Mechanisms of Action and Applications of Adrenergic Drugs. As you remember adrenergic agents are divided into two classes (depending on the type of receptors they activate 1. Alpha agonists (stimulate alpha adrenoceptors) 2. Beta agonists (stimulate beta adrenoceptors) In general, their effects resemble the responses to stimulation of adrenergic nerves, but there are often differences in the details and intensity of action of the drugs. 1. What is the effect of sympathomimetic agents on smooth muscle? Inhibition Excitation (or stimulation) Both Neither Very good. No. The answer is C. The sympathomimetic agents produce vasoconstriction in the smooth muscle, in blood vessels supplying skin and mucous membranes, also on salivary and certain sweat glands (alpha-1). On the other hand, there is a relaxation of other types of smooth muscle (e.g. in the G.I. tract, bronchial tree, the bladder and in the vasculature supplying skeletal muscle, beta-2). 2. If beta-2 receptors are considered inhibitory and thus generally relax smooth muscle and alpha-1 receptors are considered excitatory and generally contract smooth muscle, what type of agent might be useful in asthma? alpha-1 adrenoceptor agonist beta-2 adrenoceptor agonist Yes No, The answer is B. Alpha-agonists would NOT usually relax smooth muscle, especially in the bronchial tree! Beta-agonists can be used to treat asthma. 3. What is the effect of sympathomimetic agents on cardiac rate and force of contraction? Inhibition Excitation (or stimulation) Both Neither Fine. No. The answer is B. The SYMPATHOMIMETIC effect on the heart (beta-1) is an increase in both rate and force of contraction. On the other hand, compensatory reflexes may attenuate the responses. Many sympathomimetic agents stimulate alpha receptors as well as beta receptors rising the possibilities of further modification of the apparent responses. 4. What type of receptors are predominantly found in the cardiac muscle? alpha-1 receptors beta-1 receptors both neither Yes. You would think so, since they do generally produce excitation. But, the HEART has mainly beta-1 receptors and they are EXCITATORY!! No, The answer is B. Generally speaking, the heart has beta-1 excitatory adrenoceptors. Both beta-2 and alpha-1 adrenoceptors have been demonstrated in low levels in the heart but their function is uncertain. Remember, HEART : BETA-1!! 5. What is the effect of sympathomimetic agents on metabolism Inhibition Excitation (or stimulation) Both Neither Correct. No, The answer is B. There is an increase in rate of glycogenolysis in the liver and muscle and also liberation of free fatty acids (FFA) from adipose tissue. 6. Epinephrine (EPI) stimulates glycogenolysis by inhibiting phosphodiesterase, an enzyme which converts 3',5'- AMP to 5'- AMP. True False Yes. No, The answer is false. EPI stimulates the conversion of ATP to cyclic 3',5'- AMP by stimulating adenylyl cyclase. Increased cyclic 3',5'- AMP then activates phosphorylase (after several steps) causing glycogen to be converted to glucose-1-phosphate. Please don't get this confused with the METHYL XANTHINES which increase cyclic 3',5'-AMP by inhibiting phosphodiesterase, a catabolizing enzyme. You can see that both EPI the METHYLXANTHINES stimulate the conversion of glycogen to glucose-1-phosphate but through different mechanisms. Also an increase in cyclic 3',5'-AMP causes an increase in the activity of lipases, converting triglycerides to FFA and glycerol with an increase in FFA, cholesterol and lipoproteins in blood. 7. What are the CNS actions of sympathomimetic agents? Inhibition Excitation (or stimulation) Both Neither Correct No, The answer is B. Catecholamines cross the blood brain barrier relatively poorly, producing little or no actions on the CNS. AMPHETAMINE, a non-catecholamine sympathomimetic agent, crosses fairly easily resulting in CNS excitation, respiratory stimulation, increased wakefulness and a reduction in appetite. Let's look a little closer at specific sympathomimetic agents and divide them into two structural classes. 1. Catecholamines 2. Non-catecholamines The catecholamine structure consists of: <.> a phenyl ring with a meta and para OH substitution <.> an ethylamine side chain with or without substitutions 8. Which of the following are not catecholamines? Epinephrine (EPI) Norepinephrine (NOREPI) Amphetamine Isoproterenol Dopamine Very good. No, The answer is C. Amphetamine has no meta or para OH groups on the phenyl ring. This may be related to its property of entering the CNS relatively easily. I think you should also know that amphetamine does have a methyl substitution on the ethylamine side chain which probably protects it from MAO destruction leading to a relatively longer duration of action. The major catecholamine sympathomimetics which we shall discuss are: A. Epinephrine (EPI) B. Norepinephrine (NE) C. Isoproterenol (ISO). All three act directly on adrenergic receptors but their actions differ mainly in the ratio of their effectiveness in stimulating alpha and beta receptors. 9. Which of the following compounds stimulate alpha-receptors? EPI NE ISO Correct Almost Almost No, The first two foils are correct! Both EPI and NOREPI stimulate ALPHA receptors. 10. Which of athe following stimulate beta-receptors? Correct Partly All foils are correct! All three agents stimulate beta-receptors. 11. Which of the following activates predominately alpha-receptors? Correct No, The answer is B. NE produces its activity by stimulating PREDOMINATELY alpha-receptors. 12. However, NE does stimulate beta-1 receptors in the _________. Thank you for not missing this! No, The answer is heart. 13. Which of the following compounds produces its activity by acting almost exclusively on beta-receptors. EPI NE ISO Yes. No, The answer is C. Isoproterenol stimulates beta-receptors almost exclusively. 14. Which of the following compounds stimulates alpha and beta receptors approximately equally? Good. No, The answer is A. EPI stimulates both alpha and beta receptors about equally. Characteristic of this recording is: 1. the rapid rise to a peak that is proportional to the dose 2. the fall below the base line before returning to control level. 15. The rise in blood pressure after EPI is due primarily to Direct myocardial stimulation Increased heart rate Vasoconstriction All of the above A and C only Very good, But what about vagal discharge? The cardiac actions of epinephrine would probably not be of primary importance in increasing blood pressure. Perhaps the most important is the vasoconstriction (alpha-1) in many vascular beds, especially those in the skin and kidney along with the marked constriction of the veins. No. The answer is C. But what about vagal discharge? The cardiac actions of epinephrine would probably not be of primary importance in increasing blood pressure. Perhaps the most important is the vasoconstriction (alpha-1) in many vascular beds, especially those in the skin and kidney along with the marked constriction of the veins. Note that the blood pressure falls below normal before returning to the base line. 16. Which one of the following probably explains this phenomenon? A rebound phenomenon to the initial rise in pressure The vascular beta-2 receptors are more sensitive to epinephrine than are the vascular alpha-1receptors The alpha-1 receptors are more sensitive to epinephrine than the beta-2 receptors. The duration of the vagal reflex is such that an elevated blood pressure does not readjust instantaneously to normal. Yes A depressor effect of small doses and the biphasic response of larger doses are due to greater sensitivity to Epi of beta-2 receptors in vascular beds than of alpha-1 receptors. If an agent is administered prior to epinephrine infusion which blocks alpha-1 receptors, only the fall in blood pressure (the beta-2 response) is observed. This is termed EPINEPHRINE REVERSAL. You MAY see a small transitory pressor response to epinephrine due to cardiac stimulation. No. Acturally very small amonts (0.1 micrograms/KG) may cause the blood pressure to fall below normal without the primary rise. No, makes no sense! No, If the vagus is cut or blocked and the blood pressure is allowed to return to normal, the epinephrine response will still include a fall below baseline. No, The answer is B. 17. Would you see this biphasic response in a blood pressure recording of norepinephrine? yes no Correct. The answer is No. Since NOREPI is predominately an alpha-1 agonist (beta-1 effect found in the heart), you should not see the epinephrine reversal which we just discussed. Generally speaking NOREPI is somewhat less potent than epinephrine, requiring larger doses to produce equal effects. This is primarily true of its alpha action on vascular smooth muscle and its metabolic effects. 18. Which would produce the greater pressure effect, norepinephrine or epinephrine in 10 micrograms/KG doses? norepinephrine epinephrine Correct. No, The answer is Norepi. Even though epinephrine is more potent than norepinephrine in alpha stimulation, the beta dilation in skeletal muscle vasculature seen with EPI overcomes the former. NOREPI will thus probably produce a greater rise in the pressure experiment. Actually all this depends on the baroreceptor response which can be quite unpredictable since it depends on "rate" of change. Isoproterenol produces its response through beta-receptor interaction. 19. The effect of isoproterenol on heart rate would be increase decrease no effect Correct. No, The answer is A. Both heart rate and force of contraction are increased with isoproterenol. The increased cardiac output is generally sufficient to maintain the SYSTOLIC pressure at this predose level even though the MEAN pressure is reduced. Isoproternol relaxes almost all varieties of smooth muscle but its action is most pronounced on bronchial and vascular smooth muscle. 20. Which of the following are most purely alpha-1 agonists, showing little direct effect on the heart, but increasing blood pressure via vasoconstriction? Amphetamine Ephedrine Methamphetamine Phenylephrine Methoxamine Hydroxyamphetamne Metaraminol Correct. No, The last four foils are correct! 21. Which of these are the purest alpha-1 agonists? amphetamine ephedrine methamphetamine phenylephrine methoxamine hydroxyamphetamine metaraminol Great! No. The answer is phenylephrine and methoxamine. PHENYLEPHRINE and METHOXAMINE are the purest ALPHA-1 agonists. 22. Would alpha-1 agonists be used to produce mydriasis? Yes No O.K. No, The answer is A. This is a valid use since the radial muscle has alpha-1 receptors. 23. Would Alpha-1 agonists be used to relieve nasal congestion? Correct. No, The answer is Yes. Nasal decongestion is caused via vasoconstriction of the nasal vasculature (certainly an alpha-1 response). 24. Would alpha-1 agonists be used to produce anorexia? Correct. No, The answer is B. 25. Would Alpha-1 agonists be used in prophylaxis of asthma? Good. The answer is No. 26. Which one of the agents produce CNS stimulation? Amphetamine Ephedrine Methamphetamine Phenylephrine Methoxamine Hydroxyamphetamine Metaraminol Correct! No, The first three foils are correct! Amphetamine, ephedrine and methamphetamine all show CNS stimulation. These are the agents which produce anorexia, insomnia and increased alertness. 27. Which one of these is used as an ingredient in some cough syrups? Amphetamine Ephedrine Methamphetamine Phenylephrine Methoxamine Hydroxyamphetamine Metaraminol Correct! No, The answer is B. Ephedrine shows moderate alpha and beta effects and mild CNS stimulation and used in some cough syrups. Now, let's look at some of the sympatholytics that block adrenergic responses by affecting presynaptic sites. 28. Alpha-methyl-para-tyrosine blocks normal synthesis of catecholamines forming the false transmitter alpha-methyl-norepinephrine. True False Yes. No, The answer is False. Alpha-methyl-dopa forms alpha-methyl-norepinephrine while alpha-methyl-para-tyrosine INHIBITS tyrosine hydroxylase, the ENZYME responsible for the conversion of TYROSINE to DOPA - a rate limiting step. 29. Which of the drugs below blocks transmitter uptake into the synaptic vesicle, exposing the neurotransmitter to metabolism by the mitochondrial MAO? Reserpine Bretylium Cocaine None of the above Great! No, The answer is A. RESERPINE blocks uptake into nerve GRANULES while COCAINE blocks the neuronal uptake (Uptake I) at the CELL MEMBRANE. Don't get that confused!! Bretylium and guanithidine prevent the release of neurotransmitter from the presynaptic neuron. There are also sympatholytics which act at the postjunctional site. There are two major types: alpha blockers (alpha adrenergic recptor antagonists) and beta blockers (beta adrenergic receptor antagonists). 30. Generally speaking, epinephrine + an alpha-1 blocker causes ________ in blood pressure. increase decrease no change Good. No, The answer is B. The alpha-1 blocker + alpha/beta agonist (epinephrine) produces a beta-2 response (i.e. a decrease in blood pressure - remember "epinephrine reversal"). 31. Norepinephrine + alpha blockers produce _______ in blood pressure. An increase A decrease No change Correct. Probably not, since norepi is mostly an alpha agonist, very little or no response in blood pressure would be observed. Probably not, since norepi is mostly an alpha agonist, very little or no respons in blood pressure would be observed. 32. Which of the following alpha blocking agents forms a stable covalent bond with the adrenergic receptor producing a fairly long blockade? Ergot alkaloids (not widely used since they are not specific in their actions) Phenoxybenzamine Phentolamine Chlorpromazine Yes. How did you know that? No. Phentolamine is quite short acting. No, The answer is B. Phenoxybenzamine forms a stable covalent bond and alkylates the receptor site. 33. Patients on alpha blockers frequently experience postural hypotension (also known as orthostatic hypotension) upon sitting standing laying down none of the above Right! No. The answer is B. Normally upon standing there is a stimulation of the baroreceptors and subsequent vasoconstriction to keep the blood from pooling in the periphery; this response is mediated through the alpha effects of NOREPI and is therefore blocked by alpha-1 blockers. The patient may thus faint upon standing. 34. Which one of the alpha blockers listed below has been used in the diagnosis of pheochromocytoma? Ergot alkaloids Phenoxybenzamine Phentolamine Chlorpromazine Great. No, The answer is C. When the short acting alpha blocker phentolamine (5 mg dose) is administered to a patient suffering from pheochromocytoma a sudden decrease in blood pressure will occur (greater than 35/25 mm Hg within 2 minutes. Essential hypertension produces very little change after phentolamine administration. This procedure may be dangerous and pheochromocytomas are generally being diagnosed by VMA concentrations in the urine or circulating catecholamine levels.