there is a net decrease in mean BP
-The cardiac reflex senses the drop in BP and increases symp output on heart, further increasing HR
-This stimulation, on top of the b1 activation from isoproterenol, leads to a larger and prolonged increase in HR (largest increase of all the drugs, due to help from cardiac reflex)



-Binds to a1, b1, and b2 receptors (has higher affinity for b2 than it does for a1)
-There is both vasoconstriction (a1) and vasodilation (b2), but the vasodilation predominates, so there is a drop in resistance and diastolic BP (this is at low-moderate doses only, when the affinity for b2 matters)
-The b1 affects are to increase systolic BP and HR, but the diastolic BP is decreased about the same amount as the systolic BP is increased so there is very little change in mean BP
-Because of the static mean BP there is no response from the cardiac reflex and the HR remains elevated (due to b1), but not as high as when giving isoproterenol


High doses of epinephrine

-At high doses, the epi will bind more to a1 (more of these receptors than b2) so the vasoconstriction dominates the vasodilation and there is an increase in diastolic BP
-This would result in an increase in the mean BP and a response from the cardiac reflex to decrease HR


Affect of atropine with NE Rx

-NE would still increase diastolic and indirectly systolic BPs (a1) by causing vasoconstriction
-NE would also still increase HR and contraction force, further increasing systolic BP (b1)
-But if we also give atropine (muscarinic blocker) we will prevent the cardiac reflex by blocking the Ach binding to the mAchR
-This eliminates the para input on the heart and the HR is not slowed by the reflex
-Therefore the HR, diastolic and systolic BPs all remain elevated


Indirect acting sympathomimetics

-Either block reuptake of NE by NET (cocaine, amphetamines, tyramine), block metabolism of NE by MAO (MAO inhibitors), or induce the release of NE from the presynaptic neuron (amphetamines, tyramine)
-Reserpine blocks the transport of DA and (recycled) NE into the synaptic vesicle, reducing the availability of NE in the synapse



-Blocks the reuptake of NE and DA from synapse back into presynaptic cell by blocking the NET protein (uptake 1)
-Therefore these accumulate in the synapse and have a stronger effect on the postsynaptic cell
-Cocaine causes mydriasis, tachycardia (b1), elevated BP (a1 and b1), vasoconstriction-induced hyperthermia (b1)



-These also block the NET transport system, but actually do something special to it- they reverse it (also can block MAO)
-Amphetamines (and tyramine) phosphorylate the NET, and allow the transporter to move NE/DA out of the cell into the synapse
-Since there is a higher concentration of NE/DA in the cell, the net effect is an outward flow of the NTs (essentially blocking reuptake)
-Amphetamines also are taken up by synaptic vesicles and displace the NTs, increasing their concentration in the cell
-This process releases NE into the synapse and causes an increase in it's effects
-Drugs used: ephedrine and pseudoephedrine, which cause vasoconstriction (a1) of mucous membranes and reduces congestion



-Metabolic product of tyrosine, in red wine and cheese
-Taken up by the vesicles like amphetamines and displaces the NE
-Its other affects are the same as amphetamines: reverses the NET system and cause release of NE into synapse
-The affects of tyramine, amphetamines, and cocaine are all increased when used in conjunction w/ a MAO
-Therefore ppl on MAOs should avoid wine and cheese



-Blocks VMAT uptake of NE and NA and thus decreases the abundance of these NTs in the synapse


Clinical affects of pseudoephedrine

-Increase in diastolic and systolic BP from a1 (vasoconstriction)
-Increase in HR and systolic BP from from b1 (ino and chronotropic on heart)
-Since there is an increase in BP we expect the cardiac reflex to lower the HR, however the b1 activation on the heart from the drug is too great that it overrides the cardiac reflex
-Thus the HR and BP stay elevated
-If the person is on an MAO the HR and BP would both increase dramatically and stay elevated for a long time b/c you block the breakdown of NE



-Falso neurotransmitters
-Inhibition of NE synthesis
-Block of NET
-Block of VMAT
-Almost all of these (except for blocking VMAT) are no longer used


False neurotransmitter

-Methyl-DA (converted from methyl-DOPA) is taken up into the synaptic vesicles and converted to methyl-NE
-When methyl-NE is released it binds minimally to the a1 receptors, but has high affinity for a2 receptors
-Thus methyl-NE inhibits further release of NE
-Methyl-DA is no longer used
-Clonidine is a drug used that directly activates the a2 receptor thus inhibiting NE release


Inhibition of NE synthesis

-Methyl-tyr inhibits TH so Tyr cannot be converted into L-DOPA
-This effectively stops production of NE
-Methyl-Tyr is no longer used


Block of NET

-Blocking reuptake of NE will partially deplete the vesicles of NE
-Drug is taken up by NET and into the vesicle by VMAT and secreted into the synapse
-Drug has no binding affinity for the adrenergic receptors
-These drugs are no longer used


Block of VMAT

-Only sympatholytic drugs still available (reserpine), but this is rarely used
-Reserpine blocks the transport of all monoamines into the secretory vesicle (NE thats recycled and newly made DA for NE synthesis)
-Empty synaptic vesicles means no excitation of postsynaptic cell upon vesicle release
-Usually pretreat w/ tyramine to deplete the vesicle of NE, then use reserpine to prevent vesicles from bringing in NE/DA


Competitive adrenergic blockers

-Compete with adrenergic agonists for adrenergic receptors
-There is no change in the maximum response to NE, but with a competitive antagonist the dose-response curve is shifted to the right
-This means it takes more drug to get the same effect in the presence of a competitive inhibitor


Non-competitive adrenergic blockers

-These produce a depression of the maximum response w/out a parallel shift to the right
-Non-competitive antagonists bind to a site other than the adrenergic active site, or binds to the active site but binds covalently (and thus cannot be out-competed)


Effects of adrenergic blockers on CV function 1

-The effects of a1 and b1 adrenergic blockers on CV function depends on the sympathetic tone of the person
-When the tone is low (lying down), there is a minimal effect
-When the tone is high (standing up) there is a much greater effect
-The overall effect of an a1 blocker on CV function: when a person is standing and the sympathetic tone to vessels is high, they will constrict and increase BP
-An a1 blocker will prevent this vasoconstriction and decrease BP (to a greater degree than if they were lying down)


Effects of adrenergic blockers on CV function 2

-The cardiac reflex senses the decrease in BP and compensates by increasing the HR
-This HR increase will be to a greater degree for someone who is standing up than for someone who is lying down (because of the greater BP drop for standing up)
-The effect of a b1 blocker will be the same for BP (decrease), and it will decrease HR
-However b1 blockers will inhibit the cardiac reflex when it tries to speed up the HR in response to the decrease in BP
-Therefore you get a large decrease in BP when standing (less of a decrease when lying), and the HR decreases instead of increases

Decks in Neuro Class (62):