Drugs Acting on the Sympathetic Nervous System I

Sympathetic Nervous SystemIn the course of phylogeny an efficientcontrol system evolved that enabled thefunctions of individual organs to be orchestratedin increasingly complex lifeforms and permitted rapid adaptationto changing environmental conditions.This regulatory system consists of theCNS (brain plus spinal cord) and twoseparate pathways for two-way communicationwith peripheral organs, viz.,the somatic and the autonomic nervoussystems. The somatic nervous systemcomprising extero- and interoceptiveafferents, special sense organs, and motorefferents,...

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Drug-independent Effects II

Homeopathy is an alternativemethod of therapy, developed in the1800s by Samuel Hahnemann. His ideawas this: when given in normal (allopathic)dosage, a drug (in the sense ofmedicament) will produce a constellationof symptoms; however, in a patientwhose disease symptoms resemble justthis mosaic of symptoms, the same drug(simile principle) would effect a curewhen given in a very low dosage (“potentiation”).The body’s self-healingpowers were to be properly activatedonly by minimal doses of the medicinalsubstance.The homeopath’s task is not to diagnosethe...

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Drug-independent Effects I

PlaceboA placebo is a dosage form devoid of anactive ingredient, a dummy medication.Administration of a placebo may elicitthe desired effect (relief of symptoms)or undesired effects that reflect achange in the patient’s psychologicalsituation brought about by the therapeuticsetting.Physicians may consciously or unconsciouslycommunicate to the patientwhether or not they are concernedabout the patient’s problem, or certainabout the diagnosis and about the valueof prescribed therapeutic measures. Inthe care of a physician who projectspersonal warmth,...

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Adverse Drug Effects V

Drug Toxicity in Pregnancy andLactationDrugs taken by the mother can bepassed on transplacentally or via breastmilk and adversely affect the unborn orthe neonate.PregnancyLimb malformations induced by thehypnotic, thalidomide, first focused attentionon the potential of drugs tocause malformations (teratogenicity).Drug effects on the unborn fall into twobasic categories:1. Predictable effects that derive fromthe known pharmacological drugproperties. Examples are: masculinizationof the female fetus by androgenichormones; brain hemorrhagedue to oral...

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Adverse Drug Effects IV

Type 2, cytotoxic reaction. Drugantibody(IgG) complexes adhere to thesurface of blood cells, where either circulatingdrug molecules or complexes alreadyformed in blood accumulate.These complexes mediate the activationof complement, a family of proteins thatcirculate in the blood in an inactiveform, but can be activated in a cascadelikesuccession by an appropriate stimulus.“Activated complement” normallydirected against microorganisms, candestroy the cell membranes and therebycause cell death; it also promotes phagocytosis,attracts neutrophil granulocytes(chemotaxis),...

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Adverse Drug Effects III

Drug AllergyThe immune system normally functionsto rid the organism of invading foreignparticles, such as bacteria. Immune responsescan occur without appropriatecause or with exaggerated intensity andmay harm the organism, for instance,when allergic reactions are caused bydrugs (active ingredient or pharmaceuticalexcipients). Only a few drugs, e.g.(heterologous) proteins, have a molecularmass (> 10,000) large enough to actas effective antigens or immunogens,capable by themselves of initiating animmune response. Most drugs or theirmetabolites...

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Adverse Drug Effects II

Increased Sensitivity . If certainbody functions develop hyperreactivity,unwanted effects can occur even at normaldose levels. Increased sensitivity ofthe respiratory center to morphine isfound in patients with chronic lung disease,in neonates, or during concurrentexposure to other respiratory depressantagents. The DRC is shifted to the leftand a smaller dose of morphine is sufficientto paralyze respiration. Geneticanomalies of metabolism may also leadto hypersensitivity. Thus, several drugs(aspirin, antimalarials, etc.) can provokepremature breakdown...

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Adverse Drug Effects I

Adverse Drug EffectsThe desired (or intended) principal effectof any drug is to modify body functionin such a manner as to alleviatesymptoms caused by the patient’s illness.In addition, a drug may also causeunwanted effects that can be groupedinto minor or “side” effects and major oradverse effects. These, in turn, may giverise to complaints or illness, or mayeven cause death.Causes of adverse effects: overdosage. The drug is administered ina higher dose than is required for theprincipal effect; this directly or indirectlyaffects other body functions....

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Drug-Receptor Interaction IX

Time Course of Plasma Concentrationand EffectAfter the administration of a drug, itsconcentration in plasma rises, reaches apeak, and then declines gradually to thestarting level, due to the processes ofdistribution and elimination.Plasma concentration at a given point intime depends on the dose administered.Many drugs exhibit a linear relationshipbetween plasma concentration anddose within the therapeutic range(dose-linear kinetic ; note differentscales on ordinate). However, thesame does not apply to drugs whoseelimination processes are already...

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Drug-Receptor Interaction VIII

Mode of Operation of G-Protein-Coupled ReceptorsSignal transduction at G-protein-coupledreceptors uses essentially the samebasic mechanisms . Agonist bindingto the receptor leads to a change in receptorprotein conformation. Thischange propagates to the G-protein: the!-subunit exchanges GDP for GTP, thendissociates from the two other subunits,associates with an effector protein, andalters its functional state. The !-subunitslowly hydrolyzes bound GTP to GDP.G!-GDP has no affinity for the effectorprotein and reassociates with the " andsubunits ....

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Drug-Receptor Interaction VII

The insulin receptor protein representsa ligand-operated enzyme , acatalytic receptor. When insulin bindsto the extracellular attachment site, atyrosine kinase activity is “switched on”at the intracellular portion. Proteinphosphorylation leads to altered cellfunction via the assembly of other signalproteins. Receptors for growth hormonesalso belong to the catalytic receptorclass.Protein synthesis-regulating receptorsfor steroids, thyroid hormone,and retinoic acid are found in thecytosol and in the cell nucleus, respectively.Binding of hormone exposes...

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Drug-Receptor Interaction VI

Receptor TypesReceptors are macromolecules that bindmediator substances and transduce thisbinding into an effect, i.e., a change incell function. Receptors differ in termsof their structure and the manner inwhich they translate occupancy by a ligandinto a cellular response (signaltransduction).G-protein-coupled receptorsconsist of an amino acid chain thatweaves in and out of the membrane inserpentine fashion. The extramembranalloop regions of the molecule maypossess sugar residues at different Nglycosylationsites. The seven !-helicalmembrane-spanning...

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Drug-Receptor Interaction V

Enantioselectivity of affinity. If areceptor has sites for three of the substituents(symbolized in B by a cone, asphere, and a cube) on the asymmetriccarbon to attach to, only one of theenantiomers will have optimal fit. Its affinitywill then be higher. Thus, dexetimidedisplays an affinity at the muscarinicACh receptors almost 10000 timesthat of levetimide; and at !-adrenoceptors, S(-)-propranolol has anaffinity 100 times that of the R(+)-form.Enantioselectivity of intrinsic activity.The mode of attachment at thereceptor also determines whether...

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Drug-Receptor Interaction IV

Enantioselectivity of Drug ActionMany drugs are racemates, including !-blockers, nonsteroidal anti-inflammatoryagents, and anticholinergics (e.g.,benzetimide A). A racemate consists ofa molecule and its corresponding mirrorimage which, like the left and righthand, cannot be superimposed. Suchchiral (“handed”) pairs of molecules arereferred to as enantiomers. Usually,chirality is due to a carbon atomlinked to four different substituents(“asymmetric center”). Enantiomerism isa special case of stereoisomerism. Nonchiralstereoisomers are called diastereomers(e.g.,...

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Drug-Receptor Interaction III

Agonist stabilizes spontaneouslyoccurring active conformation. Thereceptor can spontaneously “flip” intothe active conformation. However, thestatistical probability of this event isusually so small that the cells do not revealsigns of spontaneous receptor activation.Selective binding of the agonistrequires the receptor to be in the activeconformation, thus promoting its existence.The “antagonist” displays affinityonly for the inactive state and stabilizesthe latter. When the system shows minimalspontaneous activity, applicationof an antagonist...

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Drug-Receptor Interaction II

Agonists – AntagonistsAn agonist has affinity (binding avidity)for its receptor and alters the receptorprotein in such a manner as to generatea stimulus that elicits a change in cellfunction: “intrinsic activity“. The biologicaleffect of the agonist, i.e., thechange in cell function, depends on theefficiency of signal transduction stepsinitiated by the activated receptor.Some agonists attain a maximaleffect even when they occupy only asmall fraction of receptors. Other ligands , possessingequal affinity for the receptor but loweractivating capacity...

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Drug-Receptor Interaction I

Types of Binding ForcesUnless a drug comes into contact withintrinsic structures of the body, it cannotaffect body function.Covalent bond. Two atoms enter acovalent bond if each donates an electronto a shared electron pair (cloud).This state is depicted in structural formulasby a dash. The covalent bond is“firm”, that is, not reversible or onlypoorly so. Few drugs are covalentlybound to biological structures. Thebond, and possibly the effect, persist fora long time after intake of a drug hasbeen discontinued, making therapy difficultto control....

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Quantification of Drug Action V

Concentration-Binding CurvesIn order to elicit their effect, drug moleculesmust be bound to the cells of theeffector organ. Binding commonly occursat specific cell structures, namely,the receptors. The analysis of drug bindingto receptors aims to determine theaffinity of ligands, the kinetics of interaction,and the characteristics of thebinding site itself.In studying the affinity and numberof such binding sites, use is made ofmembrane suspensions of different tissues.This approach is based on the expectationthat binding sites will retaintheir...

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Quantification of Drug Action IV

Disadvantages are:1. Unavoidable tissue injury during dissection.2. Loss of physiological regulation offunction in the isolated tissue.3. The artificial milieu imposed on thetissue.Concentration-Effect Curves (B)As the concentration is raised by a constantfactor, the increment in effect diminishessteadily and tends asymptoticallytowards zero the closer one comesto the maximally effective concentration.The concentration at which a maximaleffect occurs cannot be measuredaccurately; however, that eliciting ahalf-maximal effect (EC50) is readily determined.It...

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Quantification of Drug Action III

Concentration-Effect Relationship (A)The relationship between the concentrationof a drug and its effect is determinedin order to define the range of activedrug concentrations (potency) andthe maximum possible effect (efficacy).On the basis of these parameters, differencesbetween drugs can be quantified.As a rule, the therapeutic effect or toxicaction depends critically on the responseof a single organ or a limitednumber of organs, e.g., blood flow is affectedby a change in vascular luminalwidth. By isolating critical organs or tissuesfrom a larger...

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Quantification of Drug Action II

To illustrate this point, we consideran experiment in which the subjects individuallyrespond in all-or-none fashion,as in the Straub tail phenomenon. Mice react to morphine with excitation,evident in the form of an abnormalposture of the tail and limbs. The dosedependence of this phenomenon is observedin groups of animals (e.g., 10mice per group) injected with increasingdoses of morphine. At the low dose,only the most sensitive, at increasingdoses a growing proportion, at the highestdose all of the animals are affected. There is a relationship...

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Quantification of Drug Action I

Dose–Response RelationshipThe effect of a substance depends on theamount administered, i.e., the dose. Ifthe dose chosen is below the criticalthreshold (subliminal dosing), an effectwill be absent. Depending on the natureof the effect to be measured, ascendingdoses may cause the effect to increase inintensity. Thus, the effect of an antipyreticor hypotensive drug can be quantifiedin a graded fashion, in that the extentof fall in body temperature or bloodpressure is being measured. A dose-effectrelationship is then encountered.The dose-effect relationship...

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Pharmacokinetics VIII

Change in Elimination CharacteristicsDuring Drug TherapyWith any drug taken regularly and accumulatingto the desired plasma level, itis important to consider that conditionsfor biotransformation and excretion donot necessarily remain constant. Eliminationmay be hastened due to enzymeinduction (p. 32) or to a change in urinarypH (p. 40). Consequently, thesteady-state plasma level declines to anew value corresponding to the newrate of elimination. The drug effect maydiminish or disappear. Conversely,when elimination is impaired (e.g., inprogressive...

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Pharmacokinetics VII

Accumulation: Dose, Dose Interval, andPlasma Level FluctuationSuccessful drug therapy in many illnessesis accomplished only if drug concentrationis maintained at a steady highlevel. This requirement necessitatesregular drug intake and a dosage schedulethat ensures that the plasma concentrationneither falls below the therapeuticallyeffective range nor exceedsthe minimal toxic concentration. A constantplasma level would, however, beundesirable if it accelerated a loss of effectiveness(development of tolerance),or if the drug were required to bepresent...

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Pharmacokinetics VI

Time Course of Drug Plasma LevelsDuring Irregular IntakeIn practice, it proves difficult to achievea plasma level that undulates evenlyaround the desired effective concentration.For instance, if two successive dosesare omitted, the plasma level willdrop below the therapeutic range and alonger period will be required to regainthe desired plasma level. In everydaylife, patients will be apt to neglect drugintake at the scheduled time. Patientcompliance means strict adherence tothe prescribed regimen. Apart frompoor compliance, the same problemmay...

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Pharmacokinetics V

Time Course of Drug Plasma LevelsDuring Repeated DosingWhen a drug is administered at regularintervals over a prolonged period, therise and fall of drug concentration inblood will be determined by the relationshipbetween the half-life of eliminationand the time interval betweendoses. If the drug amount administeredin each dose has been eliminated beforethe next dose is applied, repeated intakeat constant intervals will result in similarplasma levels. If intake occurs beforethe preceding dose has been eliminatedcompletely, the next dose will add...

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Pharmacokinetics IV

Drug entry into hepatic and renaltissue constitutes movement into theorgans of elimination. The characteristicphasic time course of drug concentrationin plasma represents the sum ofthe constituent processes of absorption,distribution, and elimination,which overlap in time. When distributiontakes place significantly faster thanelimination, there is an initial rapid andthen a greatly retarded fall in the plasmalevel, the former being designatedthe !-phase (distribution phase), thelatter the "-phase (elimination phase).When the drug is distributed...

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Pharmacokinetics III

Time Course of Drug Concentration inPlasmaA. Drugs are taken up into and eliminatedfrom the body by various routes. Thebody thus represents an open systemwherein the actual drug concentrationreflects the interplay of intake (ingestion)and egress (elimination). When anorally administered drug is absorbedfrom the stomach and intestine, speedof uptake depends on many factors, includingthe speed of drug dissolution (inthe case of solid dosage forms) and ofgastrointestinal transit; the membranepenetrability of the drug; its concentrationgradient across...

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Pharmacokinetics II

The constancy of the process permitscalculation of the plasma volumethat would be cleared of drug, if the remainingdrug were not to assume a homogeneousdistribution in the total volume(a condition not met in reality).This notional plasma volume freed ofdrug per unit of time is termed theclearance. Depending on whether plasmaconcentration falls as a result of urinaryexcretion or metabolic alteration,clearance is considered to be renal orhepatic. Renal and hepatic clearancesadd up to total clearance (Cltot) in thecase of drugs that are eliminated...

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Pharmacokinetics I

Drug Concentration in the Bodyas a Function of Time. First-Order(Exponential) Rate ProcessesProcesses such as drug absorption andelimination display exponential characteristics.As regards the former, this followsfrom the simple fact that theamount of drug being moved per unit oftime depends on the concentration difference(gradient) between two bodycompartments (Fick’s Law). In drug absorptionfrom the alimentary tract, theintestinal contents and blood wouldrepresent the compartments containingan initially high and low concentration,respectively....

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Drug Elimination X

Lipophilic drugs that are convertedin the liver to hydrophilic metabolitespermit better control, because thelipophilic agent can be eliminated inthis manner. The speed of formation ofhydrophilic metabolite determines thedrug’s length of stay in the body.If hepatic conversion to a polar metaboliteis rapid, only a portion of theabsorbed drug enters the systemic circulationin unchanged form, the remainderhaving undergone presystemic(first-pass) elimination. When biotransformationis rapid, oral administrationof the drug is impossible (e.g.,glyceryl...

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Drug Elimination IX

Elimination of Lipophilic andHydrophilic SubstancesThe terms lipophilic and hydrophilic(or hydro- and lipophobic) refer to thesolubility of substances in media of lowand high polarity, respectively. Bloodplasma, interstitial fluid, and cytosol arehighly polar aqueous media, whereaslipids — at least in the interior of the lipidbilayer membrane — and fat constituteapolar media. Most polar substancesare readily dissolved in aqueous media(i.e., are hydrophilic) and lipophilicones in apolar media. A hydrophilicdrug, on reaching the bloodstream,probably...

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Drug Elimination VIII

During passage down the renal tubule,urinary volume shrinks more than100-fold; accordingly, there is a correspondingconcentration of filtered drugor drug metabolites . The resultingconcentration gradient between urineand interstitial fluid is preserved in thecase of drugs incapable of permeatingthe tubular epithelium. However, withlipophilic drugs the concentration gradientwill favor reabsorption of the filteredmolecules. In this case, reabsorptionis not based on an active processbut results instead from passive diffusion.Accordingly, for protonated...

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Drug Elimination VII

The Kidney as Excretory OrganMost drugs are eliminated in urine eitherchemically unchanged or as metabolites.The kidney permits eliminationbecause the vascular wall structure inthe region of the glomerular capillariesallows unimpeded passage of bloodsolutes having molecular weights (MW)<> 70000. Withfew exceptions, therapeutically useddrugs and their metabolites have muchsmaller molecular weights and can,therefore, undergo glomerular filtration,i.e., pass from blood into primaryurine. Separating the capillary endotheliumfrom the tubular epithelium,...

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Drug Elimination VI

ConjugationsThe most important of phase II conjugationreactions is glucuronidation. Thisreaction does not proceed spontaneously,but requires the activated form ofglucuronic acid, namely glucuronic aciduridine diphosphate. Microsomal glucuronyltransferases link the activatedglucuronic acid with an acceptor molecule.When the latter is a phenol or alcohol,an ether glucuronide will beformed. In the case of carboxyl-bearingmolecules, an ester glucuronide is theresult. All of these are O-glucuronides.Amines may form N-glucuronides that,unlike O-glucuronides,...

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Drug Elimination V

Enterohepatic CycleAfter an orally ingested drug has beenabsorbed from the gut, it is transportedvia the portal blood to the liver, where itcan be conjugated to glucuronic or sulfuricacid (shown in B for salicylic acidand deacetylated bisacodyl, respectively)or to other organic acids. At the pH ofbody fluids, these acids are predominantlyionized; the negative charge confershigh polarity upon the conjugateddrug molecule and, hence, low membranepenetrability. The conjugatedproducts may pass from hepatocyte intobiliary fluid and from there back intothe...

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