PharmacodynamicsUniversity of Miami

Advanced Practice Preparation

Biotransformation

• Preferable to metabolism – drugs do not normally provide new materials or energy.

• Physiochemical reactions that are not a component of usual metabolism.

• Prodrug – biotransformed from inactive to active state.• Precursor to active compound• Widely used to overcome problems with

absorption, solubility, duration of action, non-compliance, site specific drug delivery.

Prodrugs

• Azarabine – prodrug of Azauridine • Intesitinal micr0-organisms block the formation

of toxic components – azauracil.• Therapeutic effects beneficial.

• Levodopa, prodrug of dopamine• Rapidly absorbed after PO administration –

distributed to CNS.• Converted to dopamine in the basal ganglia.• Dopamine is poorly absorbed when given PO –

biotransformation is necessary.

Mechanisms of Biotransformation

• Phase I Reactions• Cytochrome P 450 microsomal enzymes.• Found in the endoplasmic reticulum of the

liver cells.• Human genome encodes 57 enzymes.• 14 metabolize steroids• 4 oxidize fat soluble vitamins• 9 metabolize fatty acids and eicosanoids

BiotransformationClassification

• Phase I biosynthetic reaction• Introduce or expose a functional group• Results in loss of pharmacologic activity

• Exception is prodrugs• Oxidations, reductions, hydroxylations, occur

BiotransformationClassification

• Phase II biosynthetic reaction• Conjugation reactions

• Covalent linkage with functional group on parent compound.

• Highly polar conjugates• Generally inactive

• Exception M-6-G• Alkylations, acetylations, methylations

occur here.

Biotransformation

• Lipophilicity of drugs facilitate passage through biologic membranes

• This property hinders elimination and biotransformation

• Renal excretion of unchanged drug plays modest role in elimination• Lipophilic drugs mostly reabsorbed

• Biotransformation generates polar molecules for excretion

Enzyme Induction• Repeated administration of same or similar drugs can

“induce” cytochrome P450

• Accelerates metabolism

• Reduction in pharmacologic activity

• CYP2B1• Induced by phenobarbital

• CYP1A1• Polycyclic aromatics

• CYP3A• Macrolide antibiotics• Anticonvulsants

Enzyme Induction

• CYP2E1• Induced by chronic EtOH• Isoniazid

• Environmental pollutants have been shown to induce P450 enzymes• Benzopyrene• Charcoal-broiled meat• Certain environmental chemicals

• Polychlorinated Biphenyls (PCBs)

Enzyme Inhibition

• Inhibition of biotransformation results in elevated levels of the parent compound• Prolonged pharmacologic effects

• Inhibition of CYP2D6 by quinidine

• Cimetidine and ketoconazole inhibit oxidative drug metabolism• Bind with heme iron

Pharmacogenetics

• Genetic polymorphisms• Autosomal recessive traits• Differences in abilities to metabolize

certain drugs• Extensive vs. poor (slow) metabolizers

• Poor metabolizers are at increased risk of adverse effects

Pharmacogenetics

• Genetic polymorphisms• Affects oxidative drug metabolism• Autosomal recessive traits• Differences in abilities to metabolize certain drugs

• Extensive vs. poor (slow) metabolizers• Poor metabolizers are at increased risk

of adverse effects

Pharmacogenetics• Genetic polymorphisms

• Poor metabolizers of debrisoquin• 8% - 10% of Caucasions• 0% - 2% of Asians

• Faulty expression of cytochrome P450 isozyme (P4502D6)

• Dextromethorphan is used to monitor pathway

Pharmacogenetics• Genetic polymorphisms

• N-acetylation• Slow acetylation of certain arylamines

• Procainamide• Hydralazine• Isoniazid

• 50% of US are slow acetylators• 10% of Japanese and Chinese are slow

acetylators• Important with drugs that have low

therapeutic index

Genetic Polymorphisms

• Debrisoquin oxidation• Alprenolol

• Amitriptyline

• Desipramine

• *Dextromethorphan

• Encainide

• Guanoxan

• Metoprolol

• N-Acetylation• p-Aminobenzoic acid

• Aminogluthemide

• *Caffiene

• Clonazepam

• Dapsone

• Hydralazine

• Isoniazid

• Procainamide

• Phenelzine

Elimination Kinetics First-order Kinetics

• Elimination is proportional to the concentration

• A constant fraction of drug is eliminated per unit time• e.g., sulfisoxazole (10% /hour)

• Elimination rate varies with the first power of the concentration

• Most drugs follow this pattern

dC(t) = -kEC(T) dt

Elimination Kinetics Zero-order Kinetics

• A constant amount of drug is eliminated per unit time• e.g., phenytoin & ethanol

• Rate is independent of concentration

• Result of overwhelmed enzyme system

• Saturation kinetics

C(t) = e-kEnt

1/2

C0

Renal Elimination of Drug

• Glomerular filtration – GRF 125 ml/min

• Drugs enter through capillary plexus

• Free drug flows into Bowman’s space

• 20% of renal plasma flow – RPF 600 ml/min

• Lipid solubility and pH have no influence here

Renal Elimination of Drugs

• Proximal Tubular Secretion• Drug not transferred to glomerular filtrate

enters through afferent arterioles into capillary plexus – surrounds the nephric lumen.

• Secretion occurs by 2 active transport systems• Anionic – deprotonated forms of weak acids• Cationic – protonated forms of weak bases• Low specificity• Competitive between multiple drugs

Renal Elimination of Drugs

• Distal tubular reabsorption• Distal convoluted tubule receives drug• Concentration exceeds capacity of

perivascular space• If uncharged, drug may diffuse out of nephric

lumen• pH manipulation plays a part here – Ion

Trapping

Biliary Elimination

• Most drugs eliminated by kidney.

• Some removed via enterohepatic recirculation.• Lipid soluble drugs present in bile• Reabsorbed• Returned to liver• Re-secreted into bil• Increase in plasma concentration of drug• Delay in elimination

Half-Life t1/2

• Time necessary for drug concentration in plasma to decrease by one half• Often related to duration of action

• If peak plasma concentration and half-life are known, then plasma concentration at any time can be estimated

t1/2 = 0.693 x Vd

CL

Accumulation

Elimination

Half-Life t1/2

Time after Peak Concentration (hr)

Plasma Concentration(mg/L)

0 100

2 50

4 25

6 12.5

8 6.25

10 3.125

Steady State

• Dosing dependent

• Accumulation vs Elimination

• Repeated dosing

• 4 to 5 half-lives are necessary for plasma drug levels to reach a steady state

• Steady state can be calculated by multiplying drug half-life by 5.• HL x 5 = SS• Approx. 90% SS value

Clearance

• Measure of the removal of drug from plasma• Expressed as volume/time

• A drug’s clearance and volume of distribution determine drug half-life

• Drugs can be cleared from plasma by several mechanisms• Hepatic transformation, renal, biliary etc.

Fig. Model for Organ Clearance of a Drug

QQCin Cout

Drug is eliminated in the bile and/or the urine

Q = blood flow (volume . time-1)C = concentration (amount . volume-1)

Organ ofElimination

(Liver or Kidney)

EC C

Cin out

in

CL Q Eorgan

Extraction ratio (no units) is a fraction between 0 and 1.

drug drug drug drug drug drug drug drug

drug drug

drug drug drug drug drug drug

Drug Modeling

• Use of modeling• Compartmental models

• Used to describe drugs’ behavior in the body

• Do not represent single tissue or fluid• Groups of similar tissues

Compartmental Models• One-compartment model

• Simplest• All body tissues and fluids• Instantaneous distribution is assumed

• Two-compartment model• Some drugs do not distribute instantaneously

to all body parts• Distribute rapidly to vessel-rich groups• More slowly to other tissues

• Peripheral compartment• Drugs move back and forth between these

compartments

One Compartment Model

• Simplest model• Comprises all body tissues and

fluids• Assumes instantaneous

distribution of the dose of the drug throughout the body

Compartment

Elimination

Drug Dose

Two Compartment Model

• Central Compartment• Highly Perfused Tissues

• Rapid Distribution of Drug

• Peripheral Compartment• Less perfused tissues

• Slower distribution of drug

Fig. One and Two Compartment Models

Dose

OneCompartment(Vd)

kin or k0

kout or ke

X0

CentralCompartment(Vc or V1)

kout or ke or k1O

Dose

kin or k0X0PeripheralCompartment(V2)k12

k21

X0 = dose of drug at time zero; units are amount

kin or k0 = infusion rate constant at time zero; units are amount . time-1

k12 = rate constant for transfer of drug from the 1st (central) to the 2nd (peripheral) compartment

k21 = rate constant for transfer of drug from the 2nd (peripheral) to the 1st (central) compartment

kout or ke = first-order elimination rate constant; units are time-1

k1O = first-order elimination rate constant from the 1st (central) compartment; units are time-1

Compartmental Models – Clinical Correlate• Digoxin

• Two-compartment pharmacokinetics• Plasma concentrations rise initially

• Decline rapidly as drug redistributes to muscle

• Plasma concentration is the central compartment

• Muscle is the peripheral compartment

Pharmacodynamics

• Study of biological and physiological effects of drugs and their mechanisms of actions.

PharmacodynamicsProperties of Drug Receptors

• Interactions with macromolecular components• Based on work by Ehrlich and Langley (1900s)• Receptor was term used to denote part of organism

that reacted with drug• All drugs do not act at receptors

• Osmotic diuretics - mannitol, urea• Non-specific membrane interactions• Antacids• Chelating agents

Properties of Drug Receptors• Drugs interact with receptors

• Receptors mediate physiologic regulators of cell function• Hormones, neurotransmitters, autocoids etc.

• Drugs may mimic the actions or block the physiologic messengers• Agonists• Antagonists• Partial agonists• Inverse agonists

Properties of Drug Receptors• Agonists

• Drugs that produce a response by activating a receptor

• Antagonists• Drugs that reduce or prevent the effects of agonists

• Partial agonists• Drugs that may act as either agonist or antagonist

Properties of Drug Receptors

• Drug receptors are often proteins• Soluble proteins• Protein in intracellular organelle (bacterial ribosomal protein)

• Membrane bound protein (Na+-K+

ATPase)

Properties of Drug Receptors

• To activate a receptor a ligand (drug) must bind to that receptor• Covalent bonds• Ionic bonds• Hydrogen bonds

Properties of Drug Receptors

• Structure-Activity relationships (drug shape)• Intrinsic activity and affinity determined by chemical structure• The fit of drug with the receptor

• Stereoisomerisms• One is a better fit with the receptor• Some drugs are racemic mixtures or

individual isomers

Antagonists• Agonists and antagonists both

occupy receptors• Only agonists activate receptors

• k3 is high for agonists

• Antagonists have little or no intrinisic activity

• k3 is equal to zero or a very low value

• Antagonists may act competitively or non-competitively

Antagonists• Competitive antagonists bind

reversibly to the same receptor site as the agonists• Prevents agonist from binding• Potency of antagonist is determined by the rate of dissociation• Usually slower than the dissociation of the agonist

Competitive Antagonism

Antagonists• Non-competitive antagonists can

act in two ways.• Irreversibly bind (covalently) with the receptor site that the agonist binds• Cannot be competed by high concentrations of agonist

• An irreversible OR reversible non-competitive antagonist may bind to a different site on the receptor• Can regulate affinity of agonist for that site

• This is an allosteric interaction

Partial Agonists

• Some drugs have intermediate activity between full agonists and antagonists• Full agonists have high efficacy

• Partial agonists only activate a fraction of the receptors that they bind to

• Effects will depend upon other agonists or antagonists that are in equilibrium with the receptor

Partial Agonists• Partial agonist may produce an effect of lessor

magnitude than that of a full agonist

• Partial agonist may produce a maximum response in the presence of spare receptors

• Partial agonists can prevent full agonists from inducing a maximum effect• By competing with full agonist for receptors

Signaling Mechanisms and Drug Action

• Receptors regulate the activity of cells• By activating or inhibiting transduction systems

• Receptors located in plasma membrane • Ligand-gated ion channels• Ligand-regulated membrane enzymes• G-protein-regulated membrane enzymes and ion

channels

• Cytoplasmic receptors

• Second messenger systems

Ligand-Gated Ion Channel

Ligand-Regulated Membrane Enzymes

G- Protein-Regulated membrane Enzymes

• Guanine nucleotide binding protein

• Heterotrimers (a, b, g subunits)

• Regulated by agonist-activated receptors

• Most receptors are monomeric • 7 transmembrane regions

• Receptor interacts with G-protein• Converts it to a form that can activate or inhibit

membrane bound enzymes• e.g., adenylyl cyclase, phospholipase C,

• Can activate or inhibit ion channels

G Protein-Regulated Membrane Enzymes

Second Messengers• Extracellular ligands can act by increasing

concentrations of second messengers• e.g., cyclic adenosine-3’5’ -monophosphate (cAMP),

calcium ions, or phosphoinositides

Points to Consider

• Drug action occurs at the cellular level.

• Drug effects influence total body functioning.

• Receptors are specialized proteins, cell membranes, or enzymes – The stronger the affinity for a receptor, the longer the drug action.

• The intensity of response elicited by a drug is a function of the dose administered.• Dosage increases, most persons response to drug is

increased

Points to Consider

• Drugs are agonists when they interact with a receptor to produce an effect of their own.

• Drugs are antagonists when they interact with a receptor to produce no response of their own, but impair the receptors ability to combine with effector molecule.

• Irreversible antagonists remain tightly bound to receptors. The binding cannot be overcome by reducing dosage.