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

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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 Drug’s safety margin Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100 Drug’s safety margin Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100

Therapeutic Index Why don’t we use a drug with a TI <1? Why don’t we use a drug with a TI <1? ED50 < LD50 = Very Bad!

Factors Altering Drug Responses Age –Pediatric or geriatric –Immature or decreased hepatic, renal function Weight –Big patients “spread” drug over larger volume Gender –Difference in sizes –Difference in fat/water distribution Age –Pediatric or geriatric –Immature or decreased hepatic, renal function Weight –Big patients “spread” drug over larger volume Gender –Difference in sizes –Difference in fat/water distribution

Factors Altering Drug Responses Environment –Heat or cold –Presence or real or perceived threats Fever Shock Environment –Heat or cold –Presence or real or perceived threats Fever Shock

Factors Altering Drug Responses Pathology –Drug may aggravate underlying pathology –Hepatic disease may slow drug metabolism –Renal disease may slow drug elimination –Acid/base abnormalities may change drug absorption or elimination Pathology –Drug may aggravate underlying pathology –Hepatic disease may slow drug metabolism –Renal disease may slow drug elimination –Acid/base abnormalities may change drug absorption or elimination

Influencing factors Genetic effects –Lack of specific enzymes –Lower metabolic rate Psychological factors –Placebo effect Genetic effects –Lack of specific enzymes –Lower metabolic rate Psychological factors –Placebo effect

Pediatric Patients Higher proportion of water Lower plasma protein levels –More available drug Immature liver/kidneys –Liver often metabolizes more slowly –Kidneys may excrete more slowly Higher proportion of water Lower plasma protein levels –More available drug Immature liver/kidneys –Liver often metabolizes more slowly –Kidneys may excrete more slowly

Geriatric Patients Chronic disease states Decreased plasma protein binding Slower metabolism Slower excretion Chronic disease states Decreased plasma protein binding Slower metabolism Slower excretion Dietary deficiencies Use of multiple medications Lack of compliance

Web Resources Basic Pharmacokinetics on the Web – ult.asp Merk Manual: Overview of Drugs – c2/5.htm Basic Pharmacokinetics on the Web – ult.asp Merk Manual: Overview of Drugs – c2/5.htm

Web Resources Merk Manual: Factors Affecting Drug Response – c2/8.htm Merk Manual: Pharmacodynamics – c2/7.htm Merk Manual: Factors Affecting Drug Response – c2/8.htm Merk Manual: Pharmacodynamics – c2/7.htm