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PharmacologyPharmacology Pharmacokinetics Pharmacodynamics Pharmacokinetics Pharmacodynamics

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PharmacologyPharmacology Pharmacokinetics Pharmacodynamics Pharmacokinetics Pharmacodynamics PharmacodynamicsPharmacodynamics The biochemical and physiologic mechanisms of drug action What the drug does when it gets there. What the drug does when it gets there. Drug Mechanisms Receptor interactions Non-receptor mechanisms Receptor interactions Non-receptor mechanisms HOW DRUGS ACT : MOLECULAR ASPECTS TARGETS FOR DRUG ACTION * receptors * ion channels * enzymes * carrier molecules PHYSICO-CHEMICAL INTERACTIONS TARGETS FOR DRUG ACTION * receptors * ion channels * enzymes * carrier molecules PHYSICO-CHEMICAL INTERACTIONS Targets for drug action A drug = a chemical that affects physiological function in a specific way. With few exceptions, drugs act on target proteins namely: enzymes carriers ion channels receptors Specificity is reciprocal: individual classes of drug bind only to certain targets, and individual targets recognize only certain classes of drug. No drugs are completely specific in their actions A drug = a chemical that affects physiological function in a specific way. With few exceptions, drugs act on target proteins namely: enzymes carriers ion channels receptors Specificity is reciprocal: individual classes of drug bind only to certain targets, and individual targets recognize only certain classes of drug. No drugs are completely specific in their actions SPECIFICITYSPECIFICITY NONspecific drug action - Not all drugs act via receptors: e.g., antacids neutralize excess gastric acid. general anaesthetics, osmotic act by virtue of their physico-chemical properties Interaction with various macromolecules (Na-K-ATPase, inhibition acetylcholinesterase, as false substrates or inhibitors for certain enzymes). Specific drug action - most drugs produce effects by acting on specific protein molecules called RECEPTORS according to interactions with targets, effects of drugs are: nonspecific specific NONspecific drug action - Not all drugs act via receptors: e.g., antacids neutralize excess gastric acid. general anaesthetics, osmotic act by virtue of their physico-chemical properties Interaction with various macromolecules (Na-K-ATPase, inhibition acetylcholinesterase, as false substrates or inhibitors for certain enzymes). Specific drug action - most drugs produce effects by acting on specific protein molecules called RECEPTORS according to interactions with targets, effects of drugs are: nonspecific specific RECEPTORSRECEPTORS Protein molecules, normally activated by transmitters or hormones. Many receptors have been cloned. Drug receptor = specialized macromolecule that binds a drug and mediates its pharmacological action. Many synthetic drugs that act either as agonists or antagonists on receptors for endogenous mediators. Protein molecules, normally activated by transmitters or hormones. Many receptors have been cloned. Drug receptor = specialized macromolecule that binds a drug and mediates its pharmacological action. Many synthetic drugs that act either as agonists or antagonists on receptors for endogenous mediators. Receptor Interactions Drugs that activate receptors and produce a response are called AGONISTS. AgonistReceptor Agonist-Receptor Interaction Lock and key mechanism Receptor Interactions Receptor Perfect Fit! Induced Fit Interaction of receptors with ligands Formation of chemical bonds mostly electrostatic and hydrogen bonds and van der Waals forces i.e., mostly noncovalent bonds (covalent are important in toxicology mostly) The bonds are usually reversible. The closer the fit and the greater the number of bonds - the stronger are attractive forces between them - the higher the affinity of the drug for the receptor. Formation of chemical bonds mostly electrostatic and hydrogen bonds and van der Waals forces i.e., mostly noncovalent bonds (covalent are important in toxicology mostly) The bonds are usually reversible. The closer the fit and the greater the number of bonds - the stronger are attractive forces between them - the higher the affinity of the drug for the receptor. The first step of drug action on specific receptors is the formation of a reversible drug-receptor complex, the reactions being governed by the Law of Mass Action rate of chemical reaction is proportional to the concentrations of reactants: R = receptor A = drug RA = drug-receptor complex k+1 = constant of association k-1 = constant of dissociation The first step of drug action on specific receptors is the formation of a reversible drug-receptor complex, the reactions being governed by the Law of Mass Action rate of chemical reaction is proportional to the concentrations of reactants: R = receptor A = drug RA = drug-receptor complex k+1 = constant of association k-1 = constant of dissociation Basic principles [R] + [A] [RA] EFFECT k +1 k -1 stimulus Modify factors Receptor Interactions Receptor Interactions Drugs called ANTAGONISTS - combine with receptors, but do not activate them. AntagonistReceptor Antagonist-Receptor Complex DENIED! Competitive Inhibition AgonistReceptor Antagonist Inhibited-Receptor DENIED! Receptor Interactions Non-competitive Inhibition MAJOR RECEPTOR FAMILIES Mostly proteins that are responsible for transducing extracellular signals into intracellular responses. 1)ligand-gated ion channels 2)G protein-coupled receptors 3)enzyme-Iinked receptors 4)intracellular receptors. (Note: Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. I.e., enzymes and structural proteins can be considered to be pharmacologic receptors). Mostly proteins that are responsible for transducing extracellular signals into intracellular responses. 1)ligand-gated ion channels 2)G protein-coupled receptors 3)enzyme-Iinked receptors 4)intracellular receptors. (Note: Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. I.e., enzymes and structural proteins can be considered to be pharmacologic receptors). Time scale: ms s hourshours Examples: NicotinicMuscarinic Cytokine R Oestrogen R GABA receptor Ach receptor Videoy-animations/http://pharmamotion.com.ar/pharmacolog y-animations/animation-mechanism-of-ionotropic- receptors-or-ligand-gated-ion-channels- lgics/http://pharmamotion.com.ar/video- animation-mechanism-of-ionotropic- receptors-or-ligand-gated-ion-channels- lgics/y-animations/http://pharmamotion.com.ar/pharmacolog y-animations/animation-mechanism-of-ionotropic- receptors-or-ligand-gated-ion-channels- lgics/http://pharmamotion.com.ar/video- animation-mechanism-of-ionotropic- receptors-or-ligand-gated-ion-channels- lgics/ Non-receptor Mechanisms Actions on Enzymes Enzymes = Biological catalysts Speed chemical reactions Are not changed themselves Drugs altering enzyme activity alter processes catalyzed by the enzymes Examples Cholinesterase inhibitors Monoamine oxidase inhibitors COX Actions on Enzymes Enzymes = Biological catalysts Speed chemical reactions Are not changed themselves Drugs altering enzyme activity alter processes catalyzed by the enzymes Examples Cholinesterase inhibitors Monoamine oxidase inhibitors COX Non-receptor Mechanisms Changing Physical Properties Mannitol Changes osmotic balance across membranes Causes urine production (osmotic diuresis) Changing Physical Properties Mannitol Changes osmotic balance across membranes Causes urine production (osmotic diuresis) Non-receptor Mechanisms Changing Cell Membrane Permeability Lidocaine Blocks sodium channels Verapamil, nefedipine Block calcium channels Bretylium Blocks potassium channels Adenosine Opens potassium channels Changing Cell Membrane Permeability Lidocaine Blocks sodium channels Verapamil, nefedipine Block calcium channels Bretylium Blocks potassium channels Adenosine Opens potassium channels Non-receptor Mechanisms Combining With Other Chemicals Antacids Antiseptic effects of alcohol, phenol Chelation of heavy metals Combining With Other Chemicals Antacids Antiseptic effects of alcohol, phenol Chelation of heavy metals Non-receptor Mechanisms Anti-metabolites Enter biochemical reactions in place of normal substrate competitors Result in biologically inactive product Examples Some anti-neoplastics Some anti-infectives Anti-metabolites Enter biochemical reactions in place of normal substrate competitors Result in biologically inactive product Examples Some anti-neoplastics Some anti-infectives Drug Response Relationships Time Response Dose Response Time Response Dose Response Latency Duration of Response Maximal (Peak) Effect Effect/ Response Time Time Response Relationships Effect/ Response Time IV SC IM Time Response Relationships Dose Response Relationships Potency Absolute amount of drug required to produce an effect More potent drug is the one that requires lower dose to cause same effect Potency Absolute amount of drug required to produce an effect More potent drug is the one that requires lower dose to cause same effect PotencyPotency Effect Dose AB Which drug is more potent? A! Why? Therapeutic Effect Dose Response Relationships Threshold (minimal) dose Least amount needed to produce desired effects Maximum effect Greatest response produced regardless of dose used Threshold (minimal) dose Least amount needed to produce desired effects Maximum effect Greatest response produced regardless of dose used Dose Response Relationships Which drug has the lower threshold dose? Effect Dose A B Which has the greater maximum effect? A A B B Therapeutic Effect Dose Response Relationships Loading dose Bolus of drug given initially to rapidly reach therapeutic levels Maintenance dose Lower dose of drug given continuously or at regular intervals to maintain therapeutic levels Loading dose Bolus of drug given initially to rapidly reach therapeutic levels Maintenance dose Lower dose of drug given continuously or at regular intervals to maintain therapeutic levels Therapeutic Index Drugs safety margin Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100 Drugs safety margin Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100 Therapeutic Index Why dont we use a drug with a TI