Overview of Pharmaceutical Industry Drug nomenclature and classification Pharmacokinetics...

Overview of Pharmaceutical Industry

Drug nomenclature and classification

Pharmacokinetics

Pharmacodynamics

Overview of Pharmaceutical Industry

Drug nomenclature and classification

Pharmacokinetics

Pharmacodynamics

Psych 181:Psych 181: Lecture 3 Lecture 3

Professor AnagnostarasProfessor Anagnostaras

Market Share & CompetitionMarket Share & CompetitionMarket Share & CompetitionMarket Share & Competition

GSK7%

Merck5%

AstraZeneca4%

BMS4%

Novartis4%

J&J4%

Aventis4%

AHP3%

Other55%

Pharmacia3%

Pfizer7%

Chrysler14%

Other34%

GM28%

Ford24%

Source: IMS Health. Figures for 2000

AutomobileAutomobilePharmaceuticalPharmaceutical

Demographics

• • Highly prevalent neuro-psychochological disorders:Highly prevalent neuro-psychochological disorders:

- Insomnia (60 million)- Insomnia (60 million)

- Migraine (40 million)- Migraine (40 million)

- Depression (20 million)- Depression (20 million)

- Anxiety Disorders (19 million)- Anxiety Disorders (19 million)

- Alzheimer's (4 million)- Alzheimer's (4 million)

- Schizophrenia (3 million)- Schizophrenia (3 million)

- Stroke (3 million)- Stroke (3 million)

- Head Injury (2.5 million)- Head Injury (2.5 million)

- Parkinson's disease (1.5 million)- Parkinson's disease (1.5 million)

- Pain (#1 Patients' complaint)- Pain (#1 Patients' complaint)

Pricing

Determine margins, research capacity, and Determine margins, research capacity, and internationalization.internationalization.

U.S. is the only country globally with a“free pricing U.S. is the only country globally with a“free pricing policy” -- new drugs cost about $2-3 per pill or policy” -- new drugs cost about $2-3 per pill or "whatever the market will bear”"whatever the market will bear”

This results in higher R&D success and higher This results in higher R&D success and higher profits.profits.

US VS. CANADA DRUG PRICES (VERMONT VS MONTREAL) XXX

Azmacort Methotrexate, 2.5 mg., 28 Prozac, 20 mg., 45$50.70 US $47.84 US $105.64 US$18.85 CA $21.00 CA $43.00 CA$31.85 $26.84 $62.64 63% 56% 59%

Celebrex, 100 mg/cap, 60 Pravachol, 20 mg., 30 Welbutrin, 1 2x daily SR150 mg, 60$77.15 US $64.38 US $81.98 US$33.75 CA $47.50 CA $45.00 CA$43.40 $16.88 $36.98 56% 26% 45%

Flonase Nasal Prilosec, 20 mg, 90Zocor, 80 mg, 30$46.00 US $360.50 US $101.82 US$23.00 CA $170.36 CA $60.00 CA$23.00 $190.14 $41.82 50% 53% 41%

Lipitor, 20 mg., 90 Propulsid, 20 mg, 200 Zoloft, 50 mg., 30$229.93 US $289.20 US $62.00 US$164.00 CA $200.00 CA $31.00 CA$65.93 $89.20 $31.00 29% 31% 50%

http://bernie.house.gov/prescriptions/drugsheet.asp

Discern unmet medical needDiscern unmet medical need

Discover mechanism of action of diseaseDiscover mechanism of action of disease

Identify target proteinIdentify target protein

Screen known compounds against targetScreen known compounds against target

Chemically develop promising leadsChemically develop promising leads

Find 1-2 potential drugsFind 1-2 potential drugs

Toxicity, pharmacologyToxicity, pharmacology

Clinical TrialsClinical Trials

Outline of Drug DevelopmentOutline of Drug Development

Approaches to drug discoveryApproaches to drug discovery

• Successful candidate drug in rats (or mice)

• Test in monkeys for toxicity and efficacy

• Market evaluation

- jobs from entire unit can be lost in a day

- big problem for scientist retention

• Clinical trials

• Approval

- every aspect of drug is regulated

- e.g., specific manufacturing process can take years to approve (Regulatory affairs dept).

Pharmacology: overviewPharmacology: overviewNomenclature & ClassificationNomenclature & Classification

PharmacokineticsPharmacokinetics

PharmacodynamicsPharmacodynamics

Principles of PharmacologyPrinciples of PharmacologyPrinciples of PharmacologyPrinciples of Pharmacology

PharmacologyPharmacology ““The branch of medicine that The branch of medicine that

deals with the uses, effects, and deals with the uses, effects, and modes of actions of drugs”.modes of actions of drugs”.

(The New Shorter Oxford English Dictionary)(The New Shorter Oxford English Dictionary)

Principles of PharmacologyPrinciples of PharmacologyPrinciples of PharmacologyPrinciples of Pharmacology

Drug NomenclatureDrug Nomenclature

What is a drug?What is a drug?(Pharmakon (G.), poisons and (Pharmakon (G.), poisons and

medicines)medicines)

Substance that is used, "primarily to bring Substance that is used, "primarily to bring about a change in some existing process about a change in some existing process or state, be it psychological, physiological or state, be it psychological, physiological or biochemical"or biochemical"

Sources of psychoactive agentsSources of psychoactive agentsSources of psychoactive agentsSources of psychoactive agents

1. Naturally occurring1. Naturally occurringExamples:Examples:

EphedrineEphedrine, which is extracted from plant , which is extracted from plant indigenous to China, ma huang (Ephedra indigenous to China, ma huang (Ephedra equisetina).equisetina).

CocaineCocaine, from the leaves of the coca plant, from the leaves of the coca plant

OpiumOpium, extracted from the unripe seed , extracted from the unripe seed pods of the opium poppypods of the opium poppy


2. Semisynthetics2. Semisynthetics

Examples:Examples:HeroinHeroin (from morphine) (from morphine)LSDLSD (from fungi that grow on (from fungi that grow on grain)grain)


3. Synthetics3. Synthetics

Examples:Examples:

MethadoneMethadone (synthetic opiate) (synthetic opiate)

AmphetamineAmphetamine (powerful (powerful stimulant)stimulant)


OpiumOpium MorphineMorphine

HeroinHeroin

MethadoneMethadone

Naming PharmaceuticalsNaming Pharmaceuticals

Chemical nameChemical name Manufacturer's laboratory designationManufacturer's laboratory designation Chemical group nameChemical group name Generic or nonproprietary nameGeneric or nonproprietary name Proprietary (brand) nameProprietary (brand) name General-use nameGeneral-use name Street namesStreet names

Drug classificationDrug classification

By OriginBy Origin By Action Relative to a PrototypeBy Action Relative to a Prototype Therapeutic UseTherapeutic Use Mechanism of ActionMechanism of Action Chemical StructureChemical Structure


Behavioral effectsBehavioral effects CNS depressantsCNS depressants

- Sedative hypnotics- Sedative hypnotics- Anxiolytics- Anxiolytics

StimulantsStimulants Narcotic analgesicsNarcotic analgesics Hallucinogens (psychedelics)Hallucinogens (psychedelics) OthersOthers


Legal Classification (Drug Schedules)Legal Classification (Drug Schedules) Schedule I (heroin, psilocybin, LSD, THC, Schedule I (heroin, psilocybin, LSD, THC,

mescaline)mescaline) Schedule II (morphine, cocaine, amphetamines)Schedule II (morphine, cocaine, amphetamines) Schedule III (ASA w/codeine, anabolic steroids)Schedule III (ASA w/codeine, anabolic steroids) Schedule IV (diazepam, phenothiazines)Schedule IV (diazepam, phenothiazines) Schedule V (cough syrup with codeine)Schedule V (cough syrup with codeine) Unscheduled Drugs (aspirin, tylenol, Prozac)Unscheduled Drugs (aspirin, tylenol, Prozac) Some states have Schedule VI (inhalants)Some states have Schedule VI (inhalants)


Area of pharmacology dealing Area of pharmacology dealing with, "the absorption, with, "the absorption, distribution, biotransformation distribution, biotransformation and excretion of drugs"and excretion of drugs"


FactorsFactors Route of administrationRoute of administration Absorption and distributionAbsorption and distribution InactivationInactivation EliminationElimination

Routes of administrationRoutes of administration Routes of administrationRoutes of administration

Oral (p.o., per os, via the mouth)Oral (p.o., per os, via the mouth) Parenteral injection (through the skin)Parenteral injection (through the skin)

Subcutaneous (s.c., s.q., subq)Subcutaneous (s.c., s.q., subq) Intramuscular (i.m.)Intramuscular (i.m.) Intravenous (i.v.)Intravenous (i.v.) Intraperitoneal (i.p., same as i.c.)Intraperitoneal (i.p., same as i.c.)

Pulmonary absorption (inhalation)Pulmonary absorption (inhalation) Topical applicationTopical application

Common administration Common administration abbreviations (mostly latin)abbreviations (mostly latin)Common administration Common administration abbreviations (mostly latin)abbreviations (mostly latin)

b.i.d.b.i.d. Twice a dayTwice a day t.i.d.t.i.d. Three times a dayThree times a day q.i.d.q.i.d. Four times a dayFour times a day p.r.n.p.r.n. as neededas needed q_q_ every (e.g., q3h, qd, q3d)every (e.g., q3h, qd, q3d) u.d.u.d. as directedas directed r.t.c.r.t.c. round the clockround the clock m.g.m.g. milligram, mcg = microgrammilligram, mcg = microgram n.p.o.n.p.o. nothing by mouthnothing by mouth h.s. h.s. At bedtimeAt bedtime p.c.p.c. after a mealafter a meal

Routes of administration Routes of administration Routes of administration Routes of administration

Drug half-life Drug half-life varies as a varies as a function of route function of route of administrationof administration

Half-life = time for Half-life = time for plasma drug plasma drug conc. to fall to conc. to fall to half of peak levelhalf of peak level

Routes of administrationRoutes of administration Routes of administrationRoutes of administration

Effects of route of administration on rate of Effects of route of administration on rate of absorption are due to many factors:absorption are due to many factors:

Surface area available for absorptionSurface area available for absorption Blood circulation at the site of Blood circulation at the site of

administrationadministration Amount of drug destroyed immediatelyAmount of drug destroyed immediately Extent of binding to inert substancesExtent of binding to inert substances

Drug distribution Drug distribution

Drug Transport Across MembranesDrug Transport Across Membranes

Most important factor in achieving active dose Most important factor in achieving active dose at site of action (e.g., brain)at site of action (e.g., brain)

Drug must pass through many cell membranesDrug must pass through many cell membranes (Cells in gut, blood vessels, glial cells, (Cells in gut, blood vessels, glial cells,

neurons)neurons)

Mechanism of transportMechanism of transportMechanism of transportMechanism of transport

Passive diffusionPassive diffusion

Limits:Limits:•• size and shape of drug moleculesize and shape of drug molecule

•• lipid solubility of druglipid solubility of drug

•• degree drug is ionized (charged)degree drug is ionized (charged)

Lipid solubilityLipid solubility

Ionization is the major factor:Ionization is the major factor:When drugs are ionized (charged) they When drugs are ionized (charged) they become much less lipid soluble, and become much less lipid soluble, and drugs tend to become ionized when drugs tend to become ionized when dissolved in solutiondissolved in solution

More ionized > less lipid soluble > More ionized > less lipid soluble > less absorption > less effectless absorption > less effect

Degree of ionizationDegree of ionization

Major factors:Major factors: Is the drug a weak acid or weak baseIs the drug a weak acid or weak base

(most drugs are weak acids or bases)(most drugs are weak acids or bases)

Is the solvent an acid or a baseIs the solvent an acid or a base

(drugs that are weak acids ionize more in (drugs that are weak acids ionize more in basic [alkaline] environments, and drugs basic [alkaline] environments, and drugs that are weak bases ionize more in acidic that are weak bases ionize more in acidic environments)environments)

Ion trapping - aspirinIon trapping - aspirin

Aspirin is a weak acid with a pKa of 3.5Aspirin is a weak acid with a pKa of 3.5

in stomach (pH 2-3), most aspirin not ionizedin stomach (pH 2-3), most aspirin not ionized in intestine (pH 5-6), more ionizedin intestine (pH 5-6), more ionized

aspirin better absorbed from stomachaspirin better absorbed from stomach in blood (pH 7.4), most ionizedin blood (pH 7.4), most ionized

once aspirin moves from stomach to blood once aspirin moves from stomach to blood is is trappedtrapped in blood (not move easily from in blood (not move easily from blood back to stomach)blood back to stomach)

Absorption - Other factorsAbsorption - Other factors

Drug must be able to survive low pHDrug must be able to survive low pH Even if ionized and not very lipid Even if ionized and not very lipid

soluble, digestive track has enormous soluble, digestive track has enormous surface area so may still get significant surface area so may still get significant absorptionabsorption

Other special barriersOther special barriers

Blood-Brain BarrierBlood-Brain Barrier

Limits the ability of drugs to Limits the ability of drugs to reach the brain, even when they reach the brain, even when they

can reach other tissuescan reach other tissues

Blood-Brain Barrier Blood-Brain Barrier

Lipid-solubletransport

Basementmembrane

Cell nucleus

(a) Typical capillary (b) Brain capillary

Intercellularcleft

Pinocytoticvesicle

Fenestra

Lipid-solubletransport

Carrier-mediatedtransport

Tightjunction

Astrocyticprocess

1.6

Astroglia: help comprise blood-brain barrierAstroglia: help comprise blood-brain barrier

QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.

astrogliasendsprocesseswhich coverblood vessel


Drug Inactivation and EliminationDrug Inactivation and Elimination

InactivationInactivation usually by metabolism usually by metabolism (biotransformation) to inactive forms(biotransformation) to inactive forms

(liver major site)(liver major site) EliminationElimination (metabolites or unchanged (metabolites or unchanged

drug; kidney major site)drug; kidney major site)

- but also lungs, sweat, saliva, feces or - but also lungs, sweat, saliva, feces or milkmilk

PharmacodynamicsPharmacodynamics

““The study of the biochemical The study of the biochemical effects of drugs and their effects of drugs and their mechanism of action”mechanism of action”

Objective is identification of the Objective is identification of the primary actions of a drugprimary actions of a drug

ReceptorsReceptors

The initial site of action of biologically active The initial site of action of biologically active agents, including drugsagents, including drugs

(The molecule a drug interacts with to initiate (The molecule a drug interacts with to initiate its biological effects)its biological effects)

To have an effect a drug must reach its To have an effect a drug must reach its receptorreceptor

- Its ability to get to the receptor is the realm - Its ability to get to the receptor is the realm of pharmacokineticsof pharmacokinetics

- What it does when it gets there is the realm - What it does when it gets there is the realm of pharmacodynamicsof pharmacodynamics

ReceptorsReceptors

D + R = DR > pharmacological effectD + R = DR > pharmacological effectDrug receptor interactions may involve many Drug receptor interactions may involve many different types of chemical bonds, but usually different types of chemical bonds, but usually weak non-covalent interactions that are weak non-covalent interactions that are reversiblereversible

(For example, ionic or electrostatic (For example, ionic or electrostatic interactions)interactions)

Drug associates and then rapidly dissociatesDrug associates and then rapidly dissociates

Law of Mass ActionLaw of Mass Action

D + R = DRD + R = DR* > * > effecteffect

The active complex (DRThe active complex (DR**) leads to a ) leads to a cellular response that is in cellular response that is in proportion to the fraction of proportion to the fraction of receptors occupiedreceptors occupied

Drugs do not produce new or unique cellular Drugs do not produce new or unique cellular responses but only modify the rate of responses but only modify the rate of ongoing cellular eventsongoing cellular events

Law of Mass ActionLaw of Mass Action

according to according to D + R = DRD + R = DR* > * > effecteffect The magnitude of a drug effect should The magnitude of a drug effect should

be proportional to the number of be proportional to the number of receptors occupied by the drug, andreceptors occupied by the drug, and

A drug should have a maximal effect A drug should have a maximal effect when all receptors are occupiedwhen all receptors are occupied

This relationship is described by the This relationship is described by the

dose-effect curvedose-effect curve

Dose-effect curvesDose-effect curves

100

75

50

25

1Log dose (mg)

10 100

Per

cen

t ef

fect

1.7

The dose-effect curveThe dose-effect curve

For an For an AGONISTAGONISTA drug that binds to receptor and has a A drug that binds to receptor and has a pharmacological effectpharmacological effect

Major characteristics are :Major characteristics are : PotencyPotency

Location (left-right) on a dose-effect curveLocation (left-right) on a dose-effect curve

Maximum effectMaximum effect

Dose where increases in dose produce no Dose where increases in dose produce no further increase in effectfurther increase in effect

PotencyPotency

AccessibilityAccessibility

Affinity Affinity (K(Kd,,dissociation dissociation constant)constant)

EfficacyEfficacy(intrinsic(intrinsicactivity)activity)

100

75

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10 100

HydromorphineMorphineCodeineAspirin

% i

ncr

ease

in

pai

n t

hre

sho

ld

1.7

More potent Less potent

PotencyPotency

hydromorphone codeinemorphine

Potency Potency

morphineHeroin (diacetylmorphine)

fentanyl

PotencyPotency

EDED5050 - Dose that produces - Dose that produces an effect in 50% of a an effect in 50% of a populationpopulation

LDLD5050 - Dose that kills 50% - Dose that kills 50% (TD = toxic dose)(TD = toxic dose)

TI - Therapeutic Index (LDTI - Therapeutic Index (LD50 50

/ED/ED5050))

Safety Margin = LDSafety Margin = LD50 50 – ED– ED5050

Drug B100

50

Log drug doseLow HighED50 TD50

100Drug A

50

Low HighLog drug doseED50 TD50

1.8

Per

cen

t re

spo

nd

ing

Desiredeffect Lethality

Maximum EffectMaximum Effect

Drugs vary in their Drugs vary in their ability to produce an ability to produce an effecteffect

They may act by They may act by different mech-different mech-anisms (at different anisms (at different receptors)receptors)

They may have more They may have more or less efficacy at or less efficacy at the same receptorthe same receptor

100

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10 100

HydromorphineMorphineCodeineAspirin

1.7

Max. effectMore

Less

Side effects and specificitySide effects and specificity

All drugs have multiple effectsAll drugs have multiple effects All drugs are “dirty”All drugs are “dirty” Degree depends on Degree depends on

dose, specificity etc.dose, specificity etc.

Side effects are unwanted or Side effects are unwanted or undesirable effects (although are undesirable effects (although are “real” effects)“real” effects)

Agonists vs AntagonistsAgonists vs Antagonists

AgonistAgonistA drug that binds to receptor and has a A drug that binds to receptor and has a cellular (pharmacological) effectcellular (pharmacological) effect

AntagonistAntagonistA drug that binds to a receptor but A drug that binds to a receptor but produces no direct cellular effectproduces no direct cellular effect

Antagonists produce their effects by Antagonists produce their effects by blocking the action of an agonist, or an blocking the action of an agonist, or an endogenous ligand (e.g., a transmitter), at endogenous ligand (e.g., a transmitter), at that receptorthat receptor

Competitive antagonistsCompetitive antagonistsCompetitive antagonistsCompetitive antagonists

Binds to same receptor as agonistBinds to same receptor as agonist Shift dose-effect for agonist to rightShift dose-effect for agonist to right Effect can be overcome by sufficient doseEffect can be overcome by sufficient dose

1.9

100 Maximum

Pretreated withcompetitiveantagonist50

LowDose of morphine

High

% e

ffec

t

Competitive antagonistsCompetitive antagonists

naloxone (Narcan)-antagonist

morphine

Noncompetitive antagonistsNoncompetitive antagonistsNoncompetitive antagonistsNoncompetitive antagonists

Shift dose-effect for agonist to rightShift dose-effect for agonist to right Effect can Effect can notnot be overcome by sufficient be overcome by sufficient

dosedose (decrease in maximum effect)(decrease in maximum effect)

1.9

100 Maximum

Pretreated withcompetitiveantagonist50

LowDose of morphine

High LowDose of morphine

High

100

50 Pretreated withnoncompetitiveantagonist%

eff

ect

Noncompetitive antagonistsNoncompetitive antagonistsNoncompetitive antagonistsNoncompetitive antagonists

Agonist can only act on the population of Agonist can only act on the population of receptors not effected by the antagonistreceptors not effected by the antagonist

(May be reversible or irreversible)(May be reversible or irreversible)

IrreversibleIrreversible may form long-lasting bond with may form long-lasting bond with receptorreceptor

Reversible Reversible acts to prevent agonist-receptor acts to prevent agonist-receptor coupling (e.g., on different site than agonist, coupling (e.g., on different site than agonist, through different mechanism)through different mechanism)


Quiz:Quiz:100

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Tolerance and sensitizationTolerance and sensitization

The effects of a drug may change The effects of a drug may change with repeated administrationwith repeated administration

ToleranceTolerance Decreased response with repeated Decreased response with repeated

administration, oradministration, or A higher dose is required to produce A higher dose is required to produce

the original effect (shift to right)the original effect (shift to right)

Cross-toleranceCross-tolerance

Tolerance and sensitizationTolerance and sensitization

SensitizationSensitization Increased response with repeated Increased response with repeated

administration, oradministration, or A lower dose is required to produce the A lower dose is required to produce the

original effect (shift to left)original effect (shift to left)

Cross sensitizationCross sensitization


Quiz:Quiz:100

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Tolerance and sensitization Tolerance and sensitization

May involve multiple mechanismsMay involve multiple mechanisms

Pharmacokinetic (dispositional) changesPharmacokinetic (dispositional) changes Pharmacodynamic changesPharmacodynamic changes

(cellular adaptations)(cellular adaptations) Behavioral (learning) factorsBehavioral (learning) factors

Overview of Pharmaceutical Industry Drug nomenclature and classification Pharmacokinetics...

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