Pharmacody Namics

8/14/2019 Pharmacody Namics

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Pharmacodynamics

Ma. Minda Luz M. Manuguid,M.D.


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Pharmacodynamics

Pharmacodynamics deals with theaction of a drug on the body; what thedrug does to the body;Mechanisms of Drug Action on thebory:

Receptor interactions

Dose-related phenomena Therapeutic action Toxic effects


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DefinitionsAgonist drug that triggers the same events as thenative ligand when it binds to a receptorAntagonist drug that prevents binding of the nativeligand to the receptor so that it sannot produce itsnormal action

Affinity ability of a drug to bind to a receptor (howwell a drug & a receptor recognize each other)Potency quantity of a drug needed to achieve adesired effect; more potent, lower EC50Quality bioavailability of the drug

Efficacy maximal effect an Agonist can achieve atthe highest practical concentration ( a measure of how well a drug produces a response); high Emax


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Definitions

2 nd messenger small nonprotein water-soluble molecule or ion that readilyspreads a signal throughout the cell by

diffusion (e.g. cyclic AMP; Calcium ions)Signal transduction process by whichextracellular inputs (e.g. drug-receptorinteractions) lead to intracellularmessages that moderate cell physiologysequencing


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TransductionDrug crosses the cell membrane, activates anintracellular receptor e.g. steroid hormonesA transmembrane receptor protein with intracellularenzyme activity is affected by a drug binding to a siteon the enzyme that can alter its activityA drug-transmembrane receptor protein complex binds& stimulates a 2 nd protein such as Tyrosine kinaseA drug binding to a transmembrane ion channelchanges ion conductance, affecting membranepotentials e.g. nicotinic Ach receptor stimulationAn agonist drug binds to a transmembrane receptor,stimulating a G protein, leading to increasedintracellular 2 nd messengers that result in many2intracellular responses e.g. adrenergic stimulation


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Benefits of a Signal Transduction Pathway

Signal amplification Increased cellular processesProteins persist in active form long enough to

process numerous molecules of substrateEach step activates more products than thepreceding step

Signal specificity

Specific cellular components (& thereforespecific cellular processes) are affected


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Drug BindingCovalent bonds sharing of a pair of electronsbetween 2 atoms; very stable, very strong-requires hundreds of kilojoules to disruptnonCovalent bonds generally weak

Hydrogen bondsVan der Waals forcesIonic / Electrostatic interactionsHydrophobic interactions

Effects of Binding :Conformation binding locks a mobile flexiblemolecule into a restricted conformationConfiguration / Stereochemistry -


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Targets for Drug ActionA drug will exert its activity through interactions at one or

more molecular targets macromolecular species thatcontrol the function of cells: surface-bound receptors & ionchannels or internal structures like enzymes & nucleicacids

Targets for Drug action: Processes of Drug Action:Receptors *chemicalIon channels *enzymaticEnzymes *thru receptorsCarriers * thru ion channels*thru 2 nd messengers


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Receptor targets for DrugAction

receptor agonist antagonist

Nicotinic Achreceptor

Acetylcholine;Nicotine

Tubocurarine

blocker Noradrenalin PropranololOpiate Morphine Naloxone5 HT2 receptor 5 HT Ketanserin

Dopamine2

receptor

Dopamine Chlorpromazin

e


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Ion channel targets for DrugAction

Ion channel Effectors:blockers ModulatorsVoltage-gated Nachannel

Localanaesthetics

Veratridine

Renal tubular Nachannel

Amiloride Aldosterone

Voltage-gated Cachannel

Divalent cations Dihydropyridines

GABA-gated Clchannel

Picrotoxin Benzodiazepines

ATP-sensitive K channel

ATP Sulfonylureas

Glutamate-gatedchannel

Dizoclipine,Ketamine

Glycine


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Enzyme targets for DrugAction

Enzyme Effectors:inhibitors FalsesubstratesAcetylcholinesterase (AChE)

Neostigmine;Organophosphates

cycloOxygenase AspirinAngiotensin-convertingenzyme (ACE)

Captopril

Xanthine oxidase AllopurinolCholine acetyltransferase

hemicholinium

Reverse

transcriptase

Didanosine


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Carrier targets for DrugAction

Carrier Inhibitors FalsesubstratesCholine carrier Hemicholinium

Noradrenalinuptake

TCA; Cocaine Amphetamine;Methyldopa

Noradrenalinuptake ( vesicular )

Reserpin

Weak acid carrierProbenecid

Na-K pump Cardiac

glycoside


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Drug ReceptorsDrug receptor macromolecular component of acell with which a drug interacts to produce aresponse; usually a protein, a drug interacts with itin a lock-&-key fashion, initiating a chain of events that leads to a pharmacologic response.

Types of Receptors: Type I : Ionotropic /Ligand-gated ion channels Type II : Metabotropic / coupled to G-protein Type III: Tyrosine Kinase-linked (e.g. Insulinreceptor)

Type IV: Steroid receptors (e.g. Thyroxine; Cortisol)


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Protein Receptors

Receptors for endogenous regulatoryligands hormones, growth factors,neurotransmitters;Enzymes of crucial metabolic orregulatory pathways Acetylcholinesterase,

Enzymes in transport processes Na/K pump;Structural proteins Tubulin;


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Drug Receptor Interactions The binding of a drug to a specific receptor causes someevent which leads to a responseResponse to a drug is graded or dose-dependentDrug-Receptor interactions follow simple mass-actionrelationships:

Only one drug molecule occupies each receptor siteBinding is reversible

For a given drug, the magnitude of response is directlyproportional to the number of receptor sites occupied bydrug molecules

The number of drug molecules is assumed to be muchgreater than the number of receptor sites


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Drug Receptor InteractionsReceptor specific macromolecule ( Proteins 90% - membrane, cytoplasmic or extracellularenzyme, nucleic acid; Lipids; Carbohydrates)which is the site of action of most drugs: Onlyaround 10% of drug actions & effects are NOTmediated thru receptors.For most drugs, the magnitude of the

pharmacological response increases as the

dose (drug concentration) increasesOnly one drug molecule occupies each receptorsite, & binding is reversible


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The Dissociation Constant

The Dissociation Constant KD drug concentration at which half maximal binding occurs: the smallerthe KD, the greater the affinity of thedrug to the receptor; the smaller theKD for a reaction, the lower the

concentration of drug required inorder to produce half maximalbinding


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Log dose Response curvecharacteristics:Maximal effect (plateau)

Potency the location of the drug response curvealong the horizontal axis: drug effect with respect todose (vs. Efficacy maximal ceiling effect)

Slope Standing curve minute changes in dose result in largeeffectsInclining curve large changes in dose needed for an effect

Variability the curve is different from drug to drug,from patient to patient, & from time to time in thesame patient. So if you want to fix the pharmacologicresponse at a certain level, you have to use a Rangeof Dose


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Log dose Response Curve

Log dose

slope

potency

variability

Maximaleffect

intensity ofeffect


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Dose ResponseRelationship

No drug can create a new effect: a drug onlymodulates a pre-existing functionDrug-receptor interaction leads toenhancement, inhibition, or blockade of molecular signals, which is then amplified thrubiochemical & physiologic events to producethe pharmacological (clinical) effect

The magnitude of a response is graded, i.e.

increases continuously as the concentration of unbound drug increases at the receptor site


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DefinitionsGRADED-RESPONSE CURVE : A plot of efficacy(some measured value, such as blood pressure) -vs-drug concentration.

EC50 = drug concentration at which 50% efficacy isattained. The lower the EC50, the more potent the drug.Emax = the maximum attained biological response out of

the drug.QUANTAL DOSE-RESPONSE CURVE : A graph of discrete (yes-or-no) values, plotting the number of subjects attaining the condition (such as death, orcure from disease) -vs- drug concentration.

ED50 : dosage at which 50% of the population attains thedesired effectLD50 : dose at which 50% of the population is killed from adrug.


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Agonists & AntagonistsAgonists drugs that interact with &activate receptors

Full agonists maximal efficacy (Emax)Partial agonists less than maximal efficacy - At

low concentrations, it increases the overallbiological response from the receptor. At highconcentrations, as all receptors are occupied, itacts as a competitive inhibitor and decreasesthe overall biological response from the receptor.

Antagonists drugs that prevent theagonists from having an effect by binding tothe receptor or to part of the effectormechanism; have no effect themselves


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AGONIST ANTAGONISTAgonist has affinityplus intrinsic activity

Antagonist has affinitybut NO intrinsicactivity

Partial agonist hasaffinity & (less)intrinsic activity

Competitiveantagonists may beovercome(surmountable)

Agonists tend todesensitize receptors

Antagonists tend toup-regulate receptors


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InhibitionCOMPETITIVE INHIBITORS : They bind to the same site asthe endogenous molecule, preventing the endogenousmolecule from binding.

The Dose-Response Curve SHIFTS TO THE RIGHT in thepresence of a competitive inhibitor. EC50 is increased: more of a drug would be required to achieve same effect. Emax doesnot change: maximum efficacy is the same, as long as you haveenough of the endogenous molecules around.

The effect of a competitive inhibitor is REVERSIBLE and can beovercome by a higher dose of the endogenous substance.

The intrinsic activity of a competitive inhibitor is 0 . It has noactivity in itself, but only prevents the endogenous substancefrom having activity.


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InhibitionNON-COMPETITIVE INHIBITORS : They either (1)bind to a different (allosteric) site, or (2) they bindirreversibly to the primary site.

The Dose Response Curve SHIFTS DOWN in the presence of a non-competitive inhibitor. EC50 is increased: more of adrug would be required for same effect. Emax decreases:

The non-competitive inhibitor permanently occupies someof the receptors. The maximal attainable response istherefore less.

The intrinsic activity of the non-competitive inhibitor isactually a negative number , as the number of functionalreceptors, and therefore the maximum attainable biologicalresponse, is decreased.


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Properties of a DrugSafety:Therapeutic Index (TI) = LD50 / ED50

The ratio of median lethal dose to median effective dose. The higher the therapeutic index, the better. That means that ahigher dose is required for lethality, compared to the doserequired to be effective.

minimum dose that produces toxicity over the minimum dosethat produces an effective therapeutic response; TI < 4=relatively greater potential for toxicity

Margin of Safety = LD1 / ED99 The ratio of the dosage required to kill 1% of population,compared to the dosage that is effective in 99% of population.

The higher the margin of safety, the better. greater differencebetween therapeutic effective dose (ED) & toxic dose (TD)


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Drug interactionsSynergism/Potentiation concomitantadministration of another drug will increase theclinical effect e.g. multi-regimen TB treatmentAddition effects of two drugs administered at thesame time will be added to each other e.g. DOLCET

Inhibition simultaneous administration of anotherdrug will decrease the effects of the first e.g. Warfarin& vitamin K Pharmacokinetic interaction giving of another drugwill affect the firsts absorption, distribution,metabolism, &/or excretion


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Adverse Effects & DrugInteractions

Side effect - part of the pharmacologic action of the drug but not the effect the drug is being usedfor; may be undesirable (adverse) e.g. gastricirritation from NSAIDSHypersensitivity reactions / Drug Allergy : Anexaggerated, immune-mediated response to adrug.

TYPE-I : Immediate IgE-mediated anaphylaxis.

e.g. Penicillin anaphylaxis .


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Immunologic Reactions TYPE-II: Antibody-Dependent Cellular Cytotoxicity (ADCC). IgGor IgM mediated attack against a specific cell type, usuallyblood cells (e.g. Hemolytic anemia : induced by Penicillin orMethyldopa; Thrombocytopenia : induced by Quinidine;Drug-induced SLE caused by Hydralazine or Procainamide.

TYPE-III: Immune-complex drug reaction Serum Sickness: Urticaria, arthralgia, lymphadenopathy, fever. Steven-

Johnson Syndrome: Form of immune vasculitis induced bysulfonamides. May be fatal. Symptoms: Erythema multiforme,arthritis, nephritis, CNS abnormalities, myocarditis.

TYPE-IV: Contact dermatitis caused by topically-applied drugsor by poison ivy.


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Drug ToxicityDrug Toxicity : dose-dependent adverse response to adrug.

Organ-Directed Toxicity: Aspirin induced GI toxicity (due toprostaglandin blockade); Epinephrine induced arrhythmias (dueto beta-agonist); Propanolol induced heart-block (due to beta-antagonist); Aminoglycoside-induced renal toxicity;Chloramphenicol-induced aplastic anemia .Neonatal Toxicity: Drugs that are toxic to the fetus ornewborn. Sulfonamide-induced kernicterus;Chloramphenicol-induced Grey-Baby Syndrome; Tetracycline -induced teeth

discoloration and retardation of bone growth.


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TeratogensTERATOGENS : Drugs that adversely affect thedevelopment of the fetus: especially dangerousduring organogenesis (3 rd to 8 th week)

Thalidomide :

Antifolates such as Methotrexate . Phenytoin : Malformation of fingers, cleft palate. Warfarin : Hypoplastic nasal structures. Diethylstilbestrol: Oral contraceptive is no longer

used because it causes reproductive cancers indaughters born to mothers taking the drug.

Aminoglycosides, Chloroquine: Deafness


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Idiosyncrasy

Drug Idiosyncrasies : An unusual response to a drug due togenetic polymorphisms, or for unexplained reasons.

Isoniazid: N -Acetylation affects the metabolism of isoniazid Slow N -Acetylation : Isoniazid is more likely to cause peripheral neuritis.

Fast N -Acetylation : Some evidence says that Isoniazid is more likely to causehepatotoxicity in this group. However, other evidence says that age (above 35 yrsold) is the most important determinant of hepatotoxicity.

Alcohol can lead to facial flushing, or Tolbutamide can lead tocardiotoxicity, in people with an oxidation polymorphism.


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Drug IdiosyncrasiesSuccinylcholine can produce apnea in people with abnormal serumcholinesterase. Their cholinesterase is incapable of degrading thesuccinylcholine, thus it builds up and depolarization blockade results.Primaquine, Sulfonamides induce acute hemolytic anemia inpatients with Glucose-6-Phosphate Dehydrogenase deficiency .

They have an inability to regenerate NADPH in RBC's ------> all reductiveprocesses that require NADPH are impaired.

Note that this is Acute Hemolytic Anemia, yet it is not classified as anallergic reaction -- it is an idiosyncrasy when caused by sulfonamides orprimaquine. Other anemias are Type-II hypersensitivity reactions.

G6PD deficiency is most prevalent in blacks and semitics. It is rare incaucasians and asians.

Barbiturates induce porphyria (urine turns dark red on standing) inpeople with abnormal heme biosynthesis.

Psychosis, peripheral neuritis, and abdominal pain may be found.


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Tolerance Pharmacokinetic Tolerance : Increase in theenzymes responsible for metabolizing the drug.e.g. Warfarin doses must be increased in patientstaking barbiturates or phenytoin, because thesedrugs induce the enzymes responsible formetabolizing warfarin.Pharmacodynamic Tolerance : Cellular tolerance,due to down-regulation of receptors, or down-regulation of the intracellular response to a drug.

Physiologic Tolerance : Two agents yieldopposite physiologic effects.


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ToleranceCompetitive Tolerance : Occurs when an agonistis administered with an antagonist. Example:Naloxone and Morphine are chemical antagonists,and one induces tolerance to the other.

Tachyphylaxis (Refractoriness /Desensitization) progressive reduction in drugeffect due to receptor desensitization

Homologous decrease in number of receptorsHeterologous decreased signal transduction

e.g.Tyramine can cause depletion of all NE stores if youuse it long enough, resulting in tachyphylaxis.


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Habituation & Addiction

Habituation getting used to adrug such that one becomesemotionally dependent on the drugAddiction true physical as well asemotional dependence on a drug; willneed pharmacologic support duringwithdrawal


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Pharmacody Namics