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Autonomic Nervous System FAQ's

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General

Question: Are we responsible for trade names of drugs?
Answer: No you will not have to know trade names for the Pharmacology exam. When you begin clinical practice it will be necessary then, so it is a good idea to start seeing both the trade (clinical) and generic names.

Dr. Ishac  | SNS | CV | PNS  | Eye | NMJ |  return to top

Sympathetic nervous system   return to Ishac   return to top

Question: Why is "dry mouth" a side effect of an alpha 2 agonist such as clonidine?
Answer: Salivary glands receive sympathetic innervation (alpha1 & beta-receptors) in addition to cholinergic inneration (muscarinic). Activation of either system will increase secretion. The cholinergic is the more important system. Clonidine acts on the presynaptic alpha2-receptor to decrease NE release and hence decrease secretions from the salivary gland, resulting in dry mouth (very common).

Question: Why do sympathomimetics make you sweaty if sweat glands have muscarinic receptors?
Answer: The Sympathetic NS regulates sweating (see table on page 81) by controlling the function of about five million sweat glands in the body. There are two main types of sweat glands within the body, both regulated by the sympathetic NS:
1. Cholinergic Sweat Glands: Thermoregulatory sweat glands throughout the body but they release ACh and synapse with muscarinic receptors.  2. Adrenergic Sweat Glands: Nervous sweating on palms, soles, and armpits and release NE and synapses with alpha1- (mostly) and some beta2-receptors. A normal rise in body temperature is sensed by the hypothalamic center from which stimuli emanate via sympathetic nerves to the sweat glands, resulting in appropriate sweating (mainly cholinergic sweat glands ie release Ach). This serves to cool the body by the loss of heat resulting from evaporation of the sweat, aided by a cool breeze. During stress or anxiety sweating occurs mainly on palms and armpits (adrenergic sweat glands) through alpha1- and beta2-receptors.

Question: Two questions. (1). Specifically, what kind of interaction is produced when tyramine is in the presence of TCAs?.. Does it produce synergistic effects. (2) Also, on the diagram on page 106, #2 states that Guanethidine displaces NE... wouldnt that counteract Guanethidine's ability to reduce Hypertension? I understand how Guanethidine's prevention of the fusion of the NE containing vesicle with the membrane facillitates the reduction of Hypertension but I dont get how displacing NE from the vessicle would result in the same effect. Afterall, ephedrine is a drug which also displaces NE from storage vesicles but this drug doesn't have any anti-hypertensive effects.
Answer: (1). TCAs block neuronal uptake, the amino acid tyramine acts like amphetamine (displaces NE from storage vesicle), it gains access into the nerve terminal through neuronal uptake. Therefore the response would be decreased in the presence of TCAs. (2). The main action of guanethidine is to prevent fusion of the vesicle and thus inhibit release. The action on NE displacement is a gradual leakage of NE and not the sudden displacement induced by the indirect amines (such as amphetamine). Over time (weeks/months) this leads to depletion of NE stores (similar to reserpine).

Question: What are the pharmacokinetics of levodopa?
Answer: Levodopa competes with certain amino acids and the absorption of levodopa may be impaired in some patients on a high protein diet.
When levodopa is administered orally it is rapidly converted decarboxylated to dopamine in extracerebral tissues so that only a small portion (about 2%) of a given dose is transported unchanged to the central nervous system. Carbidopa reduces the amount of levodopa required to produce a given response by about 75 percent and when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa. Carbidopa inhibits decarboxylation of peripheral levodopa thus decreasing potential side effects. It does not cross the blood-brain barrier and does not affect the metabolism of levodopa within the central nervous system where it needs to get to for Parkinsons treatment.

Question: What is the effect of alpha-antagonists on LDL/HDL?
Answer: Alpha-blockers such as prazosin can decrease LDL/HDL levels ie. lower LDL (bad cholesterol) and increase HDL (good cholesterol). This is not a major effect of prazosin but it is beneficial.

Question: I have a question concerning the actions of guanethidine.  I understand that it blocks the exocytosis of NE containing vesicles.   I also understand that cocaine and the TCAs inhibit pre-synaptic neuronal uptake of NE.  Is it correct that they also block the necessary uptake of guanethidine and thus indirectly block its anti-exocytosis activity.  Is this also the case for the indirect acting sympathomimetics (eg. amphetamines?)  Does this mean that mixing cocaine and amphetamine is a waste of  money?
Answer: Guanethidine has 3 actions 1. It inhibits the release of NE by preventing the storage vesicle from fusing with the membrane 2. It inhibits uptake of NE into the storage vesicle (similar to reserpine) and 3. It inhibits neuronal uptake (by using it and thus compete with other agents). Itís main action is the first point, inhibition of transmitter release. Inhibition of neuronal uptake by cocaine will reduce the effect of guanethidine because guanethidine uses neuronal uptake to get into the nerve terminal. Inhibition of neuronal uptake will also reduce the effect of the indirect amines such as amphetamine. Yes, taking cocaine first, then using amphetamine would be a waste of money.

Question: I understand that some beta blockers (i.e., pindolol possess some beta agonist activity as well. Could you explain why this is beneficial (afterall we need a BLOCKER, correct?).
Answer: Beta-blockers are very useful for a number of conditions (ie. hypertension, angina, etc). However they can have some negative effects ie. supersensitivity, rebound hypertension if suddenly withdrawn, bronchoconstriction. The partial agonist feature was developed to minimize their negative effects.

Question: I have a question about Beta-agonists/antagonists. What are the effects respectively on serum glucose and potassium when administering a Beta agonist? A Beta antagonist?
Answer: The two most important factors involved in the transport of dietary potassium into cells are insulin and beta2-adrenergic stimulation. Insulin stimulates the Na+,K+-ATPase pump, leading to a more rapid rate of potassium entry. Similarly, activation of beta2-adrenergic receptors also promotes potassium movement from plasma into cells. Beta-blockers can inhibit the uptake of K+ into cells (particularly skeletal M.) and can lead to a rise in plasma concentration of potassium (hyperkalemia).

Question: I thought that Reserpine acts by inhibiting the uptake of dopamine into the storage vesicle, and by inhibiting NE reuptake (uptake 1) which would result in a depletion of NE stores.
Answer: Reserpine acts by inhibiting uptake of both DA and NE into the storage vesicle, it does not inhibit neuronal uptake (Uptake 1). Cocaine and TCA's can inhibit neuronal uptake. Reserpine can also cause 'leakage' of NE from the storage vesicle. Over time this and the inhibition of uptake into the vesicle causes depletion of NE stores.

Question: Does tyramine in the presence of MAO inhibitors have two separate actions?  First, tyramine degredation is inhibited therefore tyramine can act as an indirect sympathomimetic.  And second, an otherwise obscure pathway is utilized to produce octamine and subsequently NE.
Answer: Tyramine is rapidly metabolized by MAO. In the presence of MAO inhibitors more NE is synthesized by the normal pathway and some NE is now produced from tyramine (this normally does not occur because of the action of MAO). The storage vesicles now high amounts of stored NE, which is what you want. However if this individual then consumes food rich in tyramine (ie. aged cheese or red wine), then this tyramine is not metabolized by MAO and acts like ampthetamine to cause displacement of NE. Since the vesicles have a large amount of transmitter, a large release occurs. The released NE causes a hypertensive crisis (increase BP and HR).

Question: ISA means that the drug has local anaesthetic activity, does it mean that if you put propranolol on the arm, it's gonna numb the area? How does stabilizing of the membrane has anything to do with local anaesthetic activity?
Answer: ISA refers to Intrinsic sympathomimetic activity (ie. Partial agonist action). This means that the agent in addition to being a beta-receptor antagonist, also has some partial agonist activity (ie. Pindolol). This feature was developed to decrease the downside of the beta-blockers (ie. supersensitivity effects as well as negative effects with asthma and diabetes). Membrane stabilizing properties (also called local anaesthetic activity) is the ability to stabilize excitable tissues (ie cardiac) and not skin. Propranolol has this property. This feature is important in the treatment of arrhythmias to decrease abnormal cardiac contractions.

Question: Your review page says that ejaculation is sympathetically controlled, while erection is parasympathetically controlled...if so, why does an alpha 1 antagonist like phenoxybenzamine cause impotence (inability to maintain an erection)?
Answer: You are correct alpha1-agonists can stimulate ejectulation, whereas alhpa1-antangonists such phenoxybenzamine can inhibit it. This is a peripheral action. The effect on impotence is a centrally mediated action.

Question: What is the mechanism behind respiratory depression with the use of imipramine and amitriptylline (the TCAs) at toxic levels. I'm assuming that it has to do with muscarinic receptor blockade?
Answer: The TCAs inhibit neuronal uptake which is their main mechanism of action. Most of the agents have some muscarinic and alpha-blocking activity. At high toxic doses these actions become prominent ie. Antimuscarinic effects: tachycardia, constipation, urinary retention, blurred vision, dry mouth; Alpha-blocking effects: hypotension, postural hypotension. At higher doses such as seen during suicides, coma and respiratory depression occur through blockade of CNS muscarinic receptors.

Question: A question about the selective beta 2 agonists, terbutaline, etc. Please elaborate on the adverse effects of these drugs. Can you elaborate on why there are the cardiovascular side effects.
Answer: Terbutaline is a beta2-agonist. It can activate the beta2-receptors in the vasculature to cause vasodilation. Beta2-receptors are present in the myocardium (see Table 1), activation of these will increase the HR. Bronchodilation is the desired effect, any other action is an adverse effect. Adverse effects will be greater if taken orally compared to inhalation. Also drug selectivity is a relative term and terbutaline can activate beta1-receptors at a higher dose.

Question: How do alpha 2 agonists cause impotence?
Answer: The effect of clonidine on impotence is a centrally mediated action and occurs in about 4% of patients. The mechanism of action is not known. Impotence and loss of libido can also occur with alpha-methyl dopa but to a lesser extent.
Alpha1-agonists can directly stimulate ejectulation, whereas alpha1-antangonists such phenoxybenzamine can inhibit it. This is a peripheral action.

Question: Can you explain the interaction between beta-receptor antagonists and potassium levels?
Answer:
The two most important factors involved in the transport of dietary potassium into cells are insulin and beta2-adrenergic stimulation. Insulin stimulates the Na+,K+-ATPase pump, leading to a more rapid rate of potassium entry. Similarly, activation of beta2-adrenergic receptors also promotes potassium movement from plasma into cells. Beta-blockers can inhibit the uptake of K+ into cells (particularly skeletal M.) and can lead to a rise in plasma concentration of potassium (hyperkalemia). Other agents that are more commonly associated with hyperkalemia include the potassium-sparing diuretics: amiloride, triamterene, and spironolactone and the ACE inhibitors such as captopril.

Question: I had a question about Dobutamine for the tx of CHF. As a selective beta 1 agonist, how does it increase contractility without increases in heart rate or oxygen consumption. I thought that beta 1 receptors were generally associated with increasing heart rate.
Answer: The actions of dobutamine are complex. Racemic dobutamine has 2 isomers (-) and (+). (-)-dobutamine is thought to have alpha1-agonist action, whereas the (+)-dobutamine is thought to have alpha-antagonist activity which could block the effects of the (-)-isomer. (+)-Dobutamine is more potent (10x) than (-)-isomer on beta-receptors. Dobutamine has more prominent effects on iontropic (force) than heart rate compared to isoproterenol. The reason for the selectivity is still unclear. It may be in part due to the fact that peripheral resistance is relatively unchanged (ISO BP is decreased). Alternately, cardiac alpha1-receptors (yes they are also present) may contribute to the inotropic effect.

Question: Will you explain why non-selective beta blockers are contraindicated for individuals with diabetes?
Answer: Beta2-receptors are present in liver cells, activation of these receptors leads to glycogen breakdown to glucose. In diabetes there is compromised glucose handling. Blockade of the beta2-receptors in diabetes would prolong the recovery from a hypoglycemia episode and mask the symptoms of hypoglycemia (ie. anxiety, tremors, palpitations). Therefore it is preferred to use a beta1-selective agent to minimize this effect.

Question: What is the significance of the fact that bretylium and guanethidine compete with TCAs for uptake process? (pg 108) Does this interfere with the TCAs action?
Answer: Neuronal uptake is an active process with limited capacity and can be saturated. The competition of guanethidine for neuronal uptake can reduce the effectiveness of agents that require it to gain access to the nerve terminal. Such as amphetamines for ADHD. TCAs or cocaine inhibit neuronal uptake and thus can decrease the action of guanethidine. Bretylium does not compete for neuronal uptake.

Question: Why can you not use NE in the treatment of shock? You mentioned something about renal vessel constriction I believe.
Answer: NE has potent alpha1-actions, causing vasoconstriction of the renal vasculature. This would restrict the blood flow to the kidneys. Whereas dopamine can better activate the D1-receptors in the kidney to dilate them and hence increase blood flow (good thing).

Question: Are phenylephrine and methoxyamine both non-selective alpha agonists or are they selective alpha-1 antagonists?
Answer: Phenylephrine & Methoxyamine are selective alpha1-receptor agonists. Their cardiovascular responses are very similar.

Question: What is the difference between Tachyphaxis and Tolerance?
Answer: Tachyphlaxis means rapidly diminishing response. It is common with the amphetamine type compounds. These compounds cause displacement of transmitter (NE) from the storage vesicles. There appears to be only a certain of amount transmitter available for this type of release. When these stores are depleted the response to these agents is also reduced. This diminished response can occur within hours/days, dose to dose. Whereas tolerance is a long term reduction (adaptation) in response ie. weeks/months.

Cardiovascular  return to Ishac  return to top

Question: Why shouldn't we give propranolol to a patient with pheochromocytoma before her operation.  I know pheochromocytoma is a catecholamine secreting tumor of the adrenal gland, so wouldn't a strong beta-blocker help to neutralize this?
Answer: The main problem with pheochromocytoma is the high BP not the tachycardia. If a beta-blocker alone is given then you allow the alpha1-activity of the catecholamines to act unopposed. This would increase the BP still further. Beta-blockers can safely be given after the BP has been stabilized with an alpha-blocker. Labetalol (beta- and alpha-blocker) can be given alone to treat the crisis.

Question: I have 2 questions: (1). When Isoproterenol is administered in the presence of Atropine, why isn't HR elevated slightly more than the control due to removal of any vagal tone? (2). Why is pulse pressure increased in high doses of Epi.
Answer: (1). You are absolutely correct. Atropine would remove the vagal tone to the heart leading to a slight increase in heart rate that would be additive to the effect of ISO. This was academic and I wanted to avoid complicating a difficult area.
(2). Changes in pulse pressure will reflect changes in cardiac contractility. EPI has increased this through actions on the beta1-receptors.

Question: Why do antimuscurinic agents cause hypotension in high concentrations? I would expect them to cause hypertension b/c they are "unmasking" the sympathetic tone.
Answer: The muscarinic and nicotinic receptors although different recognize the same transmitter (ie. Ach). Therefore the receptive site for Ach is different but close. Atropine will block muscarinic receptors, and at high toxic doses can block ganglionic nicotinic receptors to cause a fall in BP. The muscarinic receptors in the vasculature do not receive any activity, hence blocking these has no effect. Atropine does have a direct vasodilator effect at high toxic doses (Red as a beet). The other terms for atropine toxicity are 'Hot as hell' referring to decreased sweat secretion and CNS changes in thermoregulation; 'Mad as a hatter': CNS delium; 'Dry as a bone': decreased saliva and 'Blind as a bat': cycloplegia (blurred vision).

Question: I have that the reflex is stronger than NE, but weaker than EPI, but it's the HR (NOT BP) that's changing. Is this a completely different reflex controlling HR and if so, what's the pathway?
Answer: The baroreceptor reflex is concerned with changes in BP (either up or down), and not by changes in HR or pulse pressure. The strength of the reflex depends on the rate of change in BP. High EPI will cause an increase in BP as the alpha1-mediated constriction dominates over the beta2-mediated vasodilation. Because of the significant increase in BP the baroreflex has been activated. It will try to lower BP by decreasing HR. However since EPI is such a potent beta1-agonist, the reflex evoked is weaker than EPI's direct action on the heart. Therefore we still see the tachycardia although it has been reduced by the reflex. In the case of NE, the reflex evoked is stronger than the direct effect of NE on the heart so we see an increase in BP with reflex bradycardia.

Question: (1). When Isoproterenol is administered in the presence of Atropine, why isn't HR elevated slightly more than the control due to removal of any vagal tone? (2) Why is pulse pressure increased in high doses of Epi?
Answer:  (1). You are absolutely correct. Atropine would remove the vagal tone to the heart leading to a slight increase in heart rate that would be additive to the effect of ISO. This was academic and I wanted to avoid complicating a difficult area. (2). Changes in pulse pressure will reflect changes in cardiac contractility. EPI has increased this through actions on the beta1-receptors.

Question: Why is the heart rate unchanged from the control situation to atropine and high dose isoproterenol? In the control the increase in heart rate is direct and reflex mediated. If atropine eliminates the reflex wouldn't the heart rate increase less than in the control?
Answer: In the case of hi ISO the BP has fallen and the reflex has been activated. However in this example the reflex will increase the HR to attempt to counteract the fall in BP (ie. act in the same direction as the direct effect of ISO on the heart). Since this involves activation of the SNS to the heart atropine has no effect.

Question: I can't quite understand how operational alpha-2 receptors will prevent a reflex tachycardia.
Answer: Because of the fall of BP due to alpha1-receptor blockade the baroreceptor has been activated to increase the BP. One way to do this is to increase HR to increase CO. In the case of prazosin (alpha1-selective) the alpha2-receptors are still operational and can exert their inhibition of release to prevent the reflex tachycardia. Whereas phentolamine (non-selective) blocks both the alpha1- and the alpha2-receptors thus preventing the action of the alpha2-receptors (ie. allows the reflex tachycardia to occur).

Question: Can you explain the reflex response and the role of HR?
Answer: The reflex activation is determined (triggered) by changes in mean BP and not changes in HR or PP (pulse pressure). The strength of the reflex is determined by the rate of change (increase or decrease). The role of the reflex is to oppose BP changes. To do this it can increase or decrease HR or increase or decrease peripheral vasoconstriction. Thus it can change the HR when activated but it is not triggered by the HR.

Question: Can you explain the effect of atropine on the response to PE and hi ISO?
Answer: In the case of PE the fall in HR is due to the reflex (activation of the vagus N.) and this can be blocked or prevented by atropine (muscarinic blocker). In the case of hi ISO the BP has fallen and the reflex has been activated. However in this example the reflex will increase the HR to attempt to counteract the fall in BP (ie. act in the same direction as the direct effect of ISO on the heart. Atenolol (beta1-selective blocker) in this instance would block the reflex response on the heart. Propranolol (non-selective blocker) would block all actions of ISO.

Question: What is the role of diastolic and systolic BP on the reflex?
Answer: The net effect on mean BP is more important as this determines the action of the barorelex response. In most cases the changes in systolic and diastolic BP are in the same direction whereas in other instances they may differ (ie. low dose EPI, ISO). Therefore it helps to have an understanding of them. It can also provide a clue that multiple receptors are involved such as in the eg. of low dose ISO with widening of pule pressure due to actions on beta1- and beta2-receptors.

Question: Why does vasoconstriction lead to nasal decongestion?
Answer: When someone has a runny/stuffy nose such as with a cold. Fluid is leaking from the nasal vascular vessels. PE or other vasoconstrictors will decrease this and are commonly found as the active ingredient in nasal decongestions. Usually the forms are pseudoephedrine or pseudophenylephrine. Pseudoephedrine should not be used by someone taking MAOI agents, as this can cause a hypertensive crisis (similar to tyramine response).

Question: Why is it important to maintain renal blood flow during septic shock by administering Dopamine vs. NE? Wouldn't you want to activate the renin-angiotensinogin system by decreasing renal blood flow?
Answer: During shock there is a fall in BP, decreasing tissue perfusion and cerebral blood flow. We need to maintain BP to maintain adequate blood flow to the various organs and brain. NE has potent alpha1-actions, causing vasoconstriction to increase BP. But it also causes vasoconstriction of the renal vasculature, this would restrict the blood flow to the kidneys and decrease renal function. Whereas dopamine can activate alpha1-receptors to maintain BP and activate the D1-receptors in the kidney to dilate them and hence increase renal blood flow and urination (good thing). The renin-angiotension system has already been activated because of the fall in BP.

Question: How does guanethidine alone cause heart rate to increase? Since it is a sympathetic blocker, I would think that it would cause BP and HR to decrease. I understand that the baroreceptor reflex would try to increase HR in response to drop in MAP, but wouldn't that effect be blocked by guanethidine?
Answer: Guanethidine inhibits the release of NE from the nerve terminal.
1. In the heart this removes the sympathetic tone ie. removes the +5 bpm
2. In the resistance vessels this causes a large fall in TPR causing a large fall in BP
3. This triggers the reflex response which attempts to dampen the fall in BP
4. The reflex response turns off the vagus (parasympathetic NS) inhibition of HR (- 10bpm)
5. The net effect is HR increases by 5 bpm (ie. the difference between removing -10 and +5 bpm.

Question: Why do we see cardiovascular side effects as a result of using selective beta2 agonists and selective alpha1 agonists? And what is the side effect? Is it reflexive tachycardia in the case of beta2 agonists and reflexive bradycardia in the case of alpha1 agonists?
Answer: Although I state that an agent is alpha1-selective (ie. Prazosin) or beta2-selective (ie. Terbutaline), this does not mean that they act solely on alpha1- or beta2-receptors. At higher concentration they can act on the other receptors. When they do this, it is considered a side-effect. For example, Terbutaline given for asthma (beta2-action) may cause some tachycardia (beta1-action). The tachycardia is considered a side-effect. This may be minimized by inhalation vs oral administration. The term 'reflex' is used to describe heart rate changes that are not the direct action of the agent but baroreflex mediated. For example NE causes an increase in BP with reflex bradycardia. For high dose ISO, there is a fall in BP and tachycardia. In this case the tachycardia is partially direct and partially reflex mediated.

Question: If parasympathetics dominate HR, why is HR increased by nicotine, a drug that stimulates all ganglia (SNS and PNS)? I would think that if PNS dominates, then nicotine would cause the PNS effect. My reasoning makes sense w/ blood pressure...SNS dominates BP and nicotine has the SNS effect (elevation).
Answer: Under resting conditions the dominate system on HR is the parasympathetic NS (-10bpm) compared to the sympathetic NS (+5bpm). Upon stimulation however the upside (70 to 200 bpm) is greater than the downside (70 to zero bpm). There is a limit to the inhibition of HR. Therefore the sympathetics wins upon ganglionic stimulation.

Question: I'm confused with regard to the syllabus and my own notes on pgs. 96 and 99. On page 96 I have a moderate understanding of the reflex involving the baroreceptors with the carotid sinus and aortic arch which control BP, but not HR nor Pulse Pressure. On pg. 99, however, I have that the reflex is stronger than NE, but weaker than EPI, but it's the HR (NOT BP) that's changing. Is this a completely different reflex controling HR and if so, what's the pathway?
Answer: The baroreceptor reflex is concerned with changes in BP (either up or down), and not by changes in HR or pulse pressure. The strength of the reflex depends on the rate of change in BP. High EPI will cause an increase in BP as the alpha1-mediated constriction dominates over the beta2-mediated vasodilation. Because of the significant increase in BP the baroreflex has been activated. It will try to lower BP by decreasing HR. However since EPI is such a potent beta1-agonist, the reflex evoked is weaker than EPI's direct action on the heart. Therefore we still see the tachycardia although it has been reduced by the reflex. In the case of NE, the reflex evoked is stronger than the direct effect of NE on the heart so we see an increase in BP with reflex bradycardia.

Question: Why would propranolol be contraindicated for a Pheochromocytoma patient about to undergo tumor removal surgery, suffering from severe headaches and palpitations? (pharm practice exam, cbil) On drug list sheet, it state that propranolol is CI'ed for heart failure, asthma, diabetes, Raynaud D, and no mention of severe headaches. Should we associate palpitations with heart failure?
Answer: The main problem with pheochromocytoma is the high BP not the tachycardia. If a beta-blocker alone is given then you allow the alpha1-activity of the catecholamines to act unopposed. This would increase the BP still further. Remember question 6 from my review yesterday about the woman stung by a bee. Beta-blockers can safely be given after the BP has been stabilized with an alpha-blocker. Labetalol (beta- and alpha-blocker) can be given alone to treat the crisis. Until recently (2002) all beta-blockers were contraindicated for heart failure because they decreased cardiac performance. However they positive actions to decrease the cardiac post-load and decrease oxygen demand. Previously it was felt that the bad out-weighted the positive actions. Now they know that the good out-weighs the bad. This benefical effect of beta-blockers was shown for metoprolol and not propranolol. Non-selective beta-blockers can cause problems for individuals with asthma (will increase bronchial resistance), diabetes (mask low glucose state and inhibit recovery from low glucose state) and Raynaud D. (increase perpheral resistance and worsten condition). Propranolol has been approved for use for mild/moderate migraine headaches. It can decrease their intensity and frequency. The mechanism of this action is not known. No, palpitations are usually associated with hypertensive crisis; such as MAOI + Tyr etc.

Question: Why there is no reflex bradycardia when you administer guanethidine?
Answer: Guanethidine will prevent the release of NE from the nerve terminal, this will cause a fall in BP. The reflex will attempt to increase the BP by activating the alpha1-receptors to cause vasoconstriction and the beta1-receptors to increase HR. However these actions are prevented by the adrenergic neuron blocking effect of guanethidine (inhibition of NE release). Thus the overall effect with guanethidine is a fall in BP and a slight increase in HR (removal of vagal tone).

Question: I was wondering why high doses of Epinephrine don't produce a reflex bradycardia?
Answer: High EPI will cause an increase in BP as the alpha1-mediated constriction dominates over the beta2-mediated vasodilation. Because of the significant increase in BP the baroreflex has been activated. It will try to lower BP by decreasing HR. However since EPI is such a potent beta1-agonist, the reflex evoked is weaker than EPI's direct action on the heart. Therefore we still see the tachycardia although it has been reduced by the reflex. In the case of NE, the reflex evoked is stronger than the direct effect of NE on the heart so we see an increase in BP with reflex bradycardia.

Question: When high dose epi is given in conjunction with a-blocker phentolamine, then aren't the b-1 and b-2 receptors equally responsible for the result? Here is what I thought: b-1 would give us an increase in systolic BP, b-2 would give us a decrease in diastolic BP (greater then the systolic raise), rendering slight downward change in MAP--also an increase (attributed to b-1) would be seen in HR. So why does the correct graph resemble high dose iso (where b-2>b-1) and not low dose iso (where b-1 = b-2)?
Answer: BP is dependent on CO & TPR (BP=TPR x CO). Of the two TPR is more important than CO. High dose EPI in the presence of phentolamine can only act on the beta-receptors. It is a good agonist on both the B1- and B2-receptors. It's actions on the B2 (decrease TPR) are greater than it's action on B1 (increase CO), hence it resembles high dose ISO.

Question: From my understanding of things thus far, to a rise in cardiac output (CO) leads to an increase is systolic BP while an increase in TPR leads to an increase in diastolic BP (and vice versa for both examples). If the preceding is correct (which it may very well not be) then how does, for example, NE in the presence of a beta-blocker (such as propranolol) increase both systolic and diastolic blood pressures? THe alpha-1 and alpha-2 receptors cause vasoconstriction, thus increase in TPR, thus increase in diastolic BP....how does the systolic BP come into play?
Answer: BP (both systolic & diastolic) are affected by CO and TPR (ie. BP=CO x TPR). Of the two TPR usually is more important than CO. NE in the presence of propranolol causes an increase in BP (both systolic & diastolic) and a reflex bradycardia (vagus activity increased). The increase in BP is due to the large increase in TPR via alpha1-receptor activation. CO is decreased.

Question: With Prazosin and Terazosin, how come there is no reflex tachycardiac?
Answer: Phentolamine (non-selective, alpha1- and alpha2-blocker) causes a fall in BP with refex tachycardia.  Whereas Prazosin and Terazosin are selective alpha1-blockers. It is thought that since they leave the presynaptic alpha2-receptors operational, this prevents the reflex tachycardia.

Question: Could you explain why toxicity of acetylcholinesterase inhibitors includes both Hypotension and hypertension?
Answer: In the presence of AchE inhibitors the action of Ach is prolonged at all sites (ie. ganglia, neuroeffector & NMJ). The increased ganglionic stimulation leads to an increased sympathetic stimulation to the vascular smooth muscle leading to vasconstriction via alpha1-receptors (hypertension). However if the Ach concentration becomes too high then Ach begins to act like succinylcholine, resulting in a depolarizing blockade in the ganglia (ie. it resembles the actions of a ganglionic blocker). This then causes the BP to fall (hypotension).

Question: What role does atropine have in phenylephrine and NE action.  Isn't atropine blocking muscarinic receptors?
Answer: Yes atropine is a muscarinic antagonist. It will prevent the reflex bradycardia seen with NE and expose the direct cardiac stimulation of NE (ie. increase in HR).

Question: Why is there no reflexive bradycardia when phentolamine acts on NE action?
Answer: In the presence of phentolamine (alpha-blocker), NE can only act on the beta-receptors. It is not as powerful on beta-receptors as EPI. It can act on the beta1-receptors in the heart to increase HR, CO & BP. It also acts on beta2-receptors to cause vasodilatation and hence decrease BP. The overall effect is no major change in BP and hence no reflex mechanism.

Question: Why is there a small diastolic BP decrease when phentolamine acts on NE?
Answer: Peripheral resistance has a greater effect on BP than CO. This just represents that. This is not a major point.

Question: Why is there a systolic BP increase in the control case with low doses of Epi?
Answer: At low dose EPI is acting mainly at beta-receptors with a little alpha-receptor activity. At low doses EPI acts on the beta1-receptors to increase CO and hence BP. Some vasoconstriction (alpha1-action) to increase TPR and hence BP. These two actions are the cause of the increase in systolic BP. Finally vasodilatation via an action on beta2-receptors to decrease TPR and hence decrease BP. The overall effect on peripheral resistance at low dose is a fall in TPR (beta2-effect is greater than alpha1-effect).

Question: Why is there a systolic BP increase with the control case of low ISO?
Answer: See above. The logic is the same as low dose EPI without the alpha1-action.

Question: Why is there bradycardia with hi doses of Epi and propranolol? Doesn't propranolol block all the beta receptors?  so there should be only alpha working.
Answer: In the presence of propranolol, high dose EPI is acting like NE. The reflex bradycardia (increase in vagus activity is reflex mediated) is due to the rise in BP.

Question: Propranolol does not cause a change in BP, but why not if it is inhibiting some beta-2. Are we just saying since tonic beta-2 vasodilatatory effects are insignificant relative to alpha-1 vasoconstriction that any decreasing in beta-2 would cause only a minimal increase in systolic and diastolic BP?
Answer: Propranolol has two actions acutely. One is to block the beta1-receptors in the heart to decrease HR and hence decrease CO, tending to decrease BP. The second is to block the beta2-receptors in the vessels to increase TPR, tending to increase BP. The overall effect is no change in BP with a fall in HR.

Question: Why do you not get tachycardia with the alpha-1 selective blockers: ie. prazosin and terazosin?
Answer: Phentolamine (non-selective, alpha1- and alpha2-blocker) causes a fall in BP with refex tachycardia.  Whereas Prazosin and Terazosin are selective alpha1-blockers. It is thought that since they leave the presynaptic alpha2-receptors operational, this prevents the reflex tachycardia.

Question: What is the mechanism for the antihypertensive actions of Clonidine?
Answer: Clonidine is an alpha2-receptor agonist. Alpha2-receptors can be found both pre- and post-synaptic. It is thought that the alpha2 agonists like clonidine exert their antihypertensive action via post-junctional receptors in the CNS. Stimulation of these receptors inhibits the activity of the vasomotor center with subsequent decrease in sympathetic outflow from the CNS . It is not that important that they are either pre- or post-synaptic receptors, but the antihypertensive action of alpha2-agonists is due a CNS -mediated action to decrease sympathetic outflow. Clonidine can stimulate presynaptic alpha2-receptors on the nerve terminal to decrease NE release but this is not the cause of itís use as an antihypertensive agent.

Parasympathetic nervous system   return to Ishac  return to top

Question: Why is there both hypertension and hypotension under toxicity with ganglionic stimulants?
Answer: Persistent ganglionic stimulation can cause a depolarizing block much like the action of succinylcholine. The initial increased ganglionic stimulation (ie. nicotine) leads to an increased sympathetic stimulation to the vascular smooth muscle (amoung other actions) leading to vasconstriction via alpha1-receptors (hypertension). However if the nicotine stimulation is excessive then it begins to act like succinylcholine, resulting in a depolarizing blockade in the ganglia (ie. it resembles the actions of a ganglionic blocker). This then causes the BP to fall (hypotension).

Question: How does an antimuscarinic treat motion sickness?
Answer: Common motion sickness drugs fall into three classes: anticholinergics, antidopaminergics, and antihistamines; with scopolamine patch the most commonly used treatment. Nausea and vomiting are the most common complaints of motion sickness and are mediated by central neurotransmitters. In response to visual and vestibular input, increased levels of dopamine stimulate the medulla oblongata's chemoreceptor trigger zone, which in turn stimulates the vomiting center within the reticular formation of the brain stem. The vomiting center is also directly stimulated by motion and by high levels of acetylcholine. Scopolamine works by preventing the action of Ach on muscarinic receptors in the vomiting center. Yes it is actually called the vomiting center.

Question: How or why is scopolamine considered to work on muscarinic receptors in the CNS? Wouldn't it work directly on the muscarinic receptors in the GI tract or does it also (or exclusively) work on the vomiting center in the brain?
Answer: Scopolamine acts on all muscarinic receptors both peripheral (ie. heart, GI-tract) and central (ie. vomit center, since it is lipid soluble and crosses into the CNS). The clinical use of scopolamine is it's CNS action. The other actions occur and are considered side-effects ie. increase GT-activity, pupil constriction, bronchoconstriction.

Question: Can you describe what is meant by myasthenic crisis and cholinergic crisis?
Answer: Myasthenic crisis is when treatment is insufficient. This results in muscle weakness. Cholinergic crisis is when treatment is excessive and this also results in muscle weakness. Edrophonium can be used to tell the difference between the two. Edrophonium will improve muscle strength in myasthenic crisis (increase NMJ transmission) but make muscle weakness in cholinergic crisis worse (deepen the block).
 

 Question: What causes the muscarinic receptor induced "tremor" w/toxicity of AChE inhibitors? Why does tremor occur with excess PNS involvement?
Answer: Tremor is caused by repeated and unchecked stimulation by Ach at the NMJ resulting in uncontrolled and rapid twitching of muscles in the presence of AchE inhibition. Tremor can also be induced by activation of central muscarinic receptors such as the tremor observed with Parkinson's D. or oxotremorine (M-agonist) induced (it even has tremor in its name).

Question: If ACh leads to vasodilation, why do toxic doses of of ACh antagonists cause pronounced vasodilation? Is this some sort of reflex mechanism (NO-mediated)?
Answer: The muscarinic receptors in the vasculature do not receive any activity (tone), hence blocking these has no effect but activation by Ach injection will cause vasodilation. Atropine does have a direct vasodilator effect at high toxic doses (ie. Red as a beet). This is not receptor mediated nor via NO. The other terms for atropine toxicity are 'Hot as hell' referring to decreased sweat secretion and CNS changes in thermoregulation; 'Mad as a hatter': CNS delium; 'Dry as a bone': decreased saliva and 'Blind as a bat': cycloplegia (blurred vision).

Question: Organophosphate and carbamates are AchE inhibitor, so they should increase Ach and cause muscle contraction at NMJ. How come overdoses of OP and carbamate (ie nerve gas and insecticide) can cause muscle weakness and respiratory paralysis?
Answer: AchE inhibitors such as organophosphates and the carbamates cause increased levels of Ach at all sites that release Ach (ie. all ganglia, the NMJ, the parasympathetic neuroeffector site, sweat glands). This means they can have widespread actions on the autonomic nervous system (both divisions) and the somatic nervous system. At high doses the muscle weakness and respiratory paralysis is due to depolarizing block at the NMJ on the Nm-receptor (similar to the actions of succinylcholine).

 

Question: How does physostigmine reverse TCA toxicity?
Answer: The main action of TCAs is to inhibit neuronal uptake and prolong the action of NE in the neuroeffector junction. TCAs also have significant muscarinic and alpha-receptor blocking activity (see page 92). A common side effect of their use is a dry mouth (muscarinic block). At high doses such as overdose/suicide a major problem is muscarinic receptor blockade both in the periphery and CNS. Physostigmine crosses the BBB and can reverse actions at both sites.

Question: (1) Pirenzepine is an M1 selective antagonist, why is it used for peptic ulcers? Is M1 block specifically linked to a decrease in gastric secretions. (2). Can you explain how an ACHe inhibitor (i.e., benztropine) is used for the treatment of parkinson's?
Answer: (1). Yes, activation of M1-receptors increase gastric acid secretion. (2). Benztropine is a muscarinic antagonist not a AchE inhibitor. Parkinsons D. is associated with decreased central dopamine function and increased cholinergic activity. Benztropine can be used to decrease the cholinergic activity.

Question: Can you explain the significance of Cns action in Physostigme. I just don't know what this means.
Answer: Physostigmine is a tertiary amine and is very lipid soluble (ie can cross the BBB) and thus has central actions also. It can be used to reverse the effects of atropine toxicity (belladona compounds & TCA overdose). These agents have central actions and thus physostigmine is better than neostigmine which cannot cross the BBB to reverse these actions.

Question: Which ANS system dominates in the bronchioles?
Answer: Overall the balance between the sympathetic NS and parasympathetic NS in the lung is relatively even with a slight edge to the sympathetic NS. Sympathetic NS tone is dominant to the bronchial sm mediating resistance and the parasympathetic NS is the dominant system mediating bronchial secretions.

Eye return to Ishac  return to top

Question: (1). Can accommodation block occur both with excessive cholinergic activation and with anticholinergic activation? I am kind of confused about this point. (2). When there is high amounts of AChE inhibitors, nicotinic ganglia get stimulated by cross reaction (producing a hypertensive effect) and when there is high amounts of anticholinergic substances nicotinic ganglia can get blocked by cross reaction producing hypotension?
Answer: (1). Yes cyclopegia (loss of accommodation) can occur with activation or block of M-receptors in the ciliary muscle. Anything that interferes with the ability of the ciliary muscle to contract or relax will have this effect. Ganglia blockers will also cause cyclopegia but not alpha-agonists or antagonists. (2). In the presence of high levels of AChE inhibitors the actions of Ach become long lasting. Initially there is stimulation of the ganglionic N1-receptors causing hypertension. Continual stimulation of N-receptors then can causes a depolarizing block that is similar to that observed with succinylcholine. This then causes a fall in BP ie. hypotension. At high toxic doses atropine can also cause block of ganglionic N-receptors.

Question: What causes cycloplegia, I know it's loss of accommodation but what causes it?
Answer:
Cycloplegia is loss of accommodation or loss of ability to focus. Contraction or relaxation of the ciliary m. alters the shape of the lens and hence the ability to focus. To function normally the ciliary m. needs to be able to both relax and contract. This is why both muscarinic blockers (like atropine) and muscarinic agonists (like pilocarpine) as well as AchE inhibitors can cause cycloplegia. Likewise ganglionic blockers can also cause cycloplegia because they interfer with the parasympathetic transmission to the ciliary m. Note the absence of sympathetic innervation to the ciliary m. hence the lack of effect on cycloplegia.

Question: I understand that Adie's pupil is dilated tonically because of damaged Musc. receptors, but I was wondering if Pilocarpine would constrict Adie's pupil or only a normal pupil....(your chart, p 151, says it would constrict Adie's pupil, but I thought you said something about Pilocarpine being diagnostic for Adie's....if it didn't cause constriction, you would then know it was Adie's).
Answer: Pilocarpine will constrict the pupil in both normal and Adie's pupil. Adie's pupil responds poorly or not at all to light because of damage to the parasympathetic nerves (not muscarinic receptors). The Pilocarpine test is just to see that the pupil will constrict and is not by itself diagnostic for Adie's pupil. It could have been that an atropine-like agent (muscarinic blocker) was present and was responsible for the lack of response to light.

Question: Can you explain Horner's S. and Adie's pupil?
Answer:
Horner's S. is associated with damage to the sympathetic fibers to the eye (either pre- or post-ganglionic). This is associated with sagging of the eyelid and miosis of the affected eye. Adie's pupil is an individual whose pupil response to light is slow. The eye however will respond normally to autonomic agents (ie. pilocarpine).

Question: What are the actions of cocaine and hydroxyamphetamine, in Horner's syndrome. Does cocaine block both and hydroxyamphetamine block only the preganlionic?
Answer: Cocaine is a neuronal uptake inhibiter. It will potentiate the effect of any released NE. In Horner's syndrome there is damage to the sympathetic neurons (either pre- or post-gangionic). Because of the damage to the sympathetic neurons there is no NE release. Hence cocaine is without effect. In contrast, in the normal eye we would see pupil dilation. Amphetamine-like compounds (ie. hydroxyamphetamine and tyramine) cause displacement of the transmitter NE. If the damage in Horner's syndrome was pre-ganglionic then we would still have a functional post-ganglionic neuron. Hence amphetamine-like compounds would cause NE displacement which results in pupil dilation. If the damage in Horner's syndrome was post-ganglionic. Then the nerve degenerates and hence there is no transmitter to release. Therefore amphetamine is without effect.

Question: How do alpha-agonists and PGs increase outflow?
Answer: The mechanism for alpha-agonist is thought to be similar to their effectiveness in nasal congestion. Decreasing fluid leakage from the vascular vessels in the Canal of Schlemm and the Trabecular meshwork decreases the resistance to aqueous humor outflow. The mechanism of the PGs (Latanoprost) to increase outflow is unknown. Recent evidence suggests that it may function through stimulation of COX-2.

Question: By what mechanism of action do Cholinesterase inhibitors cause a loss of ciliary muscle accommodation (cycloplegia)? I was under the impression that by preventing the breakdown of Ach, one would see miosis and accommodation in the eye.
Answer: Contraction or relaxation of the ciliary muscle will affect the shape of the lens and hence it's ability to focus. Any thing that interferes with the contraction or relaxation of the ciliary muscle will affect accommodation (ie. ability to focus) and thus cause cycloplegia. This is more prominent with muscarinic blockers than AchE inhibitors, but it also occurs. Ganglionic blockers will also cause cycloplegia in addition to pupil dilation (removal of PNS & SNS tone). Alpha-agonists (ie. Phenylephrine) will dilate the pupil with no effect on accommodation.

Question: How does the alpha-2 agonist, apraclonidine decrease secretions from the ciliary epithelium in the eye when the ciliary epithelium has beta-receptors?
Answer: The ciliary epithelium cells have both alpha2-receptors and beta-receptors, activation of the alpha2-receptor or blockade of the beta-receptor will  decrease secretions. Of the two, the beta-receptors are the more important receptor. This is why beta-blockers such as Timolol are the main agents used in the chronic treatment of glaucoma.

Neuromuscular Junction  return to Ishac   return to top

Question: Can you explain the difference between the two classes of NMJ blocking drugs?
Answer: The NMJ agents are divided into two classes:
i) competitive, non-depolarizing agents eg. tubocurarine
ii) non-competitive, depolarizing agents eg. succinylcholoine (only member)
Tubocurarine acts in a very similar fashion as does phentolamine on alpha receptors or atropine on muscarinic receptors. The block can be over come by increasing the agonist (Ach) concentration ie. with cholinesterase  inhibitors such as neostigmine.  Whereas the block by succinylcholine is different. It acts much like a very long lasting Ach molecule. It initially causes stimulation (fasculations), but instead of being rapidly broken down like Ach. It causes a sustained depolarization associated with NMJ blockade and this cannot be reversed by increasing the concentration of Ach.

Question: Why does neostigmine augment the depolarizing response of succinylcholine?
Answer: Neostigmine will potentiate (worsen it) the block of the depolarizing (non-competitive) NMJ blocker succinylcholine. Succinylcholine acts like a long lasting Ach. The membrane is depolarized and remains depolarized in Phase 1 block. Increasing the Ach concentration further will only make the block longer and deeper.

Question: As the atypical pseudo-cholinesterase would cause problems with depolarizing nmj blockade, would there be a prolongation of the effects of the non depolarizing drugs such as mivacurium that are AchE metabolized.
Answer: If plasma cholinesterase activity is low (ie atypical pseudocholinesterase), then the actions of competitive NMJ blockers that are metabolized by AchE  would also be prolonged (ie mivacurium). Much like that of the depolarizing blocker, succinylcholine. However the good thing with the competitive NMJ blockers is that you can reverse this prolonged effect with cholinesterase inhibitors such as neostigmine. This is not possible with succinylcholine, it would only make the blockade deeper (see question above).

Question: How exactly does dantrolene treat malignant hyperthermia when it is inhibiting Ca release just as succinylcholine (the culprit of malignant hyperthermia) is already inhibiting Ca?
Answer: Malignant Hyperthermia [hyperpyrexia] is an inherited (pharmacogenetic) disorder of skeletal muscle, characterised by a hypermetabolic state, triggered by volatile anaesthetics (ie. halothane) and succinylcholine resulting in a rapid rise in body temp and HR. Intracellular calcium increases up to 500 fold leading to sustained muscle contraction and rigidity. Overall the incidence of MH is about 1:50,000. Dantrolene (DOC) acts by decreasing the release of calcium from the SR.

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