Sympathomimetics, adrenergic blockers, and sympatholytics

Question 1

Steps in norepinephrine (catecholamine) synthesis

Answer 1

• 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

Question 2

Sympathomimetics

Answer 2

• 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)

Question 3

Mechanisms of sympathomimetics

Answer 3

• 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

Question 4

Types of adrenergic receptors

Answer 4

• 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

Question 5

a1 stimulation

Answer 5

• 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)

Question 6

a2 stimulation

Answer 6

• 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

Question 7

b1 stimulation

Answer 7

• 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

Question 8

b2 stimulation

Answer 8

• 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

Question 9

Example of effects of a sympathomimetic

Answer 9

• 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

Question 10

Affects of NE on adrenergic receptors 1

Answer 10

• 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)

Question 11

Affects of NE on adrenergic receptors 2

Answer 11

• 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)

Question 12

Isoproterenol

Answer 12

• 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)

Question 13

Epinephrine

Answer 13

• 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

Question 14

High doses of epinephrine

Answer 14

• 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

Question 15

Affect of atropine with NE Rx

Answer 15

• 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

Question 16

Indirect acting sympathomimetics

Answer 16

• 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

Question 17

Cocaine

Answer 17

• 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)

Question 18

Amphetamines

Answer 18

• 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

Question 19

Tyramine

Answer 19

• 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

Question 20

Reserpine

Answer 20

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

Question 21

Clinical affects of pseudoephedrine

Answer 21

• 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

Question 22

Sympatholytics

Answer 22

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

Question 23

False neurotransmitter

Answer 23

• 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

Question 24

Inhibition of NE synthesis

Answer 24

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

Question 25

Block of NET

Answer 25

• 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

Question 26

Block of VMAT

Answer 26

• 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

Question 27

Competitive adrenergic blockers

Answer 27

• 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

Question 28

Non-competitive adrenergic blockers

Answer 28

• 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)

Question 29

Effects of adrenergic blockers on CV function 1

Answer 29

• 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)

Question 30

Effects of adrenergic blockers on CV function 2

Answer 30

• 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

Question 31

Prazosin

Answer 31

• This is a drug that only blocks a1 receptors and causes vasodilation (a1 specific)
• Therefore a side effect is postural hypotension
• This means that depending on the person’s posture (lying down or standing up) they will experience a drop in BP (larger when standing up)

Question 32

Phenoxybenzamine

Answer 32

• Selective a1 blocker but is long-lasting as it binds covalently to the receptors and blocks a1 vasoconstriction
• It also blocks some of the a2 effects, thus disinhibiting the a2 pathway and allowing for more NE secretion
• However the blockage of the a1 effect is so great that the a2 effect is irrelevant
• Overall you get a long-lasting decrease in BP due to vasodilation

Question 33

Phentolamine

Answer 33

• Is a short acting, reversible, non-selective a blocker (blocks both a1 and a2)
• Used to be used to cause erection by vasodilating (by blocking a1-induced vasoconstriction) the vessels in the penis, but no longer used

Question 34

Effects of b blockers

Answer 34

• All b blockers block both the b1 (wanted) and b2 (unwanted) receptors
• The b1 action is wanted since it lowers HR and BP
• The b2 action is unwanted since it constricts the airways (contraindicated in asthma) and skeletal muscle vessels causing an increase in BP

Question 35

b1 selective blockers on the CVS

Answer 35

• b1 selective drugs block b1 receptors much more than they block b2
• Both the chrono and inotropic effects of b1 in the heart are blocked, resulting in a decrease of BP and HR
• This also prevents the cardiac reflex and thus the HR is not elevated in response to the drop in BP
• Atenolol and metoprolol are commonly used b1 selective blockers

Question 36

Rx of a1 blocker after pretreating w/ b1 blocker

Answer 36

• b1 blocker produces a drop in BP and HR, cardiac reflex is inhibited by the b1 blocker
• Once at the new basal HR/BP levels, the a1 blocker is given and the BP drops even more
• The cardiac reflex cannot respond to the further drop in BP by increasing the HR b/c the b1 blockers prevent sympathetic action

Question 37

Broad spectrum (non-specific) b blockers

Answer 37

• Block b1 and b2 with equal potency
• Propanolol is most commonly used
• Blocking b1 effect is to slow HR and decrease BP, prevents cardiac reflex
• Blocking b2 will cause bronchoconstriction and vasoconstriction of skeletal muscle vessels
• This vasoconstriction of skeletal muscle vessels would cause an increase in BP, but the b1 effect on the heart is too great and overrides the b2 effect on BP
• Thus overall you get decrease in BP and HR, and cause bronchoconstriction

Question 38

Differences btwn propanolol and atenolol

Answer 38

• Propanolol blocks b1 and b2 equally, atenolol blocks mostly just b1
• This means that propanolol will decrease HR to the same extent as atenolol (equal blocking of b1 btwn the 2 drugs)
• But propanolol will cause more bronchoconstriction, since it blocks b2 to an equal degree as b1
• Atenolol will cause very little bronchoconstriction b/c very little of the drug blocks b2 receptors

Question 39

Labetolol

Answer 39

• Broad-spectrum (non-specific) b blocker (blocks b1 and b2) and also is an a1 blocker (no effect on a2)
• Therefore, this drug causes a large decrease in BP (b1 + a1 blocking effect), a decrease in HR (b1 effect + inhibiting the cardiac reflex), and bronchoconstriction (b2 effect)
• Used in hypertensive emergencies

Question 40

Rx of adrenergic receptor agonist followed by Rx of propanolol 1

Answer 40

• Since propanolol is a b1 and b2 blocker equally, it will prevent the action of any b1/b2 agonist, however all a1 agonist activity will be intact
• Epinephrine followed by propanolol: epi will activate a1, b1, and b2 receptors, but propanolol will block the b1 and b2 actions leading only to an a1 effect (vasoconstriction, increase BP, mydriasis)
• NE followed by propanolol: NE activates a1 and b1, but propanolol blocks the b1 effect. Thus only the a1 effect is produced and there is vasoconstriction, increase in BP (blockage of the b2 receptor in skeletal muscle vessels to induce vasoconstriction aids in the increase in BP), and mydriasis

Question 41

Rx of adrenergic receptor agonist followed by Rx of propanolol 2

Answer 41

• Isoproterenol followed by propanolol: Isoproterenol activates both b1 and b2 (would decrease BP due to skeletal muscle vessel dilation and increase HR due to cardiac reflex + b1 activity), however both of these effects are blocked by propanolol. Therefore there are no physiologic changes
• Phenylephrine followed by propanolol: phenylephrine activates a1 receptors only, causing an increase in vasoconstriction in the periphery (except skeletal muscle).
• Adding propanolol then does not affect the a1 activation (only blocks b1/b2), but blocking b2 in skeletal muscle leads to more vasoconstriction and thus an increase in BP. When there is combined effect of b2 blockage and a1 activation (overall vasoconstriction and increase in BP), the b1 blockage effect cannot overcome and there is a net increase in BP