Pharmacology Test 1

The Autonomic Nervous System

3.1 Describe how epinephrine, norepinephrine, adenosine and acetylcholine affect beta-receptors, g-proteins and cyclic AMP.

Epinephrine (EPI) stimulates the Beta Adrenergic Receptor (BAR) on the cell membrane. This causes the G (Gs) proteins to activate the enzyme Adenylate Cyclase (AC). The AC then takes ATP and catalyzes it to cAMP which is then broken down in AMP which is further broken down to Adenosine (ADO).

EPI BAR G AC ATP cAMP AMP ADO

Norepinephrine (NEPI) yields a similar result as EPI. It also stimulates BAR thus increasing cAMP.

NEPI BAR G AC ATP cAMP AMP ADO

ADO, as previously explained is a by-product of the metabolism of ATP after BAR stimulation. With too much stimulation, ADO moves to the outside of the cell and stimulates the ADO receptors on the membrane. This stimulates the inhibitory G proteins (Gi) which do not stimulate the AC (ATP is not catalysed to cAMP).

Acetylcholine (ACh) is released by the parasympathetic nervous system. ACh stimulates the inhibitory G proteins (Gi) which do not stimulate the AC (ATP is not catalysed to cAMP). ACh and ADO act in similar manners.

3.2 Which of the 4 neurotransmitters listed above have local effects and which have more general effects?

The neurotransmitters that have local effects are:Norepinephrine, Acetylcholine, & Adenosine

The neurotransmitter that has a more general effect is:Epinephrine

The reason why epinephrine has a more generalized effect is because this neurotransmitter is synthesized in the adrenal medulla. The pre-ganglionic neuron stimulates the adrenal medulla which in turn releases epinephrine into the bloodstream thus causing general effects in the body.

The neurotransmitters Norepinephrine and Acetylcholine cause a localized effect in the autonomic

nervous system due to their release at the presynaptic terminal of the post-ganglionic neuron attaching to the receptor proteins on the postsynaptic membrane located on the effector organ. In the somatic nervous system there are no ganglia and ACh is released from the presynaptic terminal of the somatic nerve attaching to the receptor proteins on the postsynaptic membrane located on the effector organ.

Adenosine is released when there is ischemia of the heart by which ATP in myocytes is degraded causing the final end product Adenosine which is released and acts on the adenosine receptors of the heart muscle. Works as a negative feedback loop.

3.3 What effect does norepinephrine have on intracellular cAMP production? How does norepinephrine produce these effects?

Norepi increases the production of cAMP and ultimately increases HR and contractility. This occurs because NE binds to the BAR receptor, stimulates the Gs protein which triggers AC. AC catalyzes ATP to cAMP.

3.4 What is cAMP broken down to? What more readily traverses cellular membranes, adenosine or adenosine phosphate? Why?

A. cAMP is broken down by phosphodiesterase (PDE) to become adenosine monophosphate (AMP)

B. Adenosine, because it is lipid soluble can cross the cellular membrane more easily than the larger, polar and water soluble adenosine phosphate

3.5 What is the half-life of i.v. adenosine?

The half-life of adenosine is less than 10 seconds

3.6 Where does adenosine that naturally stimulates cardiac adenosine receptors come from?

Adenosine is generated in all living cells during the breakdown of adenosine triphosphate (ATP). The adenosine receptors affect cell function by modulating the activities of the enzymes AC ( adenylyl cyclase). Through their association with stimulatory G proteins, AC enzyme produces the second messenger cAMP from ATP. In turn, cAMP activates the enzyme protein kinase A (PKA), which adds phosphate groups to various proteins. As a result of this phosphorylation, the electrical properties of the cell change, making it easier or more difficult to excite the cell, depending on which ion channels are affected. Then, cAMP break down to AMP with help of phospoterase enzyme. Finally, AMP changes to Adenosine.

3.7 How do adenosine and acetylcholine modulate sympathetic response?

AC has several names - adenylate cyclase or adenyl cyclase or adenylyl cyclase. G-proteins are regulatory proteins that stimulate (Gs) or inhibit (Gi) AC activity.

ACh and ADO interact with Gi-proteins that inhibit the activity of AC. AC is not released; AC is a protein/enzyme that is attached to the cell membrane and that converts ATP to cAMP. ADO and ACh bind to their respective receptors that are linked to Gi proteins that cause AC to function less effectively - we say ADO and ACh decrease the activity of this enzyme. In contrast ADO antagonists (eg, caffeine) and ACh antagonists (eg, atropine) block the ability of these Gi-proteins to inhibit AC.

As far as the calcium channel is concerned, this channel opens and closes with each depolarization of the cell membrane. While the cell membrane is not hyperpolarized, calcium is allowed to enter through the calcium channel. If you compare calcium channels that are not phosphorylated to those which are, calcium enters through each channel however much more enters through the phosphorylated channel.

3.8 Why does the body have two similarly acting neurotransmitters (i.e., adenosine and acetylcholine) that modulate sympathetic response?

The brain is capable of regulating the functions of the Autonomic Nervous System. It can do this through acetylcholine. This allows the body to have systemic control of the sympathetic response. The adenosine allows for local control the nervous system. The local control is essential in situations such as during a myocardial infarction when signals quickly need sent to increase oxygen supply and decrease oxygen demand. The two neurotransmitters enable close and effective control of the sympathetic response.

Acetylcholine is released from postganglionic parasympathetic neurons and is under CNS control. In contrast, adenosine allows tissue to produce local effects. In the case of the heart, ischemia causes adenosine to be released. Adenosine decreases myocardial work by decreasing heart rate, contractility and AV conduction. Because the half-life is so short, adenosine does not produce widespread effects. It should also be mentioned that adenosine has vasodilation effects that cause more oxygen to be delivered to the ischemic tissue. Adenosine also plays an important role in cerebral protection during ischemia/hypoxia.

3.9 What is the difference between a hormone and a neurotransmitter? Are epinephrine and norepinephrine hormones or neurotransmitters?

Hormones are secreted into the bloodstream by specialized endocrine cells. EPI is a hormone.

Neurotransmitters assist with communication between nerve cells and between nerve cells and effector organs. They are specific chemical signals that are released once an action potential arrives at the nerve ending or presynaptic terminal. Once released, they diffuse across the synaptic cleft or synapse and combine with specific receptors on the post synaptic target cell. NE is a neurotransmitter.

3.10 Describe in detail how milrinone and amrinone produce their pharmacologic effects?

Milrinone and amrinone are inotropes and PDE inhibitors. Inotropes enhance cardiac contractility and increase Cardiac Output. Milrinone and Amrinone achieve this effect by being PDE inhibitors and preventing the breakdown of cAMP by PDE into AMP. This allows more cAMP to stimulate Calcium into the cytoplasmic and increase contractility.

3.1 Which one of the following statements concerning the parasympathetic nervous system is correct?

The parasympathetic system maintains essential bodily functions, such as vision, movement of food, and urination. It uses acetylcholine, not Norepi, as neurotransmitters, and it discharges as discrete fibers that are activated separately. The postganglionic fibers of the parasympathetic system are short compared to those of the sympathetic division. The adrenal medulla is under the control of the sympathetic system.

3.2 Which one of the following is a characteristic of parasympathetic stimulation?

The parasympathetic nervous system is essential in the maintenance activities, such as digestion and waste removal and therefore would increase intestinal motility to facilitate peristalsis, relaxation of the bladder sphincters to cause urination, and increased bronchial secretions. Increase in heart rate is a function of the sympathetic nervous system, not the parasympathetic.

3.3 Which of the following is characteristic of the sympathetic nervous system?

The sympathetic nervous system is activated by flight or fight stimuli. To achieve rapid activation of this system, the sympathetic nervous system often discharges as a unit. The receptors that mediate the sympathetic nervous system effects on neuro-effector organs are alpha and beta receptors. Because the SNS is a division of the autonomic nervous system, it is not subject to voluntary control and functions below conscious though.

3.4 Patient presents with salivations, lacrimation, urination and defecation as a side effect of a medication. Which one of the receptors mediates the actions of this drug?

The muscarinic receptors (SLUDGE acronym) of the parasympathetic nervous system maintain essential body functions like digestion and waste elimination. The nicotinic receptors are receptors for acetylcholine. It plays a major role in skeletal muscles, ganglia, and synthesis of catecholamine in the adrenal medulla. Alpha and Beta receptors are for NE and Epi and activation of these receptors do not cause these effects.

Adrenergic Agonists

6.1 What does the chemical prefix "nor" signify (eg, in norepinephrine, normorphine, and normeperidine)?

"Nor" is used to indicate a demethylated compound. Demethylation is the chemical process of removing a methyl group from a compound. This happens in the changes of EPI to NE.

Methyl = -CH3

6.2 What is the rate-limiting step of catecholamine biosynthesis?

Tyrosine hydroxylase

6.3 What is the primary mechanism for the termination of the effect of norepinephrine? What are the other 2 mechanisms by which these effects may be terminated?

1. The PRIMARY mechanism to terminate norepinephrine is by DIFFUSION.2. It can be metabolized by COMT3. It can go back into the presynaptic cell

6.4 Is isoproterenol a catecholamine? How are isoproterenol, epinephrine and norepinephrine structurally similar?

Isoproterenol, just like Epi and NorEpi is a catecholamine. Structurally they are all sympathomimetic amines that contain 3,4-dihydroxybenzene group.

6.5 What are the roles of alpha-2 receptors? What does the text mean when it states that these receptors may behave as inhibitory autoreceptors?

"Stimulation of alpha-2-receptors causes feedback inhibitions of NorEpi released from the adrenergic neuron. This inhibitory action decreases further output from the adrenergic neuron and therefore serves as a local modulating mechanism for reducing sympathetic neuromediator output when there is high sympathetic activity hence the term inhibitory autoreceptors.

6.6 What is COMT? Where is it located? Which vasoactive drugs does it affect? Why does phenylephrine (neosynephrine) last longer than epinephrine? (hint either related to change in clearance or volume of distribution)

COMT metabolizes all catecholamines (DA, EPI, NEPI). COMT is located extracellular in the synaptic cleft. Phenylephrine (PE) differs from EPI by only one atom. However, because of this tiny difference, PE is not a catecholamine, is not susceptible to COMT metabolism, has a smaller clearance than EPI and therefore lasts much longer.

6.7 How does MAO differ from COMT (compare where these enzymes are located and contrast their actions)?

Location of MAO- IntracellularAction of MAO- Oxidizes norepinephrine (and other biogenic amines like serotonin, epinephrine and dopamine). Location of COMT- Extracellular in the intersynaptic spaceAction- Metabolizes norepinephrine (and all other catecholamines such as dopamine, epinephrine and isoproterenol).

6.8 Norepinephrine is stored in postganglionic neurons. What keeps all this this stored norepinephrine from being metabolized by MAO before it is released into the synaptic cleft?

Norepinephrine is not metabolized by MAO when it is in the storage vesicles. Outside the vesicles there is MAO in the presynaptic nerve cell that can cause metabolism. Norepinephrine that enters the cell through reuptake is vulnerable to metabolism until it enters the storage vesicles.

6.9 Catecholamine administration may produce hyperglycemia. What is the mechanism by which this occurs?

Catecholamine causes the liver to increase glycogenolysis. Hyperglycemia is also caused by an increased level of released glucagon and a decrease in level of released insulin.

6.10 What precautions should be taken when administering anesthesia to patients taking MAO inhibitors?

MAO inhibitors can interact with certain medications and result in a hypertensive crisis that can lead to stroke, heart attack or death. When possible, they should be discontinued at least 2 weeks undergoing general anesthesia. MAO inhibitors include:

•Marplan (isocarboxazid)•Matulane (procarbazine)•Nardil (phenelzine)•Pargyline•Parnate (tranylcypromine)

MAOa inhibitors must be discontinued for two weeks for the effects to wear off. Unfortunately, if you have a severely depressed or suicidal patient, there are substantial risks associated with discontinuing their MAOIs. So

ideally we would d/c these drugs for two weeks; however in practice, we are often unable to d/c these medications and try to avoid medications that may interact with MAOIs, especially halothane, meperidine, anticholinergics (eg, drugs like pancuronium which have anticholinergic properties) and indirect acting vasoactive agents.

6.11 Summarize the pharmacology of ephedrine and pseudoephedrine.

Ephedrine acts directly in beta 1 and beta 2 receptors, and indirectly on alpha 1 receptors by causing noradrenaline release. It causes a rise in blood pressure and heart rate and some bronchodilation. May cause tachycardia and hypertension. Best vasopressor to use in pregnancy as it does not reduce placental blood flow. Length of action is 5-15 min, max dose is 60 mg. It is metabolized in the liver and excreted primarily in the urine.

Pseudoephedrine is a sympathomimetic amine, structurally similar to ephedrine. It acts directly on both alpha- and, to a lesser degree, beta-adrenergic receptors. Through direct action on alpha-adrenergic receptors in the mucosa of the respiratory tract, pseudoephedrine produces vasoconstriction and reducing swollen nasal mucous membranes. It helps to increase patency in the airway reducing tissue hyperemia, edema, and congestion which promotes sinus drainage, and the opening of obstructed Eustachian tubes. The drug is widely distributed throughout the body. Nasal decongestion can occur within 30 minutes and can last from 4 to 6 hours. Pseudoephedrine is metabolized incompletely in the liver and excreted unchanged in the urine. It has also been reported to be excreted into breast milk.

For the test, be able to recognize the chemical structures of EPI, NE, and ISO

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Adrenergic Antagonists

7.1 Where are alpha and beta-receptors located in the peripheral vascular system?

Alpha 1 receptors are located on the postsynaptic membrane of the effector organ, and mediate many of the classic effects designated as alpha adrenergic (constriction on smooth muscle). Alpha 2 receptors are located on the presynaptic nerve endings and can decrease the amount of norepinephrine being released from the neuron. Beta 1 receptors are located in the heart & kidneysBeta 2 receptors are located on vasculature to skeletal muscle. (and many other organs)

7.2 Compare the pharmacology of phenoxybenzamine, prazosin, terazosin, doxazosin, tamsulosin, phentolamine and yohimbine.

All of these medications are alpha adrenergic blockers, meaning they reduce the sympathetic tone of the blood vessel resulting in decreased peripheral vascular resistance, thereby lowering BP.

Phenoxybenzamine: is a non-selective alpha antagonist, meaning it binds to alpha 1 and alpha 2 receptors. The block is irreversible and non-competitive, and the only way the body can overcome this is to make new adrenoceptors (which takes about one day or longer). So, phenoxybenzamine lasts about 24 hours after a single dose, but it may take several hours before alpha blockade develops. However, blocking alpha 1receptors will dilate the peripheral vasculature, but blocking alpha 2 receptors causes an increased release of norepinephrine (NE) in the synapse, stimulating beta receptors in the heart, and increasing cardiac output (contraindicated in patients with decreased coronary perfusion). So, it is not effective at lowering blood pressure, and has been discontinued for that use. Also, if epinephrine is given, it will actually lower the BP because the alpha adrenergic 1 receptors have been blocked, but the beta 2 receptors can still cause vasodilation (this is termed epinephrine reversal). Used for treatment of pheochromocytoma (catecholamine secreting tumor of adrenal medulla).

Phentolamine: also a non-selective alpha 1 and alpha 2 antagonist, but it produces a competitive block, and its action lasts approximately 4 hours. Causes epinephrine reversal. Also contraindicated in patients with decreased coronary perfusion due to drugs ability to trigger arrhythmias and angina pain (because it increases CO, and cardiac workload). Used for short term pheochromocytoma treatment, and used locally to prevent dermal necrosis due to norepinephrine infiltration. Prevents hypertensive crisis for patients due to abrupt withdrawal of clonidine, and due to patients receiving MAOI’s eating tyramine.

Prazosin, Terazosin, Doxazosin, and Tamsulosin: are selective and competitive alpha 1 blockers. First 3 drugs treat hypertenstion, and Tamsulosin treats benign prostatic hyperplasia (BPH) because it has some selectivity to the alpha 1-a receptor found on the prostate smooth muscle. Patients do not become tolerant to these drugs, but the first dose can cause exaggerated orthostatic hypotension (to the point of syncope). This is called the “first-dose effect”, and can be minimized by making the first dose 1/3 to 1/4 the normal dose and giving it at bedtime.

Yohimbine: is a selective competitive alpha 2 blocker. Used to relieve vasoconstriction associated with Raynaud disease. Yohimbine is an alpha-2 antagonist that will cause vasoconstriction. It is not used often but most commonly administered for treatment of impotence. All other alpha-blockers are vasodilators, yohimbine is not. Make sure you know how this works.

Summary: Phenoxybenzamine irreversible, alpha-1 and alpha-2 blocker; phentolamine reversible alpha-1 and alpha-2 blocker; "osins" are reversible alpha-1 blockers; yohimbine is reversible alpha-2 antagonist.

7.3 What is the mechanism by which prazosin may cause orthostatic hypotension?

Prazosin may cause orthostatic hypotension because it relaxes the smooth muscle of both arteries and veins. If a patient rises quickly, they may not have sufficient vascular tone to maintain their normal blood pressure against gravity.

This symptom is due to alpha-1 blockade in veins and decreased venous return. This is very similar to orthostatic hypotension seen after spinal and epidural analgesia.

7.4 Why do we give a fluid bolus to patients prior to administering spinal or epidural anesthesia?

Fluid boluses are given prior to anesthesia to provide the patient with adequate fluid volume to maintain blood pressure because the spinal or epidural anesthesia may cause a drop in BP.

See next question. Spinal or epidural anesthesia causes sympathetic blockade. This effect on alpha-1 receptors located in veins leads to venodilation, reduced preload and often hypotension. We pretreat these patients with IV fluid bolus to avoid hypotension following the neuraxial block.

7.5 Consider information depicted in Figure 7.4. Why do we usually administer fluid boluses to patients prior to epidural or spinal analgesia?

Fluid boluses are administered to patients prior to epidural or spinal analgesia because these drugs block alpha-1 receptors and in turn cause decreased peripheral vascular resistance and decreased blood pressure. So, the fluid bolus will help maintain a more stable peripheral vascular resistance and blood pressure.

7.6 How do beta-adrenergic agonists and antagonists affect serum glucose levels? Describe the role of alpha-2 and beta-receptors in control of serum glucose levels.

Beta-adrenergic agonists increase the release of endogenous stores of glucose. So, if you had a diabetic patient’s on an Epinephrine drip than their blood sugar needs to be checked frequently and their doses of insulin may need to be increased.

Beta-adrenergic antagonists lead to decreased glycogenesis and therefore decreased glucagon secretion. These drugs may weaken the normal physiologic response to hypoglycemia.

Alpha-2 receptors inhibit the release of insulin when stimulated.

Beta-receptors increase the release of glucagon when stimulated.

7.7 What clinical response would you expect after administering a combination of propranolol + isoproterenol? Epinephrine + propranolol? Norepinephrine + phentolamine?

Propranolol + Isoproterenol= Propranolol has the ability to block the action of Isoproterenol, so therefore the following effects will occur from the propranolol- bronchoconstriction, peripheral vascular constriction, decreased heart rate, force, so therefore decreased cardiac output.

Epinephrine + Propranolol= The propranolol blocks all the effects of epinephrine except its vasoconstrictive action remains unimpaired so that clinical response will be seen.

Norepinephrine + Phentolamine= Phentolamine blocks the effects of norepinephrine. You will see decreased blood pressure, phentolamine-induced reflex cardiac stimulation and tachycardia, arrhythmias, and anginal pain.

7.8 Briefly discuss the pharmacology of labetalol and carvedilol.

They are beta blockers (beta-1 and beta-2) with concurrent alpha-1 blocking actions that produce peripheral vasodilation, thereby reducing blood pressure. They are used to treat hypertension and congestive heart failure.

7.9 What are the signs, symptoms and treatment of thyroid storm (thyrotoxicosis)?

Signs and symptoms of thyroid storm are tachycardia, CHF, angina, high fever, agitation, restlessness, delirium.Treatment is a non-selective Beta Blocker such as propranolol to block the sympathetic stimulation occurring during thyroid storm. Replacement of fluids, glucose & electrolytes are often required in this hypermetabolic state. Plus means of peripheral cooling such as cooling blankets for the fever. Glucocorticoids to correct adrenal insufficiency during the stress imposed & to inhibit T4 to T3 (thyroid hormones) conversion, therefore inhibiting further sympathetic stimulation.

7.10 Which beta-blockers have "intrinsic sympathetic activity"? What does this signify? What are the clinical indications for these medications?

Acebutolol (B1 selective antagonist) and pindolol (non-selective Beta blocker).

These medications are able to “weakly” stimulate beta receptors, however, they are considered antagonists because they block the much more potent stimulation that initiated by endogenous catecholamines, such as epinephrine and norepinephrine.

Clinically, their effects cardiovascularly are lesser than other beta-blockers without the intrinsic sympathomimetic activity (ISA) feature. An important positive feature is that they do not decrease plasma HDL levels, because they have minimal effect on lipid and carbohydrate metabolism.

When considering receptors, agonists have affinity and intrinsic activity, antagonists have affinity but no intrinsic activity and partial agonists have affinity with less than complete intrinsic activity. Put another way, agonists bind to the receptor and produce an intracellular response; antagonists bind to the receptor (and in so doing block neurotransmitters from binding to the receptor) and do not lead to an intracellular response; and, partial agonists bind to the receptor and produce a submaximal intracellular response.

7.11 What beta-blockers would be safest for asthmatic patients?

Cardio-selective beta blockers or Beta 1 selective. Examples are atenolol and metoprolol.Reason: B2 blockade results in contraction of bronchiolar smooth muscle.

Know that acebutalol, atenolol, esmolol and metoprolol are cardioselective (i.e, beta-1) antagonists.

7.12 Briefly discuss the pharmacology of reserpine and guanethidine.

These medications are unique in the adrenergic antagonist as they do not work on the adrenoceptors.

Reserpine impairs the release of norepinephrine by blocking the magnesium/ATP dependent transport of biogenic amines from cytoplasm into synaptic vesicles within the adrenergic neuron.

Guanethidine blocks release of norepinephrine & displaces norepinephrine from its storage vesicle. This causes depletion of norepinephrine stores at the presynaptic nerve –except in CNS.

7.13 Why do drugs have a generic and a trade name? What is the trade name of drugs listed in Figure 7.7?

The trade name is given by the company that developed the drug and holds the patent. After the patent expires other companies can make the same "generic form" of the drug.

7.14 Where in the body can you find beta-1 receptors? Beta-2 receptors?

Beta-1: Heart and KidneyBeta-2: Vascular smooth muscle, bronchial smooth muscle, liver, skeletal muscle, eye-ciliary muscle, GI tract, gall bladder, urinary bladder detrusor muscle, uterus.

Very important: Beta-1 heart and kidneys, Beta-2 everywhere else.

Be prepared to discuss figures 7.6, 7.8, and 7.10 (these figures have important information that may be on the test).

Cholinergic Agonists

4.1 What would happen if an individual received: (1) a small dose of acetylcholine, (2) a large dose of acetylcholine?

Acetylcholine is a neurotransmitter of the parasympathetic nervous system and can act on at the muscarinic or the nicotinic receptors. Its effects in the heart mimic vagal stimulation; decreasing heart rate and stroke volume. It also decreases blood pressure by activating M3 receptors of the smooth muscles of blood vessels. It would act in the GI tract by increasing gastric and intestinal secretions as well as increasing motility. It causes an urgency to urinate as well as pupil constriction. Thus, in small doses these effects would be observed. In large doses its effects would be deadly due to cardiac failure, asystole, and muscle paralysis unless it was reversed

4.2 How do neostigmine, pyridostigmine, edrophonium, and physostigmine work? What might be the indications for each of these medications?

All of these drugs act as indirect-acting cholinergic agonists by inhibiting acetylcholinesterase.

Neostigmine is used as an antidote to neuromuscular blocking agents. It is also used in treatment of Myasthenia Gravis

Pyridostigmine is another cholinesterase inhibiter, also used to treat MG because it has a longer duration of action than neostigmine and it can be given orally.

Edrophonium acts similar to neostigmine but has a rapid onset and very short duration. Used to diagnose myasthenia gravis. Injection IV would render a rapid increase in muscle strength in someone with MG.

Physostigmine is a substrate for acetylcholinesterase. It is used to increase bladder and intestinal motility. It can be used topically to cause miosis. Used in tx of overdose of anticholinergic drugs (atropine, phenothiazines, and tricyclic antidepressants).These drugs are used to mainly diagnose MG.

4.3 In the OR, why do we frequently coadminister neostigmine and glycopyrrolate?

Nondepolarizing muscle relaxants (NDMRs) compete with ACh at the neuromuscular junction (NMJ) and cause muscle paralysis (they bind to the ACh receptor without producing an effect). We can affect the amount of ACh at the NMJ by administering an anticholinesterase inhibitor like neostigmine. If you merely administer neostigmine, ACh levels at the NMJ will increase and you will reverse the effects of the NDMR. The problem is that ACh levels will go up everywhere else too. The ACh receptor at the NMJ is a nicotinic receptor. Increased ACh stimulation of muscarinic receptors will be associated with bradycardia, increased GI motility, increased salivation and increased tracheobronchial secretions. To avoid the unwanted muscarinic effects associated with neostigmine, we coadminister an anticholinergic/antimuscarinic agent. You could administer atropine but we usually administer glycopyrrolate.

4.4 Name 4 classes of medications that may be used in the treatment of glaucoma.

Beta-blockers, Cholinergic, Alpha Agonists, Carbonic Anhydrase Inhibitors. Timolol (beta-blocker) will decrease intraocular fluid levels. Alpha agonist such as Apraclonidine decreases intraocular fluid and increases fluid drainage. Pilocarpine (cholinergic agonist) produces miosis, thus increasing drainage. Carbonic Anhydrase Inhibitor (acetazolamide) also decreases production of intraocular fluid.

4.5 Which anesthetic medications might exacerbate glaucoma?

MAY cause IOPAtropine (cholinergic antagonist) will block all cholinergic action through the inhibition of muscarinic receptors. This action will dilate the pupil, thus possibly increasing IOP. Glycopyrrolate (cholinergic antagonist)Scopolamine (cholinergic antagonist)Succinylcholine (Depolarizing NMB)

Ketamine may increase IOP

4.6 What are the mechanism of action and indications for bethanechol?

Mechanisms:Bethanechol stimulates muscarinic receptors located on smooth muscle of the gastrointestinal and urinary tracts.Indications:GU tract: it increases muscle tone in the detrusor urinae muscle and relaxes the trigone and sphincter in bladder, causing the expulsion of urine (handy in pts withnonobstructive urinary retention (i.e. neurogenic bladder), post-op&postpartum pts.)Increases GI peristalsis which assists in tx of megacolon. Uses also include relief of gastric atony after bilateral vagotomy.

4.7 What are organophosphate compounds? When are these agents used and how would you treat the toxic side-effects of these agents?

What:Compounds containing carbon-phosphorus. OP has the ability to bind covalently to AChE resulting in a "long-lasting increase at all sites where it is released." It inactivates AChE (critical for nerve function)...ACh then accumulates in the body resulting in muscle overstimulation. Causing disturbances in the cholinergic synapses and can only be reactivated very slowly, if at all.

When used:open-angle glaucoma, prevents postoperative abdominal distention and urinary retention, MG, antidote for tubocurine, produces miosis during ocular surgery, topically to reduce intraocular pressure in open-angle or narrow-angle glaucoma, antihelmintics, and also obviuosly as insecticides, and nerve gas, herbicides.

Note, only medicinal use = treatment of glaucoma. - JM

Toxic side affects-tx:symptoms: general weakness, fatigue, muscle cramps, fasciculation, paralysis, anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor,potentially coma, visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, sweating, hypercalcemia, seizures, SLUDGEM (Salivation, Lacrimation, Urination, Defication, GI motility, Emesis, Miosis)

1. Anticholernergic drugs to counteract effects of excessive AChE i.e. Atropine2. Atropine3. Cholinesterases, specifically, human serum BChE...advances in this area are being made4. Diazepam5. Atropine in conjunction with oximes6. ClassIII anti-arrythmicsCan use many of these drugs in combination to treat symptoms as well as the cause.

Treatment = atropine + 2-pralidoxime (2-PAM).

Book Questions

4.1 A patient with an acute attack of glaucoma is treated with Pilocarpine. The primay reason for tis effectiveness in this condition is?

Pilocarpine can abort an acute attack of glaucoma because it causes pupillary constriction to lower intraocular pressure It binds mainly to muscarinic receptors and can enter the brain. It is not effective in inhibiting sections.

4.2 A soldier’s unit has come under attack with a nerve agent. The symptoms exhibited are skeletal muscle paralysis, profuse bronchial secretions, miosis, bradycardia, and convulsions. The alarm indicates exposure to an organophosphate. What is the treatment?

Administer Atropine and 2-PAM. Organophosphates exert their effect by irreversibly binding acetylcholinesterase and thus can cause a cholinergic crisis. Administration of atropine will block the muscarinic sites but will not reactivate the enzyme before aging occurs. Administering pralidoxime (2-PAM) alone will not protect the patient against the effects of acetylcholine resulting from the AchE inhibition.

4.3 A patient on a diagnostic test for myasthenia gravis would be expected to have improved neuromuscular function after being treated with?

Edrophonium. Edrophonium is a short-acting inhibitor of acetylcholinesterase that is used to diagnose myasthenia gravis. It is a quaternary compound and does not enter the CNS. Donepezil, isoflurophate, and neostigmine are also AChEs but have longer actions. Donepezil is used for Alzheimer. Echothiophate has activeiting in treating open-angle glaucoma. Neostigmine is used to treat Myathenia gravis but not to diagnosis. Atropine is a cholinergic antagonist and thus would have opposite effects. 4.4 The drug of choice for treating decrease salivation accompanying head and neck irradiation is?

Pilocarpine. Pilocarpine, taken orally, has proven to be beneficial. All the others except scopolamine are cholinergic agonists. However, their ability to stimulate salivation is less than Pilocarpine, and their other effects are troubsome.

Cholinergic Antagonists

5.1 What is a belladonna alkaloid? Where does the term belladonna come from?

A group of alkaloids, including atropine and scopolamine, found in plants such as belladonna, used to dilate the pupils, dry respiratory passages, prevent motion sickness and relieve cramping of intestines and bladder. The foliage and berries are extremely toxic, containing tropane alkaloids, which cause a bizarre delirium and hallucinations. They are also used as pharmaceutical anticholinergics. The term "belladonna" comes from the italian language, meaning "beautiful lady", originating either from its usage as cosmetic for the face, or, more probably, from its usage to increase the pupil size in ladies.

5.2 What are the similarities and differences of atropine, scopolamine, glycopyrrolate, and ipratropium?

All are Cholinergic Antagonists and work by inhibiting the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation.-Atropine and Scopolamine are Tertiary amines and are able to cross the blood-brain barrier which means they can have local and central effects -Glycopyrrolate and ipratropium are quaternary amines and cannot cross the blood-brain barrier which makes their effects more local. - They all have similar side effects being blurred vision, confusion, mydriasis, constipation, urinary retention. While Atropine and scopolamine having more central adverse effects Scopolamine- short-term memory loss and sedation and atropine- restlessness, confusion, hallucinations, and delirium.-Atropine, Scopolamine, and Ipratropium are all metabolized in the liver while most glcopyrrolate metabolism occurs in the kidneys.Make sure you understand the difference between a tertiary and quaternary amine. NH3 is a tertiary amine. NH4+ is a quaternary amine. Acetylcholine is another example of a quaternary amine. Charged quaternary amines are less lipid soluble and less likely to cross into the CNS. This is why glycopyrrolate and ipratropium are less likely to produce CNS symptoms (eg, confusion, antiemetic actions of these drugs) than are the tertiary amines atropine and scopolamine.

5.3 How are anticholinergic agents used in the treatment of asthma?

Ipratropium is an inhaled anticholinergic used as bronchodilators for maintenance treatment of bronchospasm and as bronchodilators. Positively charged so does not enter systemic circulation or the CNS isolating effects to the pulmonary system.

They are given by pulmonary route, in the form of aerosol, in the preventive and curative treatment of asthma. They block contraction of smooth muscle caused by Acetylcholine (ACh), as well as having an antispasmodic effect on the bronchi. As with some other cholinergic antagonists they also decrease secretions.

5.4 Discuss "Scope patches". Include in this answer why scopolamine was selected (instead of one of the other anticholinergic).

Scopolamine patches are most commonly used to prevent the nausea and vomiting associated with motion sickness, to prevent post-operative nausea and vomiting. One Scopolamine patch is placed

behind the ear and is good for 3 days. The two anticholinergic with the greatest anti emetic effects are atropine and scopolamine, However scopolamine more readily crosses the blood-brain barrier allowing greater access to the emetic center. Increased lipid solubility also means that scopolamine will be absorbed transdermally more effectively than atropine.

5.5 What is the site of action of scopolamine when used as an antiemetic agent, as a premedicant prior to anesthesia and surgery, and when used criminally (see "Burundanga")?

The site of action of scopolamine when given for anti-emetic purpose is the GI tract. It is an antispasmodic to reduce activity of the gut. The site of action when given as a premedicant prior to anesthesia and surgery is the CNS. The site of action when taken criminally is the CNS as well. Scopolamine is an antimuscarinic, which means that it blocks muscarinic functions.

This answer is mostly correct. We prescribe "scope patches" to prevent motion sickness and for surgical patients at risk of postoperative nausea and vomiting (PONV = important abbreviation). It is believed that scopolamine exerts its antiemetic effects in the brain. Like atropine, scopolamine is an ACh receptor blocker. A major chemical difference is that scopolamine is much more lipophilic than atropine. This property allows it to penetrate the CNS better. Like atropine, scopolamine does reduce GI motility but this is probably not how it prevents PONV. The four important anticholinergic agents listed from least to most lipophilic are scopolamine, atropine, glycopyrrolate (robin) and ipratropium (atrovent).

5.6 Describe atropine toxicity.

Atropine toxicity is when there are effects on the body such as rapid heart rate, palpitations, dryness of the mouth, dilation of pupils, and blurring of near vision. CNS effects may include restlessness, confusion, hallucinations, and delirium, which may progress to depressing, collapse of the circulatory and respiratory systems. Atropine may exacerbate an attack of glaucoma due to increased intraocular pressure as well as urinary retention in the elderly. Children may exhibit rapid increases in body temperature.

From Wikipedia ... A common mnemonic used to describe the physiologic manifestations of atropine overdose is: as per Jon Blinkey "hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter".

I remember being taught this mnemonic in medical school. It refers to the symptoms of hyperthermia, mydriasis, dry mouth, flushing, and delirium.

5.7 Summarize the pharmacology of nicotine (discuss effects of low and high doses and include information from pp 124-125).

Nicotine is a CNS stimulant. At low doses nicotine causes ganglionic stimulation by depolarization and at high doses it causes ganglionic blockade. Nicotine is able to cross the blood brain barrier and produces euphoria, arousal, and relaxation. Nicotine may improve learning, attention, problem solving and reaction time, but adversely can cause irritability, tremors, intestinal cramps, diarrhea, and increased heart rate and blood pressure. This drug has a high potential for addiction that is not easily overcome.

Nicotine is a vasoconstrictor.

"At low doses nicotine causes ganglionic stimulation by depolarization and at high doses it causes ganglionic blockade." This is an important concept that is often difficult to comprehend.

You need to know which cholinergic receptors are nicotinic and which are muscarinic.

Cholinergic receptors are all stimulated by ACh. Some of these receptors may also be stimulated by nicotine (nicotinic receptors), some by muscarine (muscarinic receptors). Nicotine does not stimulate muscarinic receptors and muscarine does not stimulate nicotinic receptors.

Atropine, scopolamine, ipratropium and glycopyrrolate block muscarinic ACh receptors. These drugs are both anticholinergics and antimuscarinics.

If a molecule binds to a receptor and produces a physiologic response it is said to be an agonist at that receptor. It has affinity for the receptor and intrinsic activity. Molecules that have affinity (they bind) but do not have intrinsic activity are called antagonists or blockers.

His Extra Notes in this Section

Low dose atropine may cause bradycardia. The mechanism of action is believed to involve blocking the actions of presynaptic autoreceptors thus blocking the negative feedback loop of ACh and increasing presynaptic ACh output. This will activate muscarinic receptors on the heart and lead to bradycardia. At higher doses, atropine will bind directly to the postsynaptic muscarinic receptors and block the effect of ACh.

Concerning muscle relaxants, know the following.

There are depolarizing and nondepolarizing (NDMR) muscle relaxants.

Of the drugs we will study, only succinylcholine is a depolarizing muscle relaxant. Know that succinylcholine is broken down by a pseudocholinesterase enzyme and it has a very short duration of action (because of rapid clearance). One out of 3000 people do not have the pseudocholinesterase enzyme and if you give it to these patients it will last much longer (it

will last 6-12 hours instead of 5 - 10 minutes because clearance is greatly reduced in patients without the enzyme). This represents a pharmacogenetic difference in how individuals respond to a drug. Also important is that succinylcholine may trigger malignant hyperthermia (MH).

All other muscle relaxants we will study are NDMRs. These may be broken down into two groups: benzylisoquinolines and aminosteroids. The names of the aminosteroids end in "curonium".

Cisatracurium = benzylisoquinoline, has unique metabolism called Hoffman degradation. After administration, temperature and pH changes cause it to break down spontaneously. It is especially good for patients with abnormal liver or renal function who might have trouble metabolizing other NDMRs. It is also useful for long-term administration -- since it is not an aminosteroid, it lacks certain steroid-related side-effects that are associated with other NDMRs.

Pancuronium = long-acting, renally cleared aminosteroid with anticholinergic/antimuscarinic properties (raises HR).

Vecuronium and rocuronium = commonly used intermediate-acting, aminosteroids.

Neurodegenerative Diseases

8.1 How does acetylcholine affect sodium channels?

Binding of acetylcholine at the postsynaptic cell causes the sodium ion channel to open.

Note that in the CNS and the heart, atropine works by different mechanisms. In the brain, sodium channels are affected, in the heart adenylate cyclase is inhibited. – JM

8.2 What is the difference between inhibitory and excitatory pathways?

Stimulation of inhibitory neurons causes movement of ions that result in hyperpolarization of the postsynaptic membrane. Inhibitory neurons release neurotransmitter molecules, such as GABA or glycine the binding of these at their receptor causes: the influx of potassium and chloride hence a weak hyperpolarization that moves the postsynaptic potential away from its firing threshold.

8.3 Would a patient with Parkinson's Disease (PD) benefit from an i.v. dopamine infusion? Why or why not? (In this case, we are interested in the CNS effects of dopamine and not the cardiovascular effects.)

A patient with Parkinson’s disease would NOT benefit from a dopamine infusion because dopamine does not cross the blood-brain barrier which is where dopamine is made and utilized. Patient with PD do benefit from Levodopa that can cross the blood brain barrier.

8.4 Why do we use L-DOPA instead of tyrosine to treat PD?

L-DOPa is converted to Dopamine by a NON-RATE LIMITING enzyme called dopa decarboxylase. Whereas Tyrosine is converted to L-Dopa by a RATE LIMITING enzyme called tyrosine hydroxylase. So if tyrosine is used not all of it will be able to convert to L-Dopa; But the enzyme dopa decarboxylase will quickly convert all available L-Dopa to Dopamine.

8.5 Why do we use L-DOPA instead of DA to treat PD?

Dopamine cannot cross the brain-blood barrier.

8.6 With regards to PD, why are L-DOPA and carbidopa often coadministered?

When given together, carbidopa, a decaboxylase, blocks metabolism of L-dopa in the GI tract and peripheral cells making it more available to the brain.

8.7 What are the differences between MAOa and MAOb?

MAOa specifically metabolizes norepinephrine and serotonin while MAOb metabolizes Dopamine.

8.8 What is the mechanism of action of selegiline?

Selegiline works by selectively inhibiting MAOa and not MAOb making dopamine more available within the neuron.

8.9 Briefly describe the pharmacology of entacapone and tolcapone.

Pharmacology of Entacapone and Tolcapone: both drugs are nitrocatechols that inhibits the action of COMT, an enzyme that plays a role in the metabolism and breakdown of Levodopa. This results in increased CNS uptake of levodopa and increased brain dopamine levels.. Both drugs have different pharmacokinetics and side effects.

8.10 Briefly summarize the pharmacology of amantadine?

This antiviral drug has proven to have positive effects on a number of neurotransmitters associated with Parkinsonism. It’s found to increase the release of dopamine, block cholinergic receptors and inhibits N-methyl-D-Aspartate (NMDA, which is believed to be the primary action at therapeutic concentrations).

Correct. Note that amantadine is not a D2 (dopamine) agonist.

8.10 What is the rationale behind using acetylcholinesterase inhibitors and NMDA antagonists for the treatment of patients with Alzheimer's Disease? What are the most common toxic effects noted by patients being treated with AChE inhibitors

The loss of cholinergic neurons, a type of cortical neuron, and cholinergic transmission is one of the three distinguishing features of dementia of the Alzheimer type. In addition, the over stimulation of glutamate receptors in the CNS has shown to have excitotoxic effects on neurons and by extrapolation may be responsible for neurodegenerative or apoptotic processes.

The use of AChE inhibitors assist in Alzheimer by improving cholinergic transmission through its inhibition of AChE breakdown. On the other hand, a NMDA antagonist blocks the over stimulation of the NMDA-glutamate receptors having a neuro-protective effect.

The most common toxic effects of AchE inhibitors are tremors, bradycardia, nausea, diarrhea, myalgia and anorexia…(Tacrine is associated with hepatotoxicity)

8.11 Describe the pharmacology of bromocryptine.

Bromocriptine, a dopamine receptor agonist, restores dopaminergic neurotransmitter in ways similar to levodopa by facilitating the synthesis of dopamine. It however has a longer duration of action and hence is more suited to prevent the motor fluctuation and dyskinesias that is associated with levodopa.

Bromocriptine is a (dopamine) D2 (and D3) agonist. It does not facilitate DA synthesis.

8.12 Compare and contrast NMDA and glutamate receptors.

Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. NMDA-glutamate receptors are a specific type of glutamate receptors

8.13 Compare and contrast NMDA receptor antagonists used for the treatment of Alzheimer's Disease with ketamine and phencyclidine (PCP).

NMDA receptor antagonists used in the treatment of Alzheimer's Disease, like memantine, work by blocking the NMDA associated ion channels, although very few. In contrast, ketamine, used as an

anesthetic agent and phencyclidine, which has no therapeutic use, block almost all of the ion channels, producing a sedating effect.

8.14 Fill in the blanks: There are two classes of drugs for treatment of Alzheimer's Disease (AD): __________________ (eg. donepezil, galatamine, rivastigmine) and _____________ (eg. memantine). In AD there are decreased cholinergic neural projections. _________ receptor activity is low while ____________ receptor activity is too high (especially NMDA activity). Overstimulation of _________ receptors leads to neuronal death. NMDA receptor _________ are neuroprotective.

8.14 Fill in the blanks: There are two classes of drugs for treatment of Alzheimer's Disease (AD): Acetylcholinesterase inhibitors (eg. donepezil, galatamine, rivastigmine) and NMDA-receptor antagonist (eg. memantine). In AD there are decreased cholinergic neural projections. Cholinergic (nicotinic) receptor activity is low while glutamate receptor activity is too high (especially NMDA activity). Overstimulation of glutamate receptors leads to neuronal death. NMDA receptor antagonists are neuroprotective.

This answer is correct. We will refer to all CNS ACh receptors as cholinergic (instead of nicotinic).

8.15 Make of list of drugs covered in this chapter that activate D2 receptors directly.

Bromocriptine, apomorphine, pramipexole, ropinirole, rotigotine, amantadine, levodopa

Book Questions

8.1 Which one of the following combinations of antiparkinson drugs is an appropriate therapy?

Levodopa, carbidopa, and entacapone. To reduce the dose of levodopa and its peripheral side effects, the peripheral decarboxylase inhibitor, carbidopa is coadministered. As a result, more levodopa is available for metabolism by COMT to 3-methyldopa, which competes with dopa for active transport processes into the CNS. By administering entacapone (an inhibitor of COMT), the competing product is not formed, and more dopa enters the brain. The other choices are not appropriate because neither peripheral decarboxylase nor COMT nor monoamine oxidase metablizes amantadine or the direct-acting dopamine agonists, ropinirole and pramipexole.

8.2 Peripheral adverse effects of levodopa, including nausea, hypotension, and cardiac arrhythmias, can be diminished by including what drug in therapy?

Carbidopa. Carbidopa inhibits the peripheral decarboxylation sof levodopa to dopamine, thereby diminishing the gastrointestinal and cardiovascular effects of levodopa. The other agents listed (bromocryptine, amantadine, entacapone, ropinirole) do not decrease these side-effects.

8.3 Which of the following antiparkinson drugs may cause peripheral vasospasm?

Bromocriptine. Bromocriptine is a dopamine receptor agonist that may cause vasospasm. It is contraindicated in patients with Peripheral Vascular Disease. Ropinirole directly stimulation dopamine receptors but does not cause vasospasm. The other drugs (entacapone, carbidopa, amantadine) do not directly act on dopamine receptors.

8.4 Modest improvement in the memory of patients with Alzheimer’s disease may occur with drugs that increase transmission of which of the following receptors?

Cholinergic. Acetylcholinesterase inhibitors such as rivastigmine, increase cholinergic transmission in the CNS and may cause a modest delay in progression of Alzheimers.

Antidepressants

StimulantsCocaine and methylphenidate (Ritalin) block reuptake of NE, 5HT and DA. A major difference between the antidepressants and the stimulants is that most antidepressants do not block the reuptake of DA. The exceptions are bupropion (Wellbutrin) and MAOIs. Bupropion is the only antidepressant that blocks DA reuptake. MAOIs actually do not block DA reuptake, rather these agents enhance the effects of DA by blocking its metabolism. One way this is clinically important is that DA receptor stimulation is linked to addictive behavior and therefore bupropion and MAOIs may have a role in treatment of nicotine and other addictions.

TCAsBlock NEPI and 5HT reuptake.Differ from all other reuptake blockers because they block muscarinic, alpha-adrenergic and histaminic receptors.(Note difference between blocking reuptake and blocking the receptor.)TCAs are therefore a/w dry mouth, sedation, tachycardia and other important side effects.TCAs are also associated with seizures.TCAs may be very toxic.

SNRIsBlock NEPI and 5HT reuptakelow toxicity

SSRIsBlock 5HT reuptakelow toxicity

AtypicalsThink of these as bupropion and all othersBupropion blocks DA (very unusual for these drugs) and maybe NEPI reuptakeBupropion and TCAs lower seizure thresholdAll others atypicals block 5HT reuptake and have +/- effects on NEPI reuptake

MAOIsMAOI type a block metabolism of (and enhance effects of) NEPI, 5HT and DAMAOI type b block DA metabolism (eg. see chapter 8 - selegiline)MAOIs may be very toxic. MAOI type b are safer than type a.

Study note: Don't worry too much about individual antidepressant drugs. Try to understand the mechanisms of action and differences between the various types of antidepressants. The only individual drugs you need to focus on are bupropion (because it is unique in blocking reuptake of DA), know that selegilene is an MAOb (this drug was discussed with the Anti-Parkinson medications) and that fluoxetine (Prozac) is an SSRI.

Be prepared to discuss serotonin syndrome and this article - http://www.nytimes.com/2007/02/27/healt ... y.htm?_r=2 (This became a landmark case that had a huge impact on US health care. Among other things, it led to dramatic changes in maximal number of hours, rules for supervision and other work conditions in all US residency training programs.)

12.1 What is the mechanism of action of most antidepressant medications?

Most antidepressants act by enhancing or increasing the actions of norepinephrine and/or serotonin in the brain. This is often accomplished by blocking reuptake of norepinephrine and/or serotonin(e.g. SSRIs, SNRIs, and TCAs) or by inactivation of the enzyme MOA which inactivates the neurotransmitter molecules(e.g. MOAIs).

12.2 List several ways to enhance the action of a neurotransmitter.

The action of a neurotransmitter can be enhanced by blocking reuptake, metabolism (MOA, COMT), and receptor sites responsible for feedback inhibition(Alpha-2).

12.3 What is the biogenic amine theory of depression? How may down-regulation of presynaptic inhibitory receptors affect biogenic amine synthesis and release?

Depression is caused by a lack of monoamines (serotonin and norepinephrine) in key sites of the brain.

A decrease in presynaptic inhibitory receptor density would allow for greater synthesis and release of neurotransmitter across the synapse, leading to a therapeutic response.

12.4 What are the pharmacologic similarities and differences between tricyclic antidepressants (TCAs) and SSRIs? Include the indications and adverse effects in your discussion.

Similarities:1) Both inhibit reuptake of neurotransmitter. 2) Both are indicated to treat depression. 3)Both show little ability to block DA receptors. 4) Both cause sexual dysfunction. 5) Both should not be stopped abruptly.

Differences:1)SSRI’s are 300-3000 times more selective to inhibiting reuptake of serotonin. 2)SSRI’s are indicated to treat depression, OCD, PTSD, premenstrual dysphoric disorder, bulimia nervosa, panic disorders and anxiety. 3)TCA’s inhibit reuptake of both Serotonin and norepinephrine. 4)TCA’s also block serotonergic, histaminic, alpha adrenergic and muscarinic receptors, which causes them to have more side effects than SSRI’s (arrhythmias, worsening glaucoma, orthostatic hypotension, drowsiness, dry mouth and urinary retention). 5) TCA’s are indicated in treatment of moderate to severe depression , chronic pain, and migraine headaches.

12.5 Name two serotonin/norepinephrine reuptake inhibitors (SNRIs) (provide generic and trade names). When might these medications be indicated instead of SSRIs or TCAs?

Venlafaxine – EffexorDuloxetine – Cymbalta

SNRI’s are indicated instead of SSRI’s when patients suffer from both depression and chronic pain.SNRI’s are indicated instead of TCA’s because they have fewer adverse effects.

12.6 What are the trade names of the atypical antidepressants bupropion, mirtazapine, nefazodone, and trazodone? What is known about their mechanisms of action? When might these agents be preferred over TCAs, SSRIs or SNRIs?

Bupropion – Wellbutrin: Inhibits reuptake of both norepinephrine and dopamine. Inhibition of dopamine reuptake makes it useful in treating nicotine cravings and withdrawal.

Mirtazapine – Remeron: Blocks presynaptic alpha-2 receptors and enhances the transmission of serotonin and norepinephrine. It also blocks 5-HT-2 receptors and is sedative.

Nefazodone – Serzone and Trazadone – Desyrel : Both drugs block postsynaptic 5-HT2a receptors and increase serotonin release.

12.7 Summarize the pharmacology of TCAs.

Tricyclic antidepressants (TCAs) are used to treat a variety of mood disorders and personality disorders. They derive their name from their chemical structure which includes three rings of atoms. TCAs act similarly to serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the transporters responsible for the reuptake of norepinephrine and serotonin into the presynaptic nerve terminals. This enhances neurotransmission by increasing the extracellular concentrations of these neurotransmitters. TCAs differ from SNRIs in that they also block alpha adrenergic, histamine, and muscarinic receptors. The blockage of these additional receptors is responsible for many of TCAs many undesired side effects(altered mental status, hypotension, tachycardia, seizures...) and is why their use is considered primarily in treatment-resistant cases.

12.8 What 2 MAO inhibitors (MAOIs) are currently available in the US (provide generic and trade names)? Name a muscle relaxant, narcotic and inhalational anesthetic agent that should never be used with MAOIs. What other medications commonly administered during the intraoperative period should be used cautiously in patients taking MAOIs?

Phenelzine (Nardil, Nardelzine) and Selegiline (Emsam) are two MAOIs currently available in the US for the treatment of major depressive disorder. Selegiline is available as a transdermal patch and may also be used to treat Parkinson’s disease in small doses.

The muscle relaxant Cyclobenzaprine (Flexeril), and the opioid analgesic meperidine (Demerol), and the inhalational anesthetic halothane should be avoided in the treatment of patients on MAOIs.

In a perioperative setting indirect sympathomimetic amines such as ephedrine and methamphetamine should be avoided because they significantly increase the intraneuronal storage of norepinephrine, if needed direct acting sympathomimetics (catecholamines) should be used and carefully titrated.

12.9 What are other important points concerning the pharmacology of MAOIs? (See for example: http://books.google.com/books?id=BOqlw_ ... ia&f=false )

MAOIs increase the concentration and availability of monoamine neurotransmitters such as Norepinephrine, Serotonin, and Dopamine by inhibiting the activity of the mitochondrial enzyme

monoamine oxidase which is responsible for the inactivation of any excess of these neurotransmitters that may leak out of the synaptic vesicle when the neuron is at rest.

The inhibition of MAO by MAOIs also interferes with the gastrointestinal tracts ability to degrade the monoamine tyramine (a derivative of the amino acid tyrosine). This inability to completely digest foods containing tyramine is the reason patients are told to avoid such foods as aged cheeses and meats, chicken liver, pickled or smoked fish and alcoholic beverages, particularly red wine. Failure to avoid these foods could result in hypertensive crisis due to the release of large amounts of catecholamines from nerve terminals.

MAOIs should not be used in conjunction with Selective Serotonin Reuptake Inhibitors (SSRIs) due to the risk of the potentially fatal serotonin syndrome. A minimum of 2 weeks should be allowed after the termination of MAOI therapy and the initiation of another class of antidepressant.

12.10 What are the indications and mechanisms of action of lithium? Which second messenger system is associated with lithium? What special problems are associated with the perioperative management of patients who have been taking lithium?

Lithium is considered a mood stabilizer and is primarily used to treat patients with bipolar disorder particularly in manic episodes. The mechanism of action for Lithium is largely unknown but it is thought to interact with the transfer of cations in neuron and also to decrease signalling by interfering with the receptors coupled to the phosphatidylinositol biphosphate (PIP2) second messenger system.

Due to Lithium’s narrow therapeutic range perioperative treatment for patients taking lithium should include adequate fluid management to avoid excessive concentrations of lithium in the blood thus preventing lithium toxicity. Lithium may also potentiate the effects of non-depolarizing muscle relaxants involved in anesthesia.

We are very interested in drugs that may potentiate NDMRs.

Lithium is eliminated in urine and lithium levels should be monitored in patients with fluid and electrolyte abnormalities.

So far we have discussed two second messenger systems, cyclic AMP and PIP2. Make sure you understand the term "second messenger".

BOOK QUESTIONS

12.1 A 55 year old teacher bean to experience changes in mood. He was losing interest in work and lacked the desire to play tennis. He was preoccupied with feelings of guilt, worthlessness, and hopelessness. In addition to the psychiatric symptoms, the patient

complained of muscle aches throughout his body. Physical and lab test were unremarkable. After 6 weeks of therapy with fluoxetine, the patient’s symptoms resolved. However, the patient complains of sexual dysfunction. Which of the following drugs may be useful?

Mirtazapine. Mirtazapine is largely free from sexual side effects. However, sexual dysfunction commonly occurs with selective serotonin reutake inhibitors (fluvoxamine, sertraline, and citalopram) as well as with tricyclic antidresspants, and serotonin/norepi reuptake inhibitors. Lithium is used for treatment of bipolar and mania so would not be the choice here either.

12.2 A 25 yo woman has a long history of depressive symptoms accompanied by body aches. Physical and lab tests are unremarkable. Which of the following drugs would be helpful?

Duloxeine. Duloxetine is a serotonin/norepi reuptake inhibitor and can be used for depression associated with neuropathic pain.

12.3 A 51 yo woman with symptoms of major depression also has narrow-angle glaucoma. Which anti- depressant should be AVOIDED?

Amitriptyline. Amitriptyline has potent antimuscarinic activity and should not be given to patients with glaucoma because of risk of increased ocular pressure. Sertraline, bupropion, mirtazapine, and fluvoxamine lack antagonist activity at the muscarinic receptor and therefore would be okay.

12.4 A 36 yo man presents with symptoms of compulsive behaviour. If anything is out of order, he feels “work will not be accomplished effectively or efficiently.” He realizes his behavior is interfering with his ability to accomplish his daily tasks but he can’t sto. Which of the following drugs would be most helpful?

Fluvoxamine. Selective serotonin reuptake inhibitors are effective in treating OCD and fluvoxamine is approved for this condition. Imipramine, Amitriptyline, Tranylcypromine, and lithium will not treat OCD.

ALL FIGURES FOR CHAPTER 12

CNS Stimulants

10.1 Name 3 common, naturally occurring methylxanthines and describe where they are naturally found.

1. Theophylline --- tea2. Theobromine --- cocoa3. Caffeine --- coffee, tea, cola soft-drink, chocolate candy, cocoa

10.2 What is the principle mechanism of action of methylxanthines?

There are several mechanisms of actions of methylxanthines. The one most likely responsible for the action we see when we consume caffeine is the blocking of adenosine receptors. However, they are also thought to translocate extracellular calcium and cause an increase in cylic adenosine monophosphate and cyclic guanosine monophate caused by inhibition of phosphodesterase.

10.3 What effects do methylxanthines have on seizure threshold? When might this effect be clinically useful?

Methylxanthines include theophylline, which is found in tea: theobromine, found in cocoa: and caffeine. Methylxanthines lower the seizure threshold. It can be useful in Electroconvulsive therapy(ECT) for psychiatric patients. Although pre-treatment with caffeine or xanthines prolong the duration of ECT seizures but has not been clearly shown in controlled trials to increase efficacy.

10.4 What are several indications for caffeine?

• Increases mental alertness• Decreases fatigue• Positive inotropic and chronotropic• Mild diuretic• Relaxes smooth muscles of bronchioles• Respiratory stimulation (eg, treatment of apnea in neonates and infants)

10.5 What is the mechanism of action of nicotine?

Nicotine receptors can be found at multiple places in the CNS. At low doses there is ganglionic stimulation through depolarization. At higher doses there is a ganglionic blockade, which is the blocking of the effect of a hormone or neurotransmitter at a cell-surface receptor by a pharmacologic antagonist bound to the receptor.

10.6 Should nicotine patches be left on during the perioperative period? Explain.

Yes. Studies have shown that nicotine might have an nociceptive effect (reduction in sensitivity to pain), assisting in reducing postoperative analgesic requirements. Although there are concerns in the utilization of the nicotine patch and how it affects cardiovascular function.

You can argue either way. Some people leave them on, some will insist on removing the patch because nicotine is a vasoconstrictor.

10.7 Cocaine is an ester. Is it a benzoic-acid ester or para-amino-benzoic-acid (PABA) ester? What is the mechanism of action of cocaine? How is cocaine unique among local anesthetics.

Cocaine is a benzoic-acid ester, which blocks the reuptake of monoamine neurotransmitters (such as norepinephrine, seratonin & dopamine). It is unique among local anesthetics because of its potential to produce hypertension or local vasoconstriction through the sympathoadrenergic system. Due to these properties, it is still used in operative procedures to the throat & nose.

10.8 Discuss Question 10.1 at the end of chapter 10. What is the general approach to the treatment of cocaine toxicity?

This was the case of an extremely agitated young male in the ER who was a current cocaine user and was given Lorazepam which sedated him and made him go to sleep.

Benzodiazepines are the drug of choice in treating the anxiety and agitation of cocaine withdrawal due to their anxiolytic properties.

Cocaine can induce seizures which would require the use of IV Diazepam.

10.9 A 30 year old male presents with chest pain following cocaine administration. EKG is remarkable for multifocal PVCs. What medications would you use to treat this patient? You may need to research other sources for this question, eg, http://emedicine.medscape.com/article/813959-overview

Cocaine inhibits the re-uptake of Norepinephrine from the presynaptic neurotransmitters. This causes tachycardia, hypertension, and arrhythmias. Benzodiazepines can be given at low doses to help decrease the production of Norepinephrine at the CNS level. This can help to counteract the increased amount of Norepinephrine due to decrease uptake. Morphine could potentially be used in the same way.

In general you need to address agitation (benzodiazepines), hypertension, arrhythmias, and coronary ischemia (caused by vasospasm).

10.10 What are the mechanisms of action and toxic-side effects of amphetamines?

As with Cocaine, the effects of amphetamine on the CNS and peripheral nervous system are indirect. Amphetamine, however, achieves this effect by releasing intracellular stores of catecholamine. Amphetamine inhibits MAO, high levels of catecholamine are readily released into synaptic spaces. The major behavioural effects of Amphetamine result from a combination of its dopamine and norepinephrine release enhancing properties. Amphetamine also acts on the adrenergic system, indirectly stimulating the receptors through norepinephrine release.

The toxic-side effect The amphetamine may cause addiction, leading to dependence, tolerance, and drug- seeking behaviours. In addition, they have the following undesirable effects: insomnia, irritability, weakness, dizziness, tremor, and hyperactive reflexes, confusion delirium, panic states, and suicidal tendencies, especially in mentally ill patients. Moreover, it can cause palpitations, cardiac arrhythmias, hypertension, angina pain, and circulatory collapse. Headache chills, and excessive sweating may also occur. It can cause anorexia, N/V, abdominal cramps, and diarrhea.

10.11 What are the therapeutic uses of amphetamines?

• ADHD- improves attention span, alleviates many behavioural problems, reduces hyperkinesia • Narcolepsy- increased alertness, decreased fatigue, insomnia• Appetite suppressant

10.12 Summarize the pharmacology of methylphenidate.

Methylphenidate is Ritalin. It blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron. In turn, this enhances the release of the dopamine and norepinephrine.

10.13 Describe the pharmacologic treatment of narcolepsy.

The CNS stimulants used for the treatment of narcolepsy are amphetamine or methylphenidate.

Amphetamine has norepinephrine and dopamine release-enhancing properties. It stimulates the entire cerebrospinal axis, cortex, brainstem, and medulla. The result is increased alertness, decreased fatigue, depressed appetite, and insomnia.

Methylphenidate is a dopamine and norepinephrine reuptake inhibitor. It is believed to activate the brain stem arousal system and cortex.

10.14 Briefly summarize the pharmacology of LSD, cannabis, and phencyclidine (PCP).

Lysergic acid diethylamide (LSD): is able to bind to and activate serotonin receptors, causing an exaggerated activation of the receptor. This leads to delusions, altered perceptions (i.e. synesthesia) & rapid mood swings.

Cannabis (THC): acts on cannabinoid receptor type 1 (CB1) & type 2 (CB2). It stimulates the release of dopamine.

Phencyclidine (PCP): works to inhibit the reception of NMDA (N-methyl-D-aspartic acid) on its receptor. It causes hallucinations & neurotoxic effects, as well as dissociative anesthesia.