Edmodo Notes

71
What is Pharmacology? • study of substances that react with living systems through chemical processes – BINDING to regulatory molecules – ACTIVATING or INHIBITING normal body responses

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Edmodo Notes

Transcript of Edmodo Notes

Page 1: Edmodo Notes

What is Pharmacology?• study of substances that react with

living systems through chemical processes

–BINDING to regulatory molecules

–ACTIVATING or INHIBITING normal body responses

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Pharmacology: Areas of Study

Medical Pharmacology – science of substances used to prevent, diagnose & treat disease

Toxicology – deals with undesirable effects of chemicals on living systems (cells to ecosystems)

- Poisons & Organ toxicity

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Pharmacology: Areas of Study

2 MAIN SUBDIVISIONS:

Pharmacokinetics – processes that determine the concentration of drugs in body fluids & tissues over time

- what the body does to the drug

Pharmacodynamics – actions of drugs on target organs

- what the drug does to the body

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• Pharmacotherapeutics – use of drugs in the treatment of disease

• Pharmacogenomics – study of genetic variations that cause differences in drug response

Pharmacology: Areas of Study

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DRUG - natural product, chemical substance, or

pharmaceutical preparation for administration to diagnose or treat a disease

- any substance that brings about a change in biologic functions through its chemical actions

Nature of Drugs

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Synthetic1. Aspirin2. Barbiturates3. Local anesthetics

Nature of Drugs

Xenobiotics: chemicals not synthesized in the body

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Nature of Drugs

isolated from natural sources or synthesized in the laboratory

drugs intended for administration to patients

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Pharmaceutical Preparations

1. TABLETS AND CAPSULES 2. SOLUTIONS AND SUSPENSIONS3. SKIN PATCHES4. AEROSOL5. OINTMENTS, CREAMS, LOTIONS, AND

SUPPOSITORIES

Nature of Drugs

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Routes of Administration

1. Topical Administration2. Systemic Administration

A. Enteral Administration

3. Oral4. Rectal 5. Sublingual6. Buccal

C. Transdermal Administration

D. Inhalation Administration

Nature of Drugs

B. Parenteral Administration1. Intravenous2. Intramuscular3. Subcutaneous4. Intrathecal5. Intra-articular6. Intra-dermal7. Epidural8. Insufflation (intranasal)

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Drug Size

MW: 7 (Lithium) 59,050 (altepase)

MW 100-1000• drugs must be able to move from site

of administration to site of action

Nature of Drugs

Intravenous or Intra-arterial

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Drug Reactivity & Drug-Receptor Bonds

1. Covalent – very stronge.g. ASA + cyclooxygenase

2. Electrostatic – more common; relatively strong (ionic bonds), weak (hydrogen bonds), very weak (van der Waals forces)

3. Hydrophobic – weak; interaction of lipid-soluble drugs with cell membrane

Nature of Drugs

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Drug Reactivity & Drug-Receptor Bonds

“Drugs that form weak bonds with receptors are more selective.”

Nature of Drugs

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Drug Shape

“Complementary to its receptor as a key to a lock”

Stereoisomerism

*one enantiomer may be more potent than the other

* one enantiomer more susceptible to drug-metabolizing enzymes (duration of action)

Nature of Drugs

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Me-too drug

• structurally very similar to already known drugs, with only minor differences.

• generic drug with an identical formulation and stated indications as a drug previously approved by the FDA

• chemically related to the prototype, or other chemical compounds which have an identical mechanism of action

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Side Effects

nuisance; tolerated to gain benefit of therapeutic effecte.g. dry mouth & sedation of antihistamine

Adverse Effects

undesired and may be harmful e.g. persistent diarrhea

Toxic Effects

Poisoning, extremely harmful & may be life-threatening

Nature of Drugs

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Processes:Absorption – entrance of a drug into

the bloodstreamDistribution – various tissues & organsMetabolism – biotransformationElimination – excretion of drug (renal,

intestinal, respiratory)

PHARMACOKINETIC PRINCIPLES

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Absorption

Permeation-Movement through barriers separating

compartments

-Oral drug intestinal wall capillary wall BBB walls of capillaries perfusing the brain

PHARMACOKINETIC PRINCIPLES

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Mechanisms of Permeation

1. Aqueous diffusion – drugs diffuse through aqueous channels

• large aqueous compartments (interstitial space, cytosol) • epithelial membrane tight junctions & endothelial

pores (MW 20,000-30,000)

PHARMACOKINETIC PRINCIPLES

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Mechanisms of Permeation

2. Lipid diffusion – most important limiting factor in permeation

- lipid:aqueous partition coefficient determines how readily drug moves between aqueous & lipid media

- Ability of weak acid & weak base to move from aqueous to lipid media or vice versa varies with the pH of the medium

PHARMACOKINETIC PRINCIPLES

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Mechanisms of Permeation

Electrostatic charge of ionized molecule attracts water dipoles polar, water-soluble & lipid-insoluble complex

Weak acid – neutral molecule that can reversibly dissociate into an anion & proton

C8H7O2COOH C8H7O2COO- + H+

Neutral ASA ASA anion

Weak base – neutral molecule that forms cation by combination with a proton

C12H11O2CIN3NH3+ C12H11O2CIN3NH2

+ H+

Pyrimethanine cation Neutral Pyrimethanine

PHARMACOKINETIC PRINCIPLES

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ACID

PHARMACOKINETIC PRINCIPLES

BASE

Mechanisms of Permeation

Law of Mass Action = these reactions move to the left in acidic environment (low pH, excess protons) & to the right in alkaline environment

C8H7O2COOH C8H7O2COO- + H+

Neutral ASA ASA anion

C12H11O2CIN3NH3+ C12H11O2CIN3NH2

+ H+

Pyrimethanine cation Neutral Pyrimethanine

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Mechanisms of Permeation

3. Special Carriers– for molecules that are too large or too insoluble to lipid (peptides, AA, glucose)

- facilitated diffusion & active transport

- selective, saturable , inhibitable

PHARMACOKINETIC PRINCIPLES

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Mechanisms of Permeation

3. Special Carriers

ABC – ATP- binding cassette family- Less selective & expel foreign molecules

1. P-glycoprotein or MDR1 (multi-drug resistance type 1) transporter

Brain, testes, drug-resistant neoplastic cells

PHARMACOKINETIC PRINCIPLES

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Mechanisms of Permeation

3. Special Carriers

2. MDRP (MDR protein) transporters- for excretion of drugs & metabolites in urine &

bile- plays a role in resistance of tumors to

chemotherapeutic drugs

PHARMACOKINETIC PRINCIPLES

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Mechanisms of Permeation

3. Special Carriers

SLC (Solute carrier) family- important in uptake of Neurotransmitters

NET (Norepinephrine transporter)SERT (Serotonin transporter)VMAT (Vesicular monoamine transporter)

PHARMACOKINETIC PRINCIPLES

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Mechanisms of Permeation

4. Endocytosis/Exocytosis– for molecules that are too large & impermeant

e.g. B12 (intrinsic factor) Fe (transferrin)

Neurotransmitters

PHARMACOKINETIC PRINCIPLES

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Absorption

Bioavailability – fraction of unchanged drug reaching systemic circulation following administration

IV – 100%IM, SC, Transdermal - < 100%Oral, Rectal - < 100%

PHARMACOKINETIC PRINCIPLES

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Factors affecting Bioavailability

A. Extent of Absorption

Incomplete – Low Bioavailability

Oral administration – incompletely absorbed in the gutHydrophilic drug– cannot cross CMHydrophobic drug– can’t cross water layer adjacent to cell

Reverse transporter P-glycoprotein– pumps drug out of gut wall back into

gut lumen- inhibition of transporter (grapefruit juice) increases absorption

PHARMACOKINETIC PRINCIPLES

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Factors affecting Bioavailability

B. First-Pass Effect- portal blood delivers drug to the liver prior to entry in systemic circulation

Alternative RoutesSublingualTransdermalRectal – lower rectum insertion enter vessels

that drain into IVC

PHARMACOKINETIC PRINCIPLES

Direct access to systemic veins

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Summary

Factors controlling Rate of absorption:

1.Degree of ionization2.Surface Area3.Blood flow4.Gastric emptying time & GI motility

PHARMACOKINETIC PRINCIPLES

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Distribution

Volume of Distribution (V)- Defined with respect to blood, plasma, or water

- An apparent volume necessary to contain the amount of drug homogenously found in blood, plasma, or water

- Can vastly exceed physical volume of the body

PHARMACOKINETIC PRINCIPLES

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0.6 L/kg

0.04

L/k

g

0.4 L/kg

0.2L/kg

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Distribution

Volume of Distribution

V = Amount of drug (dose)C plasma conc.

e.g. A 500 mg New drug was administered . The plasma concentration is 0.01mg/ml. What is the V?

PHARMACOKINETIC PRINCIPLES

= 500 mg 0.01 mg/ml

= 50000 ml or 50L

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Distribution

PHARMACOKINETIC PRINCIPLES

COMPARTMENT EXAMPLE OF DRUGSTotal body water Ethanol: Small water solubleExtracellular water Gentamicin: Large water soluble Blood Heparin: Strongly plasma

protein-bound large moleculesFat DDT : highly lipid solubleBone Lead, Fluoride: ions

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DistributionBinding to Plasma Proteins

- Use to achieve ideal therapeutic regimen:

1. sufficient amount of drug reach site of action to bring desired effect

2. drug should not disappear too rapidly in site of action

PHARMACOKINETIC PRINCIPLES

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Distribution

Binding to Plasma Proteins1. Albumin – most important; high affinity to drugs

2. Glycoproteins

3. Lipoprotein

4. Globulins

PHARMACOKINETIC PRINCIPLES

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Distribution

Factors Affecting Rate of Distribution:

1. Extent of binding – free drug (unbound) able to distribute

2. Ability to diffuse through CM – lipophilic

3. Degree of perfusion – higher perfusion, faster equilibrium

Lung - 10 Kidney - 4Heart - 0.6 Brain - 0.5Muscle – 0.025 Fat - 0.003

PHARMACOKINETIC PRINCIPLES

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Distribution

Factors Affecting Rate of Distribution:

4. Properties of tissue membrane

Blood Brain Barrier – tightly joined capillaries covered by foot-like processes of astrocytes

Placental Barrier – separates fetal & maternal blood

- lipid-soluble drugs diffuse easily; water-soluble drugs diffuse poorly

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Why is this necessary?

1. Active organic drugs tend to be lipophilic & remain unionized or partially ionized in physiologic pH; readily reabsorbed in nephron

2. Lipophilic compounds are strongly bound to albumin & not readily filtered

3. Prolonged duration of action if termination is through renal excretion

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Site:KidneysBrain Skin GI tract

Gastric acid - penicillinDigestive enzymes – insulinEnzymes in intestinal wall – catecholamines

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Site:Plasmae.g. succinylcholine

lidocaine

Lungs e.g. converts Angiotensin I to Angiotensin II

Liver - principal organ of metabolism e.g. isopreterenol, meperidine, morphine

PHARMACOKINETIC PRINCIPLES

hydrolyzed by pseudocholinesterase

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Drug Biotransformation

Major Categories

Phase I Reactions- convert parent drug to a more polar metabolite by introducing or

unmasking a functional group (-OH, -NH2, -SH) to be readily excreted

Oxidations DeaminationDesulfuration ReductionsHydrolyses

e.g. Isoniazid – N-acetyl conjugate hydrolyzed to isonicotinic acid

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Major Categories

Phase II Reactions

- those not readily eliminated undergo subsequent reaction in which endogenous substrate combine with newly incorporated functional group to form highly polar conjugate

Glucuronic acid Acetic acidSulfuric acid Amino acid

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Phase II Reactions- relatively faster - previously terminal inactivation events or “true

detoxification”- May precede Phase I reaction

Conjugates- Polar molecules readily excreted & often inactive- Involves high-energy intermediates & specific

transfer enzymes

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Subcellular Site:

Endoplasmic reticulumMitochondriaCytosolLysosomesPlasma membraneMicrosomes – lamellar membranes of ER reform

into vesicles after homogenization & fractionation of cell

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Transferases – located in microsomes or cytosol1. UDP (uridine 5’diphosphate)-glucoronosyl transferase – most dominant

e.g. coupling of UDP derivative of glucuronic acid with bilirubin (Glucuronidation)

2. Sulfotransferase- sulfation of PAPS (3’phosphoadenosine 5-

phosphosulfate)

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Transferases 3.GSH (glutathione) transferase

- GSH conjugation 4. N-acetyl transferase

e.g. Isoniazid – N-acetyl conjugate - acetylation

5. Methyltransferase- transmethylases methylation

Epoxide Hydrolases – water conjugation

PHARMACOKINETIC PRINCIPLES

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Absorption

Drug

Metabolism Elimination

Lipophilic

Drug

Phase I Phase II

Conjugate

Conjugate

Conjugate

Drug metabolite with modified activity

Inactive drug metabolite

Hydrophilic

Drug

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Drug Biotransformation

Metabolism to Toxic Products

- Compounds metabolically transformed to reactive intermediates that are toxic to various organs

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation

Acetaminophen

Glucuronidation Sulfation

Non-toxic Reactive Non-toxic Glucuronide Intermediates Sulfate (N-acetylbenzoiminoquinone)

+ GSH Neucleophillic conjugation cellular proteins

Mercapturic Acid Liver Cell Death conjugate

PHARMACOKINETIC PRINCIPLES

CYP1 CYP3A4

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Drug Biotransformation: Variables in Differences

1. Genetics

Genetic polymorphissm- genetic factors influence enzyme levels- occurrence of variant allele at population

frequency ≥ 1% - resulting to altered expression &/or

function activity of gene product

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation: Variables in Differences

1. Genetics

Autosomal Recessive Traits

e.g. Succinylcholine –metabolized half rapidly in persons with deficiency

of pseudocholinesterase or butyrylcholinesterase (BCHE)

INH – slow acetylators phenotype - 50% Caucasians, less common in Asians

- high incidence of INH-induced peripheral neuritis

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation: Variables in Differences

2. Age – increase toxicity in extreme ages

Neonate – deficiency in UGT Glucoronide formation - adult value at 3-4yo

Elderly – decline of liver to recover from injury

3. SexMale – faster metabolism

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation: Variables in Differences

4. Diseases

Liver diseases – impaired hepatic drug-metabolizing enzymes

Cardiac diseases – impaired hepatic blood flowPulmonary diseases – reduced hepatic

metabolismEndocrine diseases

Hypothyroidism - reduced hepatic metabolismHyperthyroidism – increased hepatic metabolism

PHARMACOKINETIC PRINCIPLES

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Drug Biotransformation: Variables in Differences

5. Nutritional & environmental charcoal-broiled foodcruciferous vegetables

grapefruit - inhibitor

cigarette smokepesticides

PHARMACOKINETIC PRINCIPLES

inducers

inducers

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Drug Excretion

Common Pathways:Sweat SalivaMilk

Respiratory - role not significant in excretion- when drugs are metabolized into products

that can be exchanged from blood into respiratory system

- excreted by lungs

PHARMACOKINETIC PRINCIPLES

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Drug ExcretionCommon Pathways:

GI - after oral administration, portion of drug is unabsorbed & is excreted in the feces

Enterohepatic pathway lipid soluble drug liver bile intestine blood

liver

PHARMACOKINETIC PRINCIPLES

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Drug Excretion

Common Pathways:Renal

- blood filtered & reabsorbed- urinary waste products & nonabsorbable form are

excreted- excretion of drug & metabolite: water soluble

Acidic drug – basic urineBasic drug – acidic urine

PHARMACOKINETIC PRINCIPLES

Fruits VegetablesNa2HCO3

Protein rich foodProbiotics

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Drug Excretion

Clearance: measure of the body to eliminate the drugs: factor that predicts rate of elimination in relation to

drug concentration: defined in respect to blood, plasma or unbound in water

CL = Rate of Elimination (mg/min) C (mg/ml)

e.g. A 1 liter of water contains 1000mg drug. After an hour 100mg of drug has been removed. What is the clearance of this drug?100 ml/hr

PHARMACOKINETIC PRINCIPLES

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Drug Excretion

Clearance : dividing rate of elimination at each organ by conc. of drug yields respective clearance, together equal total systemic clearance

CL kidney = Rate of Elimination kidney

C

CL liver = Rate of Elimination liver

C

CL other = Rate of Elimination other

C

CL systemic = CL kidney + CL liver + CL other

PHARMACOKINETIC PRINCIPLES

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Drug Excretion

First-order elimination : constant over concentration range

: elimination is not saturable: rate of drug elimination is directly

proportional to concentration

PHARMACOKINETIC PRINCIPLES

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Dru

g C

once

ntra

tion

(%m

ax)

Time

100 – -

80 – -

60 – -

40 – -

20 – -0

- - - - - - - - -

Dru

g C

once

ntra

tion

(%m

ax)

Time

100 .0 –

10.0 –

1.0 -

0.1

- - - - - - - - - -

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Drug Excretion

Zero-order elimination• Capacity-limited elimination • Mixed-order, saturable, dose or

concentration dependent• Nonlinear or Michealis-Menten elimination

PHARMACOKINETIC PRINCIPLES

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Dru

g C

once

ntra

tion

(%m

ax)

Time

100 – -

80 – -

60 – -

40 – -

20 – -0

- - - - - - - - -

Dru

g C

once

ntra

tion

(%m

ax)

Time

100

1 0 - - - - - - - - - -

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Drug Excretion

Steady state concentration (Css)•In multiple dosing or constant infusion, drug will accumulate until amount administered per unit time is equal to amount eliminated per unit time

PHARMACOKINETIC PRINCIPLESPl

asm

a C

once

ntra

tion

(%of

st

eady

sta

te)

Time

100 – - 75 – - 50

– - 25

– -0

- - - - - - - - -

1 2 3 4 5 6 7 8

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Drug Excretion

Flow Dependent Elimination• Drugs are cleared readily• Elimination depend primarily on rate of

drug delivery to organs of elimination• Blood flow is main determinant of drug

delivery

PHARMACOKINETIC PRINCIPLES

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Drug Excretion

Half life• Time required to change the amount of

drug in the body by ½ during elimination or constant infusion

• Time course will depend on V & CL

t1/2 = 0.7 x V CL

PHARMACOKINETIC PRINCIPLES

Elimination can be described by exponential process, time taken for 2-fold decrease is proportional to log 2 (0.7)

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Drug Excretion

Half life• Indicates time required to attain 50% steady state or to

decay 50% from steady state

PHARMACOKINETIC PRINCIPLESPl

asm

a C

once

ntra

tion

(%of

st

eady

sta

te)

Time (half lives)

100 – - 75 – - 50

– - 25

– -0

- - - - - - - - -1 2 3 4 5 6 7 8

Drug accumulation in constant rate of infusion

Drug elimination after constant rate of infusion reached steady state

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Drug Accumulation

• Whenever drug doses are repeated, drug will accumulate in the body until dosing stops

• Detectable if dosing is shorter than 4 half-lives• Inversely proportional to fraction of a dose lost in each

dosing interval

PHARMACOKINETIC PRINCIPLES

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Drug Excretion

Average concentration (Cav)•In repeated doses, concentration fluctuates around a mean (Css) with peak & trough values

PHARMACOKINETIC PRINCIPLESPl

asm

a C

once

ntra

tion

(%of

st

eady

sta

te)

Time

100 – - 75 – - 50

– - 25

– -0

- - - - - - - - -1 2 3 4 5 6 7 8

Peak

Trough Css

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PHARMACODYNAMIC PRINICPLES:

Objectives:

1. Identify the different target proteins and discuss their mechanisms of drug-receptor interactions

2. Discuss the concepts of affinity, intrinsic activity, selectivity and specificity

3. Describe signal transduction mechanisms, the different types of G-proteins, and second messenger system

4. State the occupancy theory and receptor inactivation theories

5. Describe the different dose-response curves and the pharmacologic parameters derived from these curves