Pharmacodynamics

Pharmacodynamics

Pharmacodynamics – deals with the action of a drug on the body; what the drug does to the body;

Mechanisms of Drug Action on the bory:Receptor interactionsDose-related phenomenaTherapeutic actionToxic effects

Definitions Agonist – drug that triggers the same events

as the native ligand when it binds to a receptorAntagonist – drug that prevents binding of the

native ligand to the receptor so that it cannot produce its normal action

Affinity – ability of a drug to bind to a receptor (how well a drug & a receptor recognize each other)

Potency – quantity of a drug needed to achieve a desired effect; more potent, lower EC50

Quality – bioavailability of the drugEfficacy – maximal effect an Agonist can

achieve at the highest practical concentration ( a measure of how well a drug produces a response); high Emax

Definitions

2nd messenger – small nonprotein water-soluble molecule or ion that readily spreads a ‘signal’ throughout the cell by diffusion (e.g. cyclic AMP; Calcium ions)

Signal transduction – process by which extracellular inputs (e.g. drug-receptor interactions) lead to intracellular messages that moderate cell physiology sequencing

Mechanisms of Signal Transduction

1 – Drug crosses the cell membrane, activates an intracellular receptor e.g. steroid hormones

2 – transmembrane receptor protein with intracellular enzyme activity is affected by a drug binding to a site on the enzyme that can alter its activity e.g. Ouabain

3 – A drug-transmembrane receptor protein complex binds & stimulates a 2nd protein such as Tyrosine kinase

4 – A drug binding to a transmembrane ion channel changes ion conductance, affecting membrane potentials e.g. nicotinic ACh receptor stimulation

5 – An agonist drug binds to a transmembrane receptor, stimulating a G protein, leading to increased intracellular 2nd messengers that result in many 2ºintracellular responses e.g. adrenergic stimulation

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G protein Signal transduction

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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 the preceding

stepSignal specificity

Specific cellular components (& therefore specific cellular processes) are affected

Drug Binding Covalent bonds – sharing of a pair of

electrons between 2 atoms; very stable, very strong- requires hundreds of kilojoules to disrupt

nonCovalent bonds – generally weak – Hydrogen bondsVan der Waals forces Ionic / Electrostatic interactionsHydrophobic interactions

Effects of Binding:Conformation – binding locks a mobile flexible molecule into a

restricted conformationConfiguration / Stereochemistry – change may alter biologic effects

Targets for Drug Action

“A drug will exert its activity through interactions at one or more molecular targets – macromolecular species that control the function of cells: surface-bound receptors & ion channels or internal structures like enzymes & nucleic acids”

Targets for Drug action: Processes of Drug Action:

Receptors *chemicalIon channels *enzymaticEnzymes *thru receptorsCarriers * thru ion channels

*thru 2nd messengers

Receptor targets for Drug Action

receptor agonist antagonist

Nicotinic Ach receptor

Acetylcholine; Nicotine

Tubocurarine

β blocker Noradrenalin Propranolol

Opiate Morphine Naloxone

5 HT2 receptor

5 HT Ketanserin

Dopamine2 receptor

Dopamine Chlorpromazine

Ion channel targets for Drug Action

Ion channel Effectors: blockers

Modulators

Voltage-gated Na channel

Local anaesthetics

Veratridine

Renal tubular Na channel

Amiloride Aldosterone

Voltage-gated Ca channel

Divalent cations

Dihydropyridines

GABA-gated Cl channel

Picrotoxin Benzodiazepines

ATP-sensitive K channel

ATP Sulfonylureas

Glutamate-gated channel

Dizoclipine, Ketamine

Glycine

Enzyme targets for Drug Action

Enzyme Effectors: inhibitors

False substrates

Acetylcholinesterase (AChE)

Neostigmine; Organophosphates

cycloOxygenase Aspirin

Angiotensin-converting enzyme (ACE)

Captopril

Xanthine oxidase Allopurinol

Choline acetyl transferase

hemicholinium

Reverse transcriptase

Didanosine

Carrier targets for Drug Action

Carrier Inhibitors False substrates

Choline carrier Hemicholinium

Noradrenalin uptake

TCA; Cocaine Amphetamine; Methyldopa

Noradrenalin uptake (vesicular)

Reserpin

Weak acid carrier

Probenecid

Na-K pump Cardiac glycoside

Proton pump in gastric mucosa

Omeprazole

Drug ReceptorsDrug receptor – macromolecular component

of a cell with which a drug interacts to produce a response; usually a protein, a drug interacts with it in a “lock-&-key” fashion, initiating a chain of events that leads to a pharmacologic response.

Types of Receptors:Type I : Ionotropic /Ligand-gated ion

channelsType II : Metabotropic / coupled to G-proteinType III: Tyrosine Kinase-linked (e.g. Insulin

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

Cortisol)

Protein Receptors

Receptors for endogenous regulatory ligands – hormones, growth factors, neurotransmitters;

Enzymes of crucial metabolic or regulatory pathways – Acetylcholinesterase,

Enzymes in transport processes – Na/K pump;

Structural proteins – Tubulin;

Drug – Receptor InteractionsThe binding of a drug to a specific receptor

causes some event which leads to a responseResponse to a drug is graded or dose-

dependentDrug-Receptor interactions follow simple

mass-action relationships: Only one drug molecule occupies each receptor siteBinding is reversible

For a given drug, the magnitude of response is directly proportional to the number of receptor sites occupied by drug molecules

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

Drug – Receptor Interactions

Receptor – specific macromolecule ( Proteins – 90% - membrane, cytoplasmic or extracellular enzyme, nucleic acid; Lipids; Carbohydrates) which is the site of action of most drugs: Only around 10% of drug actions & effects are NOT mediated thru receptors.

For most drugs, the magnitude of the pharmacological response increases as the dose (drug concentration) increases

Only one drug molecule occupies each receptor site, & binding is reversible

The Dissociation Constant

The Dissociation Constant – KD – drug concentration at which half maximal binding occurs: the smaller the KD, the greater the affinity of the drug to the receptor; the smaller the KD for a reaction, the lower the concentration of drug required in order to produce half maximal binding

Log dose – Response curvecharacteristics:Maximal effect (plateau)Potency – the location of the drug response

curve along the horizontal axis: drug effect with respect to dose (vs. Efficacy – maximal ceiling effect)

Slope Standing curve – minute changes in dose result in large effects Inclining 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 the same patient. So if you want to fix the pharmacologic response at a certain level, you have to use a Range of Dose

Log dose – Response Curve

Log dose

slope

potency

variability

Maximal effect

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Dose – Response Relationship

No drug can create a new effect: a drug only modulates a pre-existing function

Drug-receptor interaction leads to enhancement, inhibition, or blockade of molecular signals, which is then amplified thru biochemical & physiologic events to produce the 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

Definitions GRADED-RESPONSE CURVE: A plot of

efficacy (some measured value, such as blood pressure) -vs- drug concentration. EC50 = drug concentration at which 50% efficacy is attained. 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, or cure from disease) -vs- drug concentration. ED50: dosage at which 50% of the population attains the desired

effect LD50: dose at which 50% of the population is killed from a drug.

Agonists & AntagonistsAgonists – drugs that interact with &

activate receptorsFull agonists – maximal efficacy (Emax)Partial agonists – less than maximal efficacy - At low

concentrations, it increases the overall biological response from the receptor. At high concentrations, as all receptors are occupied, it acts as a competitive inhibitor and decreases the overall biological response from the receptor.

Antagonists – drugs that prevent the agonists from having an effect by binding to the receptor or to part of the effector mechanism; have no effect themselves

AGONIST ANTAGONIST

Agonist has affinity plus intrinsic activity

Antagonist has affinity but NO intrinsic activity

Partial agonist has affinity & (less) intrinsic activity

Competitive antagonists may be overcome (surmountable)

Agonists tend to desensitize receptors

Antagonists tend to up-regulate receptors

InhibitionCOMPETITIVE INHIBITORS: They bind to

the same site as the endogenous molecule, preventing the endogenous molecule from binding. The Dose-Response Curve SHIFTS TO THE RIGHT in the

presence of a competitive inhibitor. EC50 is increased: more of a drug would be required to achieve same effect. Emax does not change: maximum efficacy is the same, as long as you have enough of the endogenous molecules around.

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

The intrinsic activity of a competitive inhibitor is 0. It has no activity in itself, but only prevents the endogenous substance from having activity.

InhibitionNON-COMPETITIVE INHIBITORS: They

either (1) bind to a different (allosteric) site, or (2) they bind irreversibly to the primary site. The Dose Response Curve SHIFTS DOWN in the presence of a

non-competitive inhibitor. EC50 is increased: more of a drug would be required for same effect. Emax decreases: The non-competitive inhibitor permanently occupies some of the receptors. The maximal attainable response is therefore less.

The intrinsic activity of the non-competitive inhibitor is actually a negative number, as the number of functional receptors, and therefore the maximum attainable biological response, is decreased.

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 a

higher dose is required for lethality, compared to the dose required to be effective.

minimum dose that produces toxicity over the minimum dose that 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 difference

between therapeutic effective dose (ED) & toxic dose (TD)

Drug interactionsSynergism/Potentiation – concomitant

administration of another drug will increase the clinical effect e.g. multi-regimen TB treatment

Addition – effects of two drugs administered at the same time will be added to each other e.g. DOLCET

Inhibition – simultaneous administration of another drug will decrease the effects of the first e.g. Warfarin & vitamin K

Pharmacokinetic interaction – giving of another drug will affect the first’s absorption, distribution, metabolism, &/or excretion

Adverse Effects & Drug Interactions

Side effect - part of the pharmacologic action of the drug but not the effect the drug is being used for; may be undesirable (adverse) e.g. gastric irritation from NSAIDS

Hypersensitivity reactions / Drug Allergy: An exaggerated, immune-mediated response to a drug. TYPE-I: Immediate IgE-mediated anaphylaxis. e.g.Penicillin

anaphylaxis.

Immunologic ReactionsTYPE-II: Antibody-Dependent Cellular Cytotoxicity (ADCC). IgG or

IgM mediated attack against a specific cell type, usually blood cells (e.g.Hemolytic anemia: induced by Penicillin or Methyldopa; 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 by sulfonamides. May be fatal. Symptoms: Erythema multiforme, arthritis, nephritis, CNS abnormalities, myocarditis.

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

Drug Toxicity

Drug Toxicity: dose-dependent adverse response to a drug. Organ-Directed Toxicity: Aspirin induced GI toxicity (due to

prostaglandin blockade); Epinephrine induced arrhythmias (due to 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 or newborn. Sulfonamide-induced kernicterus;Chloramphenicol-induced Grey-Baby Syndrome; Tetracycline-induced teeth discoloration and retardation of bone growth.

Teratogens

TERATOGENS: Drugs that adversely affect the development of the fetus: especially dangerous during organogenesis (3rd to 8th 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 in daughters born to mothers taking the drug.

• Aminoglycosides, Chloroquine: Deafness

Idiosyncrasy

Drug Idiosyncrasies: An unusual response to a drug due to genetic 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

cause hepatotoxicity in this group. However, other evidence says that age (above 35 yrs old) is the most important determinant of hepatotoxicity.

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

Drug IdiosyncrasiesSuccinylcholine can produce apnea in people with abnormal serum

cholinesterase. Their cholinesterase is incapable of degrading the succinylcholine, thus it builds up and depolarization blockade results.

Primaquine, Sulfonamides induce acute hemolytic anemia in patients with Glucose-6-Phosphate Dehydrogenase deficiency.

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

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

• G6PD deficiency is most prevalent in blacks and Semites. It is rare in Caucasians and Asians.

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

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

Tolerance Pharmacokinetic Tolerance: Increase in the

enzymes responsible for metabolizing the drug. e.g. Warfarin doses must be increased in patients taking barbiturates or phenytoin, because these drugs induce the enzymes responsible for metabolizing 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 yield opposite physiologic effects.

Tolerance

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

Tachyphylaxis (Refractoriness / Desensitization) – progressive reduction in drug effect due to receptor desensitization Homologous – decrease in number of receptorsHeterologous – decreased signal transduction e.g. Tyramine can cause depletion of all NE stores if you use it long

enough, resulting in tachyphylaxis.

Habituation & Addiction

Habituation – getting used to a drug such that one becomes emotionally dependent on the drug

Addiction – true physical as well as emotional dependence on a drug; will need pharmacologic support during withdrawal

Thank You

pharmacogenomics