1. IV G. Well-established Second Messengers cAMP Second messenger: Cyclic AMP 1. cAMP is 2nd messenger - released into cytoplasm due to 1st messenger (hormone) binding; a number of others in eukaryotic cells 2. 2nd messengers can activate many cell activities leading to large-scale, coordinated response

2. IV G. Well-established Second Messengers cAMP mediates such hormonal responses as: the mobilization of stored energy *the breakdown of carbohydrates in the liver *the breakdown of triglycerides in fat cells increased rate and strength of heart muscle contraction the conservation of water by the kidneys cAMP inducing agent=vasopressin Ca++ homeostasis cAMP inducing agent = parathyroid hormone many many other responses mediated by cAMP Beta- adrenergic catecholamines

3. IV G. Well-established Second Messengers cAMP GTP Agonist binding AC Activation of Gs and stimulation of the effector Adenylyl Cyclase (AC) ATP cAMP Conversion of ATP to cyclic AMP (cAMP) by AC. Cat Reg cAMP-dependent protein kinase [CAMP kinase] Reg= regulatory region Cat= catalytic region

4. IV G. Well-established Second Messengers cAMP GTP Agonist binding AC ATP cAMP Cat Reg cAMP-dependent protein kinase [CAMP kinase] cAMP Binding of cAMP to Reg sites releases the cat regions which can phosphorylate proteins. Substrate P ATP Cellular Response Cat

5. IV G. Well-established Second Messengers cAMP Substrate P Cellular Response Can include any of these: *Enzyme activation *Protein synthesis *Muscle relaxation *Nerve stimulation *Hormone secretion

6. IV G. Well-established Second Messengers cAMP When the agonist stimulus stops, the intracellular actions of cAMP are terminated by three mechanisms (1-3). GTP Agonist dissociates AC ATP cAMP GDP GTP hydrolysis 5’-AMP Cyclic nucleotide phosphodiesterases X X CAMP kinase activation is inhibited Re-establishment of the tetramer Substrate P P Phosphatases Diminished cellular response Cat Reg Phosphorylated substrate generated by CAMP kinase is de-phosphorylated 1 2 3

7. IV G. Well-established Second Messengers cAMP GTP Agonist dissociates AC ATP cAMP GDP GTP hydrolysis 5’-AMP Cyclic nucleotide phosphodiesterases X FYI Caffeine Theophylline Other methylxanthines Act as competitive inhibitors of phosphodiesterases What would you expect the effect of caffeine on cAMP levels to be? How about on CAMP kinase?

8. IV G. Well-established Second Messengers cAMP Different cells express different types of substrates for CAMP kinase, which helps explain some of the tissue- specific effects: CAMP Phosphorylase Kinase ATP P Glucose released from glycogen Glycogen Synthase CAMP ATP Glycogen Synthase P Inhibition of glycogen synthesis In Liver Activated by phosphorylation inactivated by phosphorylation

9. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides Another well-studied 2 nd messenger system involves receptor- mediated stimulation of phosphoinositide hydrolysis. Some of the agonists, hormones and growth factors that trigger this pathway bind to G-protein coupled receptors (G q - coupled) Receptor acetylcholine (muscarinic) alpha1-adrenergic platelet activating factor serotonin (5-HT 1C and 5-HT 2) 2 nd messenger Ca++ & phosphoinositides

10. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides Inositiol-Phosphate Pathway A. Ligand binding activates G protein B. G protein activates phospholipase C (PLC) C. PLC hydrolyzes phosphatidyl inositol 4,5 bis-phosphate to diacylglycerol (DAG) and inositol 1,4,5 tris-phosphate (IP3) - both second messengers 1. IP3 goes to ER where it stimulates the - release of calcium and activates protein kinases 2. DAG stays in membrane where it binds and activates protein kinase C (PKC)

11. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides PLC family that produces two second messengers, diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) by hydrolyzing the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). GTP Agonist binding PLC PIP2 DAG IP3 Gq protein stimulation

12. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides IP3 goes to ER where it stimulates release of calcium activates protein kinases GTP Agonist binding PLC PIP2 DAG IP3 Gq protein stimulation Ca++

13. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides Released Ca++ binds to calmodulin. GTP Agonist binding PLC PIP2 DAG IP3 Gq protein stimulation Ca++ Ca++ release ER Calmodulin

14. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides Calmodulin becomes activated and stimulates signaling through calcium/ calmodulin dependent protein kinases GTP Agonist binding PLC PIP2 DAG IP3 Ca++ Ca++ release ER Ca++ Calcium/Calmodulin-Dependent Protein Kinase

15. Calmodulin IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides GTP Agonist binding PLC PIP2 DAG IP3 Ca++ Ca++ release ER Ca++ Calcium/Calmodulin-Dependent Protein Kinase Inactive Active P

16. Calmodulin IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides Ca++ Calcium/Calmodulin-Dependent Protein Kinase Substrate P ATP Cellular Response active

17. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides GTP Agonist binding PLC PIP2 DAG IP3 Gq protein stimulation Meanwhile, DAG stays in membrane where it binds and activates protein kinase C (PKC) PKC inactive

18. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides GTP Agonist binding PLC PIP2 DAG IP3 Gq protein stimulation Activated PKC will phosphorylate certain substrates involved in cellular response. PKC active Substrate P ATP, Ca++ Cellular Response

19. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides In addition to general calcium/calmodulin-dependent protein kinases that can phosphorylate a wide variety of substrates, Different cell types may contain one or more specialized Calcium/calmodulin-dependent protein kinases with limited substrate specificity (eg. myosin light chain kinase). At least nine different types of PKC have been characterized.

20. IV G. Well-established Second Messengers Ca++ (Calcium) and Phosphoinositides Multiple mechanisms exist to terminate signaling by this PLC pathway: IP3 is rapidly dephosphorylated by phosphatases DAG is either phosphorylated and converted back to into phospholipids or deacylated to yield arachidonic acid Ca++ is actively removed from the cytoplasm by calcium ion pumps (into ER) These and other nonreceptor elements of the calcium- phosphoinositide signaling pathway are now becoming targets for drug development.

21. IV G. Well-established Second Messengers cGMP cGMP (cyclic guanosine-3’,5’-monophosphate) has established signaling roles in only a few cell types. In intestinal mucosa and vascular smooth muscle, cGMP-based signal transduction is initiated when: *ligand binds to extracellular domain of receptor *ligand binding stimulates intracellular guanylyl cyclase activity *cGMP activates cGMP-dependent protein kinases GTP cGMP Guanylyl cyclase cGMP-dependent protein kinase Substrates get phosphorylated

22. IV G. Well-established Second Messengers cGMP Increased cGMP ANF- R GCactivity Atrial natriuretic factor Binds its receptor GTP cGMP cGMP accumulation Guanylyl cyclase NO GTP cGMP cGMP accumulation The lipid-soluble gas nitric oxide (NO) is released by nearby vascular endothelial cells And direct activates the enzyme. Several vasodilator drugs mimic NO

23. IV H. Phosphorylation: a Common Theme *Reversible phosphorylation is involved in almost all 2 nd messenger systems. *Phosphorylation plays a key role in every step of signaling: Regulation of receptors (eg. autophosphoryltion; desensitization) Regulation of kinases and kinase-substrates modulating cellular responses

24. IV H. Phosphorylation: a Common Theme Think of phosphorylation as a molecular ‘memory’ phosphorylation records the memory dephosphorylation erases the memory, often taking longer than is required for dissociation of ligand Lastly, cAMP, Ca++ and other 2 nd messengers can use the presence or absence of kinases or kinase substrates to produce different effects in different cell types.

25. V. Receptor Classes and Drug Development Receptor Subtypes Evidence for receptor subtypes arose because agonists that supposedly mimicked the same neurotransmitter had radically different postsynaptic effects at different sites. For example, although both smooth and striated muscle contain acetylcholine receptors, nicotine exerts potent agonistic effects on striated muscle, yet is nearly ineffective on smooth muscle. Similarly, muscarine exerts potent agonistic effects on smooth muscle, yet is much less effective on striated muscle. Thus acetylcholine receptors come in at least two varieties, nicotinic and muscarinic.

26. V. Receptor Classes and Drug Development The same chemical can act on completely different receptor classes: Acetylcholine activates nicotinic acetylcholine receptors *Ligand-gated ion channel activates muscarinic acetylcholine receptors *G-protein coupled receptor (Gq) Each receptor class usually includes multiple subtypes of receptor, often with significantly different signaling or regulatory properties.

27. V. Receptor Classes and Drug Development The same chemical can act on completely different receptor classes: Norepinephrine activates many structurally-related receptors beta-adrenergic G protein-coupled, Gs; increased heart rate alpha1-adrenergic G protein-coupled, Gq; vasoconstriction alpha2-adrenergic G-protein coupled, Gi; opening of K+ channels; decreased heart rate

28. V. Receptor Classes and Drug Development The existence of multiple receptor classes and subtypes for the same ligand has opened up opportunities fro drug development: Propranolol, a selective antagonist of beta-adrenergic receptors can reduce heart rate without preventing the sympathetic nervous system from inducing vasoconstriction (because it acts at beta-adrenergic and not alpha) (alpha mediates vasoconstriction)

29. V. Receptor Classes and Drug Development Drug selectivity may apply to structurally identical receptors expressed in different cells for example: the drug tamoxifen acts as an *antagonist on estrogen receptors in mammary tissue (useful as treatment in breast cancer) *agonist on estrogen receptors in bone. (may help against osteoporosis) *partial agonist on estrogen receptors in the uterus (stimulates endometrial cell proliferation)

30. V. Receptor Classes and Drug Development Drug selectivity may apply to structurally identical receptors expressed in different cells WHY? different cell types express different accessory proteins which interact with steroid receptors and change the functional effects of drug- receptor interaction.

31. V. Receptor Classes and Drug Development NEW DRUG DEVELOPMENT not confined to agents that act on receptors clinically useful agents might be developed that act selectively on specific: G proteins kinases phosphatases or the enzymes that degrade 2 nd messengers

32. VI.Relationship Between Drug Dose and Clinical Response When faced with a patient who needs treatment: *variety of possible drugs which one will drug will produce a maximal benefit? what kind of dosing regimen is required? The prescriber must understand: *how drug-receptor interactions underlie the relations between dose and response in patients *are there known variations in responsiveness to the drug? Toxic side effects?

33. VI A.Dose and Response in Patients Graded Dose-Response Curves show effects on a continuous scale and the intensity of the effect is proportional to the dose. (what we’ve been discussing thus far) EFFECT (% of maximum) Log concentration

34. Which is more potent? A  lower dose needed to elicit 50% max response VI A.Dose and Response in Patients Graded Dose-Response Curves When choosing among drugs and determining appropriate doses of drug, it is important to consider each drug’s potency and maximal efficacy. AB Potency refers to the concentration EC50 or dose ED50 of drug required to produce 50% of that particular drug’s maximal effect. Response 100% 50% Log [Drug] EC50

35. VI A.Dose and Response in Patients AB Response 100% 50% Log [Drug] EC50 Which is more potent? C  lower dose needed to elicit 50% of a particular drug’s max response 25% Potency refers to the concentration EC50 or dose ED50 of drug required to produce 50% of that particular drug’s maximal effect. C EC50 NOTE: Drug C acts as a partial agonist.

36. VI A.Dose and Response in Patients Efficacy the measure of an effect produced by a drug. In this example, the maximal efficacy of drug C is less than the maximal efficacies of drugs A and B. Drugs A and B have the same efficacy. AB Response 100% 50% Log [Drug] ED50 25% C ED50

37. VI A.Dose and Response in Patients Efficacy depends on factors such as: route of administration absorption distribution throughout the body clearance from the blood or the site of action

38. VI A.Dose and Response in Patients Shape of Dose-Response Curves Extremely steep dose response curves may have important clinical consequences if the upper portion of the curve represents an undesirable extent of response (eg. coma caused by a sedative-hypnotic). Steep dose-response curves can also be produced by a receptor-effector system in which most receptors must be occupied before any effect is seen. EFFECT (Sedation) Log [Drug] More desirable sleep coma Undesirable

39. VI A.Dose and Response in Patients Quantal Dose-Effect Curves Graded dose-reponse curves are limited in their application to clinical decision making: *impossible to use them if pharmacologic response is an ‘either-or’ event (a quantal event) prevention of: convulsions, arrhythmias, death *clinical relevance of a graded dose response curve in a single patient may be limited in its application to other patients potential variability among patients in *severity of disease *responsiveness to drug

40. VI A.Dose and Response in Patients Quantal Dose-Effect Curves These problems may be avoided by: determining the dose of drug required to produce an effect of specific magnitude in large numbers of patients (or animals) and then plotting the cumulative frequency distribution of responders vs. the log dose. Patients tend to respond to drugs in a distribution similar to a Gaussian normal curve. Percent of Individuals Responding To Treatment (eg. for headache) 100 Log [Drug] 50 ED50 Dose at which 50% of patients exhibit the specified quantal effect

41. VI A.Dose and Response in Patients Quantal Dose-Effect Curves Quantal dose-effect curves may also be used to generate information regarding the margin of safety. Toxic effects of a drug on humans or animals can also be assessed by plotting the cumulative frequency distribution of responders vs. the log dose. As for the therapeutic effects, potentially toxic effects of drugs display a distribution similar to a Gaussian normal curve in people or animals. In order for a drug to have a high margin of safety in patients or animals, therapeutic effects should be observed at lower doses than toxic effects.

42. VI A.Dose and Response in Patients Percent of Individuals Responding 100 Log [Drug] 50 TD50 Dose at which 50% of patients exhibit a toxic effect ED50 Dose at which 50% of patients exhibit the specified quantal effect Cumulative percent of patients exhibiting therapeutic effect Cumulative percent of patients exhibiting toxic effect Quantal curve of a hypothetical drug that provides relief for headaches. Therapeutic effects and toxic effects do not overlap

43. VI A.Dose and Response in Patients Percent of Individuals Responding 100 Log [Drug] 50 TD50 Dose at which 50% of patients exhibit a toxic effect ED50 Dose at which 50% of patients exhibit the specified quantal effect Cumulative percent of patients exhibiting therapeutic effect Cumulative percent of patients exhibiting toxic effect Quantal curve of a second drug that provides relief for headaches. Therapeutic effects and toxic effects slightly overlap

44. VI A.Dose and Response in Patients Percent of Individuals Responding 100 Log [Drug] 50 TD50 Dose at which 50% of patients exhibit a toxic effect ED50 Dose at which 50% of patients exhibit the specified quantal effect Cumulative percent of patients exhibiting therapeutic effect Cumulative percent of patients exhibiting toxic effect Quantal curve of a third drug that provides relief for headaches. Therapeutic effects and toxic significantly overlap

45. VI A.Dose and Response in Patients Percent of Individuals Responding No overlap in the quantal dose-response curve is highly desired (to avoid unwanted toxic effects), but not always possible. The margin of safety of a drug will depend on the ratio between ED50 and TD50. 100 Log [Drug] 50 TD50 ED50 The therapeutic index is defined as the ratio of TD50 ------- ED50 What can be said of a drug’s safety if this ratio is equal or close to 1?

46. VI A.Dose and Response in Patients The therapeutic index (TI) of a drug in humans is almost never known most studies involving obvious toxicity are halted toxicity studies in animals are used to estimate a drug’s therapeutic index. In summary, Both graded and quantal dose-effect curves provide information concerning the potency and selectivity of drugs. The graded dose-response curve indicates the maximal efficacy of a drug. The quantal dose-effect curve indicates the potential variability of responsiveness among patients.

47. VI B.Variation in Drug Responsiveness Individuals may vary in responsiveness to a drug. Responses include: idiosyncratic an unusual response very rarely observed in most patients hypo-responsive drug effect is smaller than expected hyper-responsive drug effect is larger than expected

48. VI B.Variation in Drug Responsiveness Individuals may vary in responsiveness to a drug. Responses include: tolerance responsiveness decreases as a consequence of continued drug administration tachyphylaxis responsiveness diminishes rapidly after administration of the drug When these effects occur, the dose should be modified or the drug itself changed.

49. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness Individuals may vary in responsiveness to a drug. FACTORS to be considered in variable drug responses: agebody size sexdisease state simultaneous administration of other drugs Four general mechanisms may contribute to variations in drug responsiveness. variable drug response may be caused by more than one of these mechanisms

50. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 1. alteration in concentration of drug that reaches the receptor *rate of drug absorption *altered drug distribution in body compartments *altered drug metabolizing enzymes repeated measurements of drug concentrations in blood during the course of treatment are often helpful in dealing with the variability of clinical response caused by pharmacokinetic differences among individuals.

51. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 2. variation in concentration of an endogenous receptor ligand example: saralasin, a weak partial agonist of angiotensin receptors this agent will lower blood pressure in patients with hypertension and lots of angiotensin in patients with low levels of angiotensin, this agent will elevate blood pressure

52. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 3. alterations in number or function of receptors *increases or decreases in the number of receptor sites likely to account for much of the variability in response to SOME drugs among individuals (particularly drugs that act at receptors for hormones, catecholamines, neurotransmitters) Not rigorously established in humans.. BUT: eg. thyroid hormone increases the number of beta- adrenergic receptors in rat heart muscle and cardiac sensitivity to catecholamines. tachycardia has been observed in patients with overactive thyroid glands.

53. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 3. alterations in number or function of receptors in some cases, the agonist can induce a ‘down-regulation’ of its own receptor eg. receptor internalization and degradation >>> synthesis in other cases, an antagonist may increase the # of receptors in a cell or tissue by preventing down-regulation. When the antagonist is withdrawn, the elevated number of receptors can produce an exaggerated response to physiological concentrations of the a agonist.

54. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 3. alterations in number or function of receptors Withdrawal symptoms can often occur when administration of an agonist is discontinued. the # of receptors which has been decreased by drug-induced down-regulation is too low for endogenous agonist to produce effective stimulation. For example, clonidine an agonist of the alpha2-adrenergic receptor whose activity reduces blood pressure Can produce hypertensive crisis if withdrawn abruptly, probably because the drug down-regulates alpha2 receptors.

55. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 3. alterations in number or function of receptors Various therapeutic strategies can be used to address receptor-specific changes in drug responsiveness: *tolerance may require increasing the dose or substituting a different drug *the down- or up- regulation of receptors may make it dangerous to discontinue certain drugs abruptly. the patient may have to be weaned slowly from the drug and watched carefully for signs of withdrawal.

56. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 4. changes in components of response distal to receptor Although drugs act through receptors, drug response depends on the functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systems. CHANGES IN POSTRECEPTOR PROCESSES represent the largest and most important class of mechanisms that cause variations in drug responses.

57. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 4. changes in components of response distal to receptor Characteristics that may limit the clinical response: age and general health of the patient severity and pathophysiologic mechanism of the disease wrong diagnosis (e.g.) congestive heart failure will not respond to agents that increase myocardial contractility if the pathophysiologic mechanism is unrecognized stenosis of the mitral valve rather than myocardial insufficiency.

58. NOT COVERED IN LECTURE... PLEASE READ VI B.Variation in Drug Responsiveness 4. changes in components of response distal to receptor Unsatisfactory therapeutic response can often be traced to compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. For example, tolerance to an antihypertensive vasodilator agent may be due to compensatory increases in sympathetic nervous response as well as fluid retention by the kidney. The patient in which something like this is occurring may require additional drugs to achieve a useful therapeutic response.

59. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Drugs are classified according to their primary effect BUT no drug causes only a single, specific effect! It is more appropriate to say that drugs are selective, rather than specific, in their actions and receptor affinities. that is, they bind one or a few types of receptor more tightly than any other receptors.

60. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Selectivity can be measured by: *comparing binding affinities of a drug to different receptors *comparing EC50 values for different effects of a drug Two types of drug effects: Beneficial (Therapeutic) Toxic (side effect)

61. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by the same receptor-effector mechanism: Direct pharmacologic extension of the therapeutic actions eg. bleeding caused by excess anticoagulant therapy (the dose makes the poison) HOW to deal with this? judicious management of dose can avoid toxicity (along with careful patient monitoring) not administering the drug at all (use of an alternate drug)

62. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by the same receptor-effector mechanism: In some instances, a drug is clearly necessary and beneficial but produces unacceptable toxicity at doses that yield benefit. (in such cases, addition of another drug may be possible) eg. prazosin, an alpha1-adrenergic receptor antagonist acts on receptors in vascular smooth muscle to reduce blood pressure as a consequence, patients may suffer postural hypotension when standing (sudden drop in BP when standing)

63. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by the same receptor-effector mechanism: as a consequence, patients may suffer postural hypotension when standing (sudden drop in BP when standing) Appropriate management? In addition to alpha1 receptors, BP is regulated by changes in blood volume and tone of arterial smooth muscle. Giving a diuretic and a vasodilator may allow the dose of prazosin to be lowered with relief of postural hypotension and continued control of blood pressure.

64. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by the same receptor-effector mechanism: DRUG Receptor DRUG Receptor Toxic Therapeutic Occur within the same tissue eg. vascular smooth muscle; prazosin

65. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by the same receptor-effector mechanism: Postural hypotension: While at rest, quadrupeds have a distinct orthostatic advantage over bipedal humans because their blood reservoirs (mostly veins) are at a similar level as the brain and heart. In contrast, a human in the act of standing has approximately 750 mL of thoracic blood abruptly translocated downward. Standing fills venous blood reservoirs below the heart, removes venous return from the heart, and reduces cerebral perfusion because of the hydrostatic change in BP. In contrast, more than 70% of a dog's vascular capacitance is situated at or above cardiac level, and the dog's brain is at a similar level.

66. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by the same receptor-effector mechanism: Postural hypotension (cont): Upright posture in humans, therefore, is a fundamental stressor. Upright posture requires rapid and effective circulatory and neurologic compensations to maintain BP, cerebral blood flow, and consciousness. Without these compensatory mechanisms, the brain's precarious position well above the neutral cardiac point (roughly at the right atrium) and the presence of large venous reservoirs below the neutral point would cause BP to decrease rapidly because of gravitational pooling of blood within the dependent veins; cerebral ischemia and loss of consciousness would follow rapidly. Once consciousness and postural tone are lost, the resultant fall would render a person recumbent, remobilizing the blood and restoring consciousness. Evolution apparently has dictated a trade-off between manual dexterity and orthostatic competence. http://www.emedicine.com/ped/topic2860.htm

67. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by identical receptors but in different tissues or by different effector pathways: Many drugs produce their desired effects and toxic effects by acting at the same receptor digitalis glycosides (inhibit Na+/K+ ATPase) augment cardiac contractility BUT also cardiac arrhythmias, g.i. effects, vision methotrexate inhibition of dihydrofolate reductase death of tumor cells BUT also, death of healthy cells

68. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by identical receptors but in different tissues or by different effector pathways: Therapeutic strategies to avoid these toxicities? *drug should ALWAYS be administered at the lowest dose that produces acceptable benefit (complete abolition of symptoms may not be achieved) *adjunctive drugs that act through different receptor mechanisms may allow lowering the dose of the first drug, decreasing its toxicity. *specifically placing the drug in parts of the body where it will have reduced toxicity (eg. infusion of drug into a tumor)

69. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by identical receptors but in different tissues or by different effector pathways: DRUG Receptor DRUG Receptor Toxic Therapeutic Tissue 1 Tissue 2 eg. digitalis; therapeutic in cardiac contractility; toxic effects in gastrointestinal tract and eye

70. VII.Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs Beneficial and toxic effects mediated by different types of receptors: New drugs are emerging with improved receptor selectivity. DRUG Receptor 1 DRUG Receptor 1 Response 1 Receptor 2 DRUG Receptor 2 DRUG Response 2 eg. alpha and beta-adrenergic agonists