P H A R M A C O K I N E T I C S

The drug must be capable of reaching the site of action BLOOD DRUG
Drug must have necessary properties to be transported From: its site of administration To: its site of action

must remain at the site of action long enough EFFECTS

The drug must achieve these criteria without inducing SYSTEMIC unacceptable CIRCULATION toxicity in the patient

SITE OF ACTION

Dose
• Dose is the amount of a chemical that gets inside of your body. • Measured in mg of chemical/kg of weight The Dose Makes The Poison

Typical dose-response curve 100 % response 50 0 10 100 1000 Log scale dose (mg/kg) .

0 0 0 .2 0 1 . 0 0 1 0 . 0 0 0 0 0 . 1 0 1 . 0 0 0 0 0 . 0 0 0 0 0 1.8 0 Response 0 .0 1 0 .6 0 0 .0 0 0 .4 0 0 .The intensity of response is related to concentration of the drug at the site of action Response changes with concentration R e s p o n s e v C o n c e n t r a t io n 1 .2 0 0 . 0 0 1 0 0 . 0 0 1 1 C o n c e n t r a t io n Maximal response Linear response (20-80%) No response (semi-log) Receptor Drug Molecule .

A dose at which there is no measurable effect Upper dose where there is a maximal response DOSE DOSAGE .

Dose .the dose producing the desired (therapeutic) effect in 50% of the test animals • Toxic dose TD50 .Response • Effective dose ED50 .the dose lethal to 50% of test animals when administered by stated route .the dose toxic to the specified organ in 50% of the test animals administered by the stated route • Lethal dose LD50 .

• .

‫‪Dose -response‬‬ ‫‪w‬‬ ‫افزایش‬ ‫قدرت‬ ‫انقباض‬ ‫قلب‬ ‫آریتمی اختلل تهوع‬ ‫قلبی بینایی‬ ‫مرگ‬ .

Therapeutic Index • Therapeutic index = toxic dose/effective dose • This is a measure of a drug’s safety – A large number = a wide margin of safety – A small number = a small margin of safety .

Warfarin: A Small Therapeutic Index Percent of Patients 100 Desired Therapeutic Effect Unwanted Adverse Effect 50 0 0 Log Drug Concentration .

Penicillin: A Large Therapeutic Index Percent of Patients 100 Desired Therapeutic Effect Unwanted Adverse Effect 50 0 0 Log Drug Concentration .

PARAMETERS • LD50 .ED50 & TD50 LD50 TD50 ED50 ED50 Margin of safety (TI) .

NSAID (IBUPROFEN) Wide TI Normal dose = 400-3200 mg/day (THEOPHYLLINE) BLOOD CONC = 10-20 µg/ml below this conc (not much effect ) above 20 µg/ml (serious toxicities) .

How Do We Study Pharmacology? .

General Concepts Drug Dose Administration Disintegration of Drug Absorption/distribution metabolism/excretion Drug/Receptor Interaction Drug Effect or Response Pharmaceutical Pharmacokinetics Pharmacodynamics Pharmacotherapeutics .

Objectives • By the end of this session. CL. students should be able to: – Define the four processes involved in pharmacokinetics – Define parameters which can affect • drug absorption • drug distribution • drug metabolism • drug excretion – Define half life. Vd and bioavailability and describe the relevance of these to drug action – Calculations .

eg: GUT (one body Compartment) to move to its site of action eg: Brain (another compartment) Drug is given into : HOW? .A young child given an intramuscular injection might ask "How will that 'ouch' get from there to my sore throat"? The answer to this question is the basis of pharmacokinetics.

ABSORPTION DISPOSITION ELIMINATION DISTRIBUTION EXCRETION METABOLISM .WHAT IS PHARMACOKINETICS? PHARMACOKINETICS is the study of the kinetics of drug absorption and disposition.

be excreted Pharmacokinetic models .The factors involved in a drug getting to and remaining at its sites of action Pharmacokinetics A bsorption .how the drug is taken into the body D istribution -how the drug is moved into various tissues M etabolism --how the drug is changed into a form that can Passage of drugs across membranes E xcretion .how the drug is removed from the body Drug should be inactivated or excreted from the body at a reasonable rate so its actions will be of appropriate duration.

Healthy volunteers Patients with average ability to : ADME “Standard “ Dose .

Pharmacokinetics .

antagonist …. Efficacy. Bmax. Emax. ED50. . TI Agonist. Kd. Potency EC50.Pharmaco dynamics study the mechanisms by which drugs work also study endogenous agents Receptors & spare R Affinity.

yPK/PD links PK with PD so that the time course of effect is described for a given dose regimen PK along with PD tells the clinician • how much. Conc PK Dose PD Time Effect Time . how often and how long to dose.

Pharmacodynamics (PD): Pharmacokinetics (PK): What the drug does to the body What the body does to the drug D osage Plasm a C oncen . Site of A ction E ffects Pharm acokinetics Pharm acodynam ics .

.DRUG THERAPY Goal : To Rapidly Deliver and Maintain therapeutic (non toxic) levels of drugs in the target tissues.

The drug will appear at the target organ : • How rapidly? • In what concentration? • For how long? .

To Obtain : Right effect At the Right intensity Right time For the Right duration With MIN risk OF HARM At the .

Routes of Drug Delivery Parenteral (IV) Inhaled Oral Parenteral (SC. IM) Rectal Transdermal Topical .

drugs must be absorbed. .HOW DO DRUGS GET INTO THE BODY? Unless injected directly into the blood stream.

Absorption • Must be able to get medications into the patient’s body • Drug characteristics that affect absorption: – Molecular weight. & formulation • Factors affecting drug absorption related to patients: – Route of administration. contents of GI tract . ionization. solubility. gastric pH.

WHAT IS DRUG ABSORPTION? The movement of drug molecules across biological barriers (mostly layers of cells) from the site of administration to the blood stream. Site of Administration DRU G BIOLOGICAL BARRIER Vascular System .

THE TRANSPORT ACROSS THE MEMBRANES A. Passive diffusion and filtration B. Specialized transport

Passage of drugs across membrane

Cellular uptake inside vesicles
Highly ionized (sulphonic acids and Q ammonium compd) from GIT Low L-W PC but still go through

Levodopa and methyldopa

Ficks Law

at constant temp

R = Diffusion Rate
(flux – molecules per unit time)

A (C2 – C1) • R = K --------------d
A = Surface area d = thickness of membrane > 1
K = Diffusion constant of compound (Temp dependent) Permeability coefficient

Wt • Lipid Solubility • Ionization .K • Function of : • Steric configuration • M.

ionized forms of drugs Acidic drugs are ionized in basic environment Basic drugs are ionized in acidic environment .IONIZATION decreases membrane permeability Ionized forms of compounds have low lipid solubility Why? • non-ionized forms of drugs are more soluble in lipids and absorbed better than water-soluble.

6 to 7.Many drugs are weak organic acids or bases (weak elctrolytes) • Weak acids aspirin in intestines are mostly ionized (intestinal pH ranges from 6.NH3+ Degree of Ionization depends on : pH of Medium pKa of the molecule What is pKa? .+ H+ R-NH2 + H+ = R.5) • Weak bases atropine in stomach are mostly ionized (stomach pH ranges from 1 to 2) Weak acids Weak bases DISSOCOATE R-COOH = R-COO.

Henderson-Hasselbach equation pKa = pH at which 50% of a substance is ionized [A-] [HA] WEAK acid pH = pKa + log pH = pKa + log [B] [BH+] WEAK base pKa Dissciation constant .

= 10 [U] WEAK ACID Benzoic Acid Small changes in pH may greatly influence the Degree of drug ionization. .pKa [I] ---------------.Henderson Hasselbach pH .

pH [I] ---------------.= 10 [U] WEAK BASE Aniline .Henderson Hasselbach pKa .

4 Where & Why ? .Henderson Hasselbach Morphine pKa = 8 Stomach pH = 2 Plasma pH = 7.

Concen in blood may not be indentical to conc at the site of action .

Basic Parameters • In the next few slides the basic concepts and paramaters will be described and explained. • Some of the parameters are therefore a little abstract as we know the body is much more complicated ! . • In pharmacokinetics the body is represented as a single or multiple compartments in to which the drug is distributed.

Pharmacokinetic Parameters ---------------------------Clearance Volume of distribution Half – life Bioavailability .

CONCEPT OF DRUG CLEARANCE (CL) Quantifies ELIMINATION Think of drug clearance as removal of drug from body by body’s garbage disposal systems! .

mL/min) .5 L/hr 4 mg/L Is the volume of body fluid cleared of drug per time unit (L/h.DRUG CLEARANCE: Example: Rate of Drug Elimination (Excretion rate) = 10 mg/hr [D]P (Concentration) = 4 mg/L 10 mg/hr CL = = 2.

DRUG CLEARANCE: CL is usually constant over a wide range of [D]P CL The rate of elimination is directly proportional to the drug conc [D]P This is a consequence of the fact that most drugs are eliminated from body by 1st order kinetics .

Clearance (CL) Blood. Serum Which Particular fluid assay ? Serum Clearance (CL) of 200 ml/min In one minute all of the drug could have been eliminated from 200 ml of serum ---------------------------------------- . Plasma.

i...Total Body Clearance (CL) ------------------------------------CL = CLren + CLhep + CLother • CL = (CLliver + CLg.) . tract + CLkidney + CLlung + .

Clearance „ Clearance also plays a role in determining the steady-state of a drug or toxicant: concentration „ Csteady-state = Rate of administration/ CL .

CONCEPT OF DRUG CLEARANCE: INTRODUCTION TO Cl Cl is a major determinant of [D]P at STEADY STATE ([D]PSS) INPUT STEADY STATE LEVEL (Kidney & Liver) OUTPUT .

Clearance • Ability of organs of elimination (e. liver to “clear” drug from the bloodstream • Volume of fluid which is completely cleared of drug per unit time • Units are in L/hr or L/hr/kg • Pharmacokinetic term used in determination of maintenance doses .g. kidney.

& formulation • Factors affecting drug absorption related to patients: – Route of administration.Absorption • Must be able to get medications into the patient’s body • Drug characteristics that affect absorption: – Molecular weight. contents of GI tract . gastric pH. solubility. ionization.

Distribution • Membrane permeability – cross membranes to site of action • Plasma protein binding – bound drugs do not cross membranes – malnutrition = albumin =  free drug • Lipophilicity of drug – lipophilic drugs accumulate in adipose tissue • Volume of distribution .

Most of the administered drug is found in areas of the body that are remote from the drug’s site of action. only a very small portion of the total amount of a drug that is in the body is actually in contact with its receptors.Drug Distribution • At any given time. .

Volume of Distribution • An abstract concept • Gives information on HOW the drug is distributed in the body • Used to calculate a loading dose .

Drug Distribution • It takes time for a drug to distribute in the body • Drug distribution is affected by elimination • Wide distribution often accounts for many of the side effects of a drug .

Basic Parameters • In the next few slides the basic concepts and paramaters will be described and explained. • Some of the parameters are therefore a little abstract as we know the body is much more complicated ! . • In pharmacokinetics the body is represented as a single or multiple compartments in to which the drug is distributed.

BRAIN & SPLEEN . RED CELLS LUNGS LIVER. Highly Vascular PLASMA.THE BODY AS COMPARTMENTS -------------------------- 1.

Low Vascular FAT DEPOSITS .THE BODY AS COMPARTMENTS -------------------------- 2.

• Drugs may be deposited in fatty tissue which may become a resevior • low blood flow. cannot absorb or release quickly • bone & teeth may accumulate drugs which bind to calcium. tetracycline .

Plasma Protein Binding • Many drugs bound to circulating plasma proteins such as albumin • Only free drug can act at receptor site Receptor Site Protein-bound drug A bound drug has no effect! Free Drug .

Effective TOXIC .9 1 % bound molecules free 90.0 100 100-fold increase in free pharmacologically active concentration at site of action.Alter plasma binding of drugs 1000 molecules 99.

Highly Protein Bound Drugs
• > 95% bound
– – – – – – – Thyroxine Warfarin Diazepam Frusemide Heparin Imipramine Amitriptylline

• > 90% but < 95% bound
– – – – Glibenclamide Phenytoin Propranolol Sodium Valproate

Changes in plasma protein binding are significant for drugs which are greater than 90% bound to plasma proteins

Plasma Proteins that Bind Drugs
• albumin: binds many acidic drugs and a few basic drugs This is more important quantitatively ∀ β-globulin and an α1acid glycoprotein have also been found to bind certain basic drugs

A bound drug has no effect!
• • • • Amount bound depends on: 1) free drug concentration 2) the protein concentration 3) affinity for binding sites

[bound drug] % bound: ---------------------------------- x 100 [bound drug] + [free drug]

Binding % of some BDZs • • • • Flurazepam Alprazolam Lorazepam Diazepam 10 % 70 % 90 % 99 % No generalization for a pharmacological or chemical class .

Pharmacokinetic Parameters ---------------------------Clearance Volume of distribution Half – life Bioavailability .

Volume of Distribution „ The Volume of Distribution is the apparent volume into which a drug or toxicant distributes. and provides a proportionality constant between blood (or plasma) concentration and the amount in the body: ƒ Volume of Distribution = Amount / Concentration .

. which is distributed in blood only.000 liters (as is seen with Quinacrine. „ to about 50.„ Volume of distribution Volume can range from about 3 liters (as is seen with Tolbutamide. which distributes and binds to many tissues).

. the body behaves like a well-stirred beaker.VOLUME OF DISTRIBUTION (VD) OF DRUGS (Stir) As a first approximation.. i.e. chemicals are dispersed throughout the container (body) rather quickly.

VOLUME OF DISTRIBUTION OF DRUGS: DEFINITION OF VD Add DRUG to Beaker Obtain Sample Assay for C (Stir) Calculate Volume C = Amount Added ÷ Volume of Beaker Volume of Beaker = Amount Added ÷ C .

VOLUME OF DISTRIBUTION OF DRUGS: DEFINITION OF VD Dose Body with DRUG Obtain Plasma Sample Assay for CP Calculate Volume (This volume is called VD) By DEFINITION: VD = A/CP (where A is amount of drug in body and CP is concentration of drug in plasma) .

a clinically useful value. a reproducible value. the word “volume” 3. this regard. . is used in a metaphorical sense. In 2.VOLUME OF DISTRIBUTION OF DRUGS: DEFINITION OF VD WARNING: VD is a calculated value that should not be taken literally as representing some real volume!!!!!! VD is: VD is not a real volume with 1. a calculated value. an independent existence.

Volume of Distribution (Vd) The ‘apparent’ volume of distribution:  A theoretical volume only: NO PHYSICAL BASE NO PHYSIOLOGICAL BASE Volume in which drug appears to distribute Vd not physical volume. Vd is proportionality constant Vd = Dose(known)/Cp(known) .

Quantifies Distribution .Volume of Distribution (Vd) Vd = D / C .Drug Concentration (C) mg/L Amount of drug in the body (D) mg .

25 L/kg .Volume of Distribution • Drugs are distributed unevenly between various body fluids and tissues according to their physical and chemical properties – For example. gentamicin • Very good water solubility • Very poor lipid solubility (do not enter cells) Gentamicin stays mainly in blood and body water 0.

VOLUME OF DISTRIBUTION OF DRUGS: DETERMINANTS OF VD Distribution into Body Compartments Small VD vs Large VD Restriction of Drug to Limited Areas of Body Free Assess of Drug to Many Areas of Body .

VOLUME OF DISTRIBUTION OF DRUGS: DETERMINANTS OF VD Tissue Binding ↓↓ CP ↑↑ VD = A ↓↓ CP .

VOLUME OF DISTRIBUTION OF DRUGS: DETERMINANTS OF VD Plasma Protein Binding A ↑↑CP ↑↑CP ↓↓VD = .

VOLUME OF DISTRIBUTION OF DRUGS: DETERMINANTS OF VD Distribution into Fat ↓↓ Cp ↑↑ VD = A ↓↓ CP .

Pharmacokinetic Parameters ---------------------------Clearance Volume of distribution Half – life Bioavailability .

693/kel Elimination rate constant How long a drug is expected to remain in the body after termination of dosing? .Half – life (t1/2) • Half life is the time required to reduce the plasma concentration to half of its original value t1/2 = 0.

Elimination rate constant Kel = ----------- 0.693 t1/2 CL ----.1/2 = 0.05 or 5% per hour . If 2 g of the drug is present in the body and 0.= Kel Vd Fraction of the drug present at any time that would be eliminated in unit time. then k = 0.1 g is eliminated every hour.

1 hr -1 100 L 10 % of the “Volume” is cleared (of drug) per hour kel = Fraction of drug in the body removed per hour .Clearance = 10 L/hr Volume of Distribution = 100 L What is the Elimination Rate Constant (kel) ? CL = kel x Vd kel = 10 Lhr -1 = 0.

CL = kel x Vd If V increases then k must decrease as CL is constant .

Half Life 110 100 90 Concentration (m g/L) 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 Tim e (hours) Half-life is the time taken for the concentration of drug in blood to fall by a half .

Significance • Say a patient is taking a drug and has a toxic blood level of 16mg/L • Say – The blood level you want is 2mg/L – Drug half life is 8 hours How long will it take for the blood level to fall back to the level you want? .

Significance Half life = time taken for blood level to reduce by 50% Therefore: 16mg to 8mg = 8 hours 8mg to 4 mg = 8 hours 4mg to 2mg = 8 hours Total: 24 hours .

regular-interval dosing .Time Course of dru action • Distribution Half Life: • time for drug to reach 50% of its peak concentration • Elimination Half Life: • time for drug concentration to fall 50% • Steady State Concentration: • the level of drug achieved in blood with repeated.

12 Plasma Concentration 10 8 6 4 2 0 TOXIC RANGE THERAPEUTIC RANGE SUB-THERAPEUTIC 0 1 2 3 4 5 6 7 8 9 Dose .

Time to Steady State • Time to steady state depends on half life Tss = 4 x t½ Steady-state occurs after a drug has been given for approximately 4-5 elimination half-lives. C C p a v t Fr al eo a sa st oh i s r c t d t e u l v t ehe ya f .

Secondary pharmacokinetic parameter and depends on CL & Vd 0.Half . Therefore t1/2 is not an exact index of drug elimination. Vd .Life (t1/2) t1/2 = ---------------CL Both Vd and CL may change independently.693 .

First order kinetics (t1/2) remains constant because Vd and CL do not change with dose Zero order kinetics (t1/2) increases with dose because CL progressively decreases as dose is increased Aspirin 4 hr Digoxin 40 hr Penicillin-G Digitoxin 30 min 7 days .

Pharmacokinetic Parameters ---------------------------Clearance Volume of distribution Half – life Bioavailability .

An Important Concept: BIOAVAILABIITY The fraction of the administered dose that reaches the systemic circulation of the patient Serum Concentration Injected Dose Oral Dose Time .

route oral route 4 6 Time (hours) 8 10 .70 60 Plasma concentration Bioavailability= (AUC)o (AUC)iv 50 40 30 20 10 0 0 2 i.v.

Bioavailability Extent of absorption of a drug following its administration by routes other than IV injection .

 100 mg Oral . liver metabolism Incomplete absorption Enterohepatic cycling & elimination into . 70 mg absorbed unchanged Bioavailability = 70 % Iv admin = 1 Oral admin < 1 Bioavailability  lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism Gut wall. gut.

propranolol.    First Pass hepatic metabolism Lidocaine. insulin Nature of drug formulation Particle size – salt form Bioavailabilit y . Morphine. Pentazocine Solubility of drug Chemical instability Penicillin G in gastric acid.

Example – same drug, 3 different formulations could have same bioavailability
IV Oral – not S/R Oral - SR

Plasma conc

Time

Time Course
• Steady State Concentration:
• the level of drug achieved in blood with repeated, regular-interval dosing

Water level = DRUG BUCKET with a HOLE Elimination .

Example: Oral Dose    A single oral dose will give you a single peak plasma concentration The drug concentration then continuously declines Repeated doses result in Plasma Concentration Time .

.

Important Point pharmacokinetic profile of a drug also depends on its mode of administration …  The .

Example: Intravenous Infusions   Plasma concentration rises until elimination = input Faster infusions get more drugs on board. but does not change the time to achieve a steady Plasma Concentration Fast Infusion Slow Infusion Time Time at which steady state is achieved .

T1/2 = 12 h .

‫‪Multiple dosing‬‬ ‫مکرر.دوز ثابت .فواصل زمانی معین‬ ‫4‬ .

‫نیمه عمر دارو‬ ‫ساعت 42‬ ‫روزی دو قرص‬ ‫2‬ ‫‪SS‬‬ ‫روزی یک قرص‬ ‫1‬ ‫‪SS‬‬ ‫6‬ ‫4‬ .

1 .

Effect of Dose: Increasing the dose gives: Higher plasma concentration Larger peak to trough variation Cp Example: Dihydrocodeine Better to give 30mg every 4 hours than 60mg every 8 hours Dose = 60mg Pain relief Dose = 30mg Time .

Effect of dosage interval: Increasing the dose interval gives: Lower plasma concentrations Larger peak to trough variation E. gentamicin Giving a dose every 12 hours may avoid toxicity Dose interval = 8hours Cp Peak Trough Dose interval = 12 hours Time .g.

7 6 5 4 3 2 1 0 0 5 10 15 20 plasma conc toxic effective Time 25 .

7 6 5 4 3 2 1 0 0 5 10 15 20 Cumulation and use of loading doses plasma conc toxic Loading Dose = Vd x plasma conc effective Time 25 .

12 Plasma Concentration 10 8 6 4 2 0 TOXIC RANGE THERAPEUTIC RANGE SUB-THERAPEUTIC 0 1 2 3 4 5 6 7 8 9 Dose .

one or more doses per day for several days or weeks . • • Most are given as a course of therapy.Multiple dosing • In a medical/dental context some drugs are given as single doses but this is unusual.

e. . steady state is reached.Multiple dosing • On multiple dosing plasma concentration will rise and fall with each dose and body load will increase until Rate in = Rate out administration = elimination i.

.At each dose the level will oscillate through a range The objective is to achieve therapeutic levels quickly. to remain within the therapeutic window with acceptable variation at each dose and with a regimen which promotes compliance.

7 6 5 4 3 2 1 0 plasma conc Time 0 5 10 15 20 25 .

At Steady State Rate in = Rate out F x Dose / Dosing Interval = SSC x CL Dosage Plasma level Cpss = Dose Rate/ CL 2 x Cpss = 2 x Dose Rate/ CL F = fraction of dose administered .

What is Steady State (SS) ? Why is it important ? • Rate in = Rate Out • Reached in 4 – 5 half-lives (linear kinetics) • Important when interpreting drug concentrations in TDM or assessing clinical response .

Important Concepts • VD is a theoretical Volume and determines the loading dose • Clearance is a constant and determines the maintenance dose • CL = kel x VD • CL and VD are independent variables • k is a dependent variable .

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