Pharmacokinetics.

Pharmacokinetics

SYSTEMIC CIRCULATION BLOOD SITE OF ACTION DRUG EFFECTS

its site of administration toxicity in the patient
The drug must be capable of reaching the site of action must remain at the site of action long enough BLOOD DRUG SITE OF ACTION EFFECTS Drug must have necessary properties to be transported From: its site of administration To: its site of action The drug must achieve these criteria without inducing unacceptable toxicity in the patient SYSTEMIC CIRCULATION

Definitions Pharmacokinetics is the study of the time course of the drug concentration in the body, i.e., "what the body does to the drug". Therapeutic drug monitoring is the measurement of the serum level of a drug and the coordination of this serum level with a therapeutic range. The therapeutic range is that range of serum drug concentrations which have been shown to be efficacious without causing toxicity in the majority of patients. Clinical pharmacokinetics deals with the application of pharmacokinetic principles to the safe and effective therapeutic management of drug dosage in an individual patient.

L = Liberation, the release of the drug from it's dosage form.
A = Absorption, the movement of drug from the site of administration to the blood circulation. D = Distribution, the process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues). M = Metabolism, the chemical conversion or transformation of drugs into compounds which are easier to eliminate. E = Excretion, the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes.

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

Drug Absorption Orally
Rectually (drug embedded in a suppository, which is placed in the rectum) Parenterally (given in liquid form by injection with a needle and syringe) Inhaled –thru the lungs as gases, as vapors, or as particulars carried in smoke or in an aerosol Absorbed through the skin Absorbed through mucous membranes 7

Drug Absorption -caveats
Orally Drug must be soluble and stable in stomach fluid (not destroyed by gastric acids), enter the intestine, penetrate the lining of the stomach or intestine, and pass into the blood stream. 8

Drug Absorption -disadvantages
May occasionally lead to vomiting and stomach distress. How much of the drug will be absorbed into the bloodstream cannot always be accurately predicted because of the genetic differences between people and because differences in the manufacture of the drugs. The acid in the stomach destroys some drugs. 9

Drug Absorption -caveats
Rectually Rarely used unless patient is vomiting, unconscious, or unable to swallow Drug Absorption -disadvantages Rectually Often irregular, unpredictable, and incomplete Many drugs irritate the membranes that line the rectum. 10

Drug Absorption Parenterally Intravenous –directly into a vein
Intramuscular –directly into muscle Subcutaneous –just under the skin 11

Drug Absorption Parenterally
Often produces a more prompt response than does oral administration because absorption is faster. Permits a more accurate dose because the unpredictable processes of absorption are bypassed. 12

Drug Absorption -disadvantages
Parenterally Leaves little time to respond to an unexpected drug reaction or accidental overdose. Requires the use of sterile techniques. Once a drug is administers by injection, it cannot be recalled. Drugs that cannot become completely soluble before injection, cannot be injected intravenuously. 13

Drug Absorption Inhaled
Lung tissues have a large surface area with large blood flow, allowing for rapid absorption of drugs. 14

Drug Absorption Absorbed through the skin Provides continuous,
controlled release of a drug from a reservoir through a semipermeable membrane. Potentially minimizes side effects associated with rapid rises and falls in plasma concentration of the drug contained in the patch. 15

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

Who took the largest dose of Tylenol?
65 kg kg kg kg 300 mg mg mg mg 17

Calculating Dose: 50 mg  2.5 lb = 20 mg/kg
300 mg  62.5 kg = 4.8 mg/kg

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

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
100 Desired Therapeutic Effect Unwanted Adverse Effect Percent of Patients 50 Log Drug Concentration

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

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

Drug Concentrations in the Plasma
50 40 30 20 10 But what’s missing here that is needed for this info to be of any use? Drug Concentration in Plasma (Cp) mcg/mL Time since administration of drug (hours)

Drug Concentrations in the Plasma
Toxic Concentrations 50 40 30 20 10 Drug Concentration in Plasma (Cp) mcg/mL Therapeutic Concentrations (Therapeutic Range) Subtherapeutic Concentrations Time since administration of drug (hours)

Onset and duration of drug action
Drug concentration in blood 2 4 6 8 10 12 Time (hour)

Drug concentration in blood MEC 2 4 6 8 10 12 Time (hour)

MTC Drug concentration in blood MEC 2 4 6 8 10 12 Time (hour)

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

CONCEPT OF DRUG CLEARANCE:
INTRODUCTION TO Cl Toxic Threshold [D]PSS (Therapeutic Window) Therapeutic Threshold [D]P (mg/L) Multiple Doses Single Dose Time (hrs) [D]PSS = [D]P at steady state

toxic plasma conc effective Time

Loading Dose = Vd x plasma conc
toxic plasma conc Loading Dose = Vd x plasma conc effective Cumulation and use of loading doses Time

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

Multiple dosing Rate in = Rate out
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.e. steady state is reached.

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

Question What maintenance dose is required for drug A if;
Target average SS concentration is 10 mg/L CL of drug A is L/kg/hr Patient weighs 75 kg Answer on next slide.

Answer Maintenance Dose = CL x CpSSav
CL = L/hr/kg x 75 = L/hr Dose = L/hr x 10 mg/L = mg/hr So will need x 24 mg per day = 270 mg

Example: Maintenance Dose Calculations
A target plasma theophylline concentration of 10 mg/L is desired to relieve acute bronchial asthma in a patient. mean clearance = 2.8 L/h/70 kg. Since the drug will be given as an intravenous infusion, F = 1. Dosing rate = CL × TC = 2.8 L / h / 70 kg × 10 mg / L = 28 mg / h / 70 kg Therefore, in this patient, the proper infusion rate would be 28 mg/h/70 kg.

Maintenance dose =Dosing rate/F × Dosing interval
If the asthma attack is relieved, the clinician might want to maintain this plasma level using oral theophylline, which might be given every 12 hours using an extended-release formulation to approximate a continuous intravenous infusion. Foral = 0.96 When the dosing interval is 12 hours, the size of each maintenance dose would be: Maintenance dose =Dosing rate/F × Dosing interval = mg / h/ 0.96 × 12 hours = 350 mg If an 8-hour dosing interval was used, the ideal dose would be 233 mg; and if the drug was given once a day, the dose would be 700 mg.

Question What is the loading dose required for drug A if;
Target concentration is 10 mg/L VD is 0.75 L/kg Patients weight is 75 kg Answer is on the next slide

Answer: Loading Dose of Drug A
Dose = Target Concentration x VD VD = 0.75 L/kg x 75 kg = L Target Conc. = 10 mg/L Dose = 10 mg/L x L = 565 mg This would probably be rounded to 560 or even 500 mg.

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. Drug is given into : eg: GUT (one body Compartment) to move to its site of action eg: Brain (another compartment) HOW?

Pharmacokinetics Absorption –the process by which the drug moves into the body from external source Distribution –the drug is distributed throughout the body (including fetus) Metabolism –detoxification or breakdown of the drug into metabolites that no longer exert any effect Elimination –metabolic waste products are removed from the body 46

Pharmacokinetics Pharmacokinetics in its simplest form describes the time course of a particular drug’s actions: the time to onset and the duration of effect. *Triazolam is a benzodiazepine derivative generally used as a sedative to treat insomnia. *Lorazepam initially marketed under the brand names Ativan and Temesta, is a benzodiazepine drug with short to medium duration of action. It has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant and muscle relaxant.

Pharmacokinetics

PK/PD PD PK Dose 49

Drug Body Molecular size Lipid solubility Ionization Absorption
Distribution Elimination

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?

“7 Rights” of Safe Medication Administration
Right Drug Right Dose Right Time Right Route Right Patient Right Reason Right Documentation

WHY BE CONCERNED ABOUT HOW DRUGS GET INTO BODY?
This issue importantly affects: Bioavailability - % of dose that gets into body Bioequivalence - similarity between two formulations of same drug Speed of Drug Onset - how long it takes the drug to begin working Dosing Interval - how often the drug should be given Site of Action - whether the drug stays local or acts systemically

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 Vascular System DRUG BIOLOGICAL BARRIER

Weak acids Weak bases DISSOCOATE
Many drugs are weak organic acids or bases (weak elctrolytes) Weak acids aspirin in intestines are mostly ionized (intestinal pH ranges from 6.6 to 7.5) Weak bases atropine in stomach are mostly ionized (stomach pH ranges from 1 to 2) Weak acids Weak bases DISSOCOATE R-COOH = R-COO- + H+ R-NH2 + H+ = R- NH3+ Degree of Ionization depends on : pH of Medium pKa of the molecule What is pKa?

Ionized forms of compounds have low lipid solubility Why?
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, ionized forms of drugs Acidic drugs are ionized in basic environment Basic drugs are ionized in acidic environment

[A-] [HA] Henderson Hasselbach pH = pKa + Log ----------------
pKa = pH at which 50% of a substance Is ionized pH = pKa + Log [A-] [HA]

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

[I] [U] Henderson Hasselbach = WEAK ACID 10 pH - pKa ----------------
Benzoic Acid

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

Moral of the story... Acidic drugs are best absorbed from acidic environments Basic drugs are best absorbed from basic environments

WHAT AFFECTS DRUG ABSORPTION?
The rate of drug absorption will be affected by: Rate of release of drug from pharmaceutical preparation Membrane permeability of drug Surface area in contact with drug Blood flow to site of absorption Destruction of drug at or near site of absorption

WHAT DETERMINES RATE OF RELEASE OF DRUG FROM PHARMACEUTICAL
PREPARATION? A: DOSAGE FORM Solutions: No Delay, Immediate Release Capsules & Tables: Delay (Dissolution) Followed by Rapid Release Creams, Ointments & Suppositories: No Delay, but Slow Release

WHAT DETERMINES RATE OF B: ADDITIVES (EXCIPIENTS)
RELEASE OF DRUG FROM PHARMACEUTICAL PREPARATION? B: ADDITIVES (EXCIPIENTS) Decrease Rate of Dissolution Binders Lubricants Coating Agents Increase Rate of Dissolution Disintegrants Variable Effects on Rate of Dissolution Diluents Coloring Agents Flavoring Agents

PREPARTAION? C: MANUFACTURING PARAMETERS Tablet Compression - Hard tablets dissolve more slowly Tablet Shape - Round tablets dissolve more slowly Tablet Size - Large tablets dissolve more slowly

PREPARATION? D: DELAYED RELEASE PREPARATIONS Enteric Coating - Dissolve in intestines, not stomach

PREPARATION? E: SUSTANED RELEASE PREPARATIONS Reservoir Diffusion Products - Drug diffuses from pill core through membrane shell Matrix Diffusion Products - Drug diffuses through matrix in which it is embedded Matrix Dissolution Products - Drug released as matrix dissolves Osmotic Tablets - Drug pumped out of tablet by osmotic forces Ion-Exchange Products - Drug bound to resin exchanges with endogenous ions

WHAT DETERMINES MEMBRANE PERMEABILITY OF DRUGS?
A: LIPOPHILICITY increases membrane permeability Presence of Aliphatic and Aromatic Structures Absence of Polar Groups

WHAT DETERMINES MEMBRANE PERMEABILITY OF DRUGS?
B: IONIZATION decreases membrane permeability Weak acids in intestines are mostly ionized (intestinal pH ranges from 6.6 to 7.5) Weak bases in stomach are mostly ionized (stomach pH ranges from 1 to 2)

WHAT DETERMINES SURFACE AREA FOR ABSORPTION?
ANATOMY Low Surface Area: eyes, nasal cavity, buccal cavity, rectum, stomach, large intestines High Surface Area small intestines, lungs

WHETHER A DRUG IS DESTROYED AT OR NEAR SITE OF ADMINISTRATION?
WHAT DETERMINES WHETHER A DRUG IS DESTROYED AT OR NEAR SITE OF ADMINISTRATION? BIOCHEMISTRY Liver - hepatic enzymes (“first pass” effect) Colon - intestinal microflora Stomach - digestive enzymes and acids

ADMINISTRATION FOR DRUGS? Directly Into Target Tissue
WHAT ARE THE ROUTES OF ADMINISTRATION FOR DRUGS? PARENTERAL ENTERAL Oral Sublingual Rectal Intravenous (IV) Intra-arterial (IA) Subcutaneous (SC) Intradermal (ID) Intramuscular (IM) Intraperitoneal (IP) Lungs (Inhalation) Skin (Topical) Nose (Intranasal) Eye (Opthalmic) Ear (Otic) Vagina Urinary Bladder Directly Into Target Tissue

SAFETY High Low CONVENIENCE High Low
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF ORAL, IV, IM AND SC ADMINISTRATION? SAFETY High Oral > SC > IM > IV Low CONVENIENCE High Oral > SC > IM > IV Low

BIOAVAILABILITY High and Reliable Low and/or Variable ONSET OF ACTION
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF ORAL, IV, IM AND SC ADMINISTRATION? BIOAVAILABILITY High and Reliable IV > IM = SC > ORAL Low and/or Variable ONSET OF ACTION Immediate IV > IM > SC > Oral Delayed

INTERACTIONS WITH FOOD Risk No Risk
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF ORAL, IV, IM AND SC ADMINISTRATION? INTERACTIONS WITH FOOD Risk Oral > IV = IM = SC No Risk COMMERCIAL AVAILABILITY OF DOSAGE FORMS High Oral > IM = SC = IV Low VOLUME OF DRUG High Oral = IV > IM > SC Low

WHY CONSIDER OTHER ROUTES OF ADMINISTRATION?
Sublingual - Rapid absorption that bypasses liver Rectal - Great for patient that is vomiting or cannot (will not) swallow medication

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

Is the volume of body fluid cleared of
DRUG CLEARANCE: Example: Rate of Drug Elimination (Excretion rate) = 10 mg/hr [D]P (Concentration) = 4 mg/L 10 mg/hr CL = = 2.5 L/hr 4 mg/L Is the volume of body fluid cleared of drug per time unit (L/h, mL/min)

Clearance (CL) Blood, Plasma, 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

Total Body Clearance (CL)
CL = (CLliver + CLg.i. tract + CLkidney + CLlung + ...) Dose / Area under the curve (AUC) e.g. mg / (mg.h /L) = L/h

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

Cl is a major determinant of [D]P at STEADY STATE ([D]PSS)
INPUT STEADY STATE LEVEL (Kidney & Liver) OUTPUT

Elimination Drugs leave the body through: Kidneys Lungs Bile Skin
Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug. *other routes for excreting drugs include the air we exhale, bile, sweat, saliva, and breast milk.*

Elimination Drugs leave the body through: Kidneys:
1) Excrete most of the products of body metabolism 2) Closely regulate the levels of most of the substances found in body fluids Psychoactive drugs are often reabsorbed out of the kidneys, so the liver has to enzymatically transform the drugs so with minimal reabsorption they can exit in urine. Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug.

Elimination Drugs leave the body through: Lungs
Only occurs with highly volatile or gaseous agents Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug.

Elimination Drugs leave the body through: Skin
Small amounts of a few drugs can pass through the skin and be excreted in sweat. Most drugs leave the body in urine as the unchanged molecule or as a broken-down metabolite of the original drug.

Pharmacokinetics Distribution –the drug is distributed throughout the body 88

Drug Distribution Body Membranes that Affect Drug Distribution
1. Cell membranes 2. Walls of the capillary vessels in the circulatory system 3. Brain-blood barrier 4. Placental barrier In the case of a psychoactive drug, most of the drug circulates outside the brain and therefore does not contribute directly to its pharmacological effects {this means that to get even a small amount of the drug to our brain, we may have to flood the rest of our bodies with it –which can cause terrible side effects like organ failure}. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Drug Distribution 1st Body Membrane that Affects Drug Distribution
Cell membranes Permeable to small lipid (fatty) molecules Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Drug Distribution 2nd Body Membrane that Affects Drug Distribution
Walls of the capillary vessels in the circulatory system Does not depend on lipid solubility Only drugs that do not bind to plasma proteins pass through capillary pores. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Drug Distribution 3rd Body Membrane that Affects Drug Distribution
Brain-blood barrier The rate of passage of a drug into the brain is determined by two factors: (1) the size of the drug molecule and (2) its lipid (fat) solubility. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Drug Distribution 4th Body Membrane that Affects Drug Distribution
Placental barrier Oxygen and nutrients travel from the mother’s blood to that of the fetus, while carbon dioxide and other waste products travel from the blood of the fetus to the mother’s blood. Fat-soluble substances (including all psychoactive drugs) diffuse rapidly and without limitation. Indicates that drugs that bypass the stomach bypass these enzymes and are metabolized differently.

Distribution Distribution is the process by which a drug diffuses or is transferred from intravascular space to extravascular space (body tissues). These spaces are described mathematically as volume(s) of distribution. In the simplest of terms, a drug's volume of distribution is that volume of bodily fluid into which a drug dose is dissolved. Volume of distribution = Dose / drug concentration

Central volume (Vc) The central volume of distribution (Vc) is a hypothetical volume into which a drug initially distributes upon administration. This compartment can be thought of as the blood in vessels and tissues which are highly perfused by blood.

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

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

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

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

One, two, and three compartment pharmacokinetic models
One, two, and three compartment pharmacokinetic models. Fortunately many of the processes involved in drug movement around the body are not saturated at normal therapeutic dose levels. The pharmacokinetic - mathematical models that can be used to describe plasma concentration as a function of time can then be much simplified. The body may even be represented as a single compartment or container for some drugs. For other drugs a two or three compartment model is found to be necessary.

Body before and after a rapid I. V
Body before and after a rapid I.V. bolus injection, considering the body to behave as a single compartment. In order to simplify the mathematics it is often possible to assume that a drug given by rapid intravenous injection, a bolus, is rapidly mixed. This slide represents the uniformly mixed drug very shortly after administration.

Oral curve and beakers. We can picture oral administration as water flowing from one bucket (representing the GI tract) into a second beaker (representing the body). At first drug flows into the 'body' beaker and the level rises, as drug concentration rises, then after peaking the levels start to fall as elimination overtakes absorption.

Intravenous bolus injection with a two compartment model
Intravenous bolus injection with a two compartment model. Often a one compartment model is not sufficient to represent the pharmacokinetics of a drug. A two compartment model often has wider application. Here we consider the body is a central compartment with rapid mixing and a peripheral compartment with slower distribution. The central compartment is uniformly mixed very shortly after drug administration, whereas it takes some time for the peripheral compartment to reach a pseudo equilibrium.

WHY BE CONCERNED ABOUT WHERE DRUGS GO?
Where drugs go determines Where Drugs Act: Ciprofloxacin [Cipro®] penetrates the prostate gland and therefore is effective in bacterial prostatitis, whereas most antibiotics do not enter the prostate and are therefore ineffective in prostatitis. Fexofenadine [Allegra®] is largely excluded from the brain and therefore is a “nonsedating” antihistamine, whereas most antihistamines freely enter the brain and cause marked drowsiness.

Where drugs go influences Where Drugs Are Eliminated: Penicillin is actively transported into the proximal tubules and is therefore rapidly excreted by the kidneys. Inhalation anesthetics distribute to alveolar spaces and therefore are eliminated by the lungs.

Where drugs go influences How Long Drugs Last In the Body : Raloxifene [Evista®]) (for treatment of osteoporosis in postmenopausal women) is transported by the liver into the intestines where it is reabsorbed (enterohepatic recirculation). This greatly increases the time raloxifene lasts in the body.

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)

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

VOLUME OF DISTRIBUTION OF DRUGS: Plasma Protein Binding
DETERMINANTS OF VD Plasma Protein Binding A VD = CP CP

VOLUME OF DISTRIBUTION OF DRUGS:
DETERMINANTS OF VD Distribution into Fat  Cp A  VD =  CP

Volume of Distribution
Gives information on HOW the drug is distributed in the body Used to calculate a loading dose

Plasma Protein Binding
Many drugs bound to circulating plasma proteins such as albumin Only free drug can act at receptor site Protein-bound drug Free Drug Receptor Site Example Drug 20% bound Reduction of 5% in bound drug Unbound plasma concentration increases from 80% to 85% (negligible) Drug 95% bound (e.g. phenytoin) Unbound plasma concentration increases from 5% to 10% (significant) If drug is widely distributed in tissues, the increase in unbound drug is rapidly redistributed to body tissues and unbound plasma concentration rapidly returns to negligible amount A bound drug has no effect! 113

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

Half Life Half-life is the time taken for the concentration of drug in blood to fall by a half

t1/2 = ---------------- Half - Life (t1/2) CL 0.693 . Vd
Both Vd and CL may change independently. Therefore t1/2 is not an exact index of drug elimination. Secondary pharmacokinetic parameter and depends on CL & Vd

Secondary pharmacokinetic parameter and depends on CL & Vd
Half - Life (t1/2) Vd t1/2 = CL Is the time it takes for the concentration to fall to half of its previous value Secondary pharmacokinetic parameter and depends on CL & Vd

A drug has a half life of 10 seconds. You give a patient a dose of 6mg
A drug has a half life of 10 seconds. You give a patient a dose of 6mg. After 30 seconds how much of the drug remains? Time Amount 0 sec 6 mg 10 sec 3 mg 20 sec 1.5 mg 30 sec 0.75 mg

Time Course of drug 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, regular-interval dosing

Time to Steady State Tss = 4 x t½
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. 121

Bioavailability Destroyed in gut Not absorbed Destroyed by gut wall
by liver to systemic circulation Dose

i.v. route oral route Plasma concentration Time (hours)

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

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

Therapeutic equivalence
Biequivalence Drugs with comparable Bioavailability Therapeutic equivalence Efficacy & Safety

Bioavailability Affected by: Dosage form
Dissolution and absorption of drug Route of administration Stability of the drug in the GI tract (if oral route) Extent of drug metabolism before reaching systemic circulation Presence of food/drugs in GI tract

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

bioequivalent Two drug products are said to be bioequivalent if they are pharmaceutical equivalent or pharmaceutical alternatives, and if their rates and extents of absorption do not show a significant difference.

Purpose of BE Therapeutic equivalence (TE)
Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring. The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner.

Fundamental Bioequivalence Assumption
When a generic drug is claimed bioequivalent to a brand-name drug, it is assumed that they are therapeutically equivalent. 132

Generic Drugs Safety Concern
They’re cheaper, but do they work as well? 133

Safety Concern Generic and brand-name drugs do exactly the same thing and are completely interchangeable. I would hesitate to substitute a generic for a brand-name drug for those patients who have been on the drug for years. However, I would not hesitate to suggest a doctor start a new patient on the generic version. 134

Drug Switchability The switch from a drug (e.g., a brand-name drug or its generic copies) to another (e.g., a generic copy) within the same patient whose concentration of the drug has been titrated to a steady, efficacious and safe level Individual Bioequivalence (IBE) Post-approval meta-analysis for BE review 135

DRUG METABOLISM

Drug Metabolism (we’re still talking about Pharmacokinetics)
CYP450

Biotransformation Relatively harmless Potentially toxic xenobiotic
Metabolic activation Detoxification Inactive metabolite Reactive intermediate

Converting lipophilic to water soluble compounds
(non-polar) Xenobiotic Phase I - Activation Reactive intermediate Phase II - Conjugation Conjugate Water soluble (polar) Excretion

Metabolism –detoxification or breakdown of the drug into metabolites that no longer exert any effect
140

How Drug go out from body ?

Biotransformation Xenobiotic metabolism
DRUG METABOLISM Biotransformation Xenobiotic metabolism

Affected by genetic and environmental factors Active/Inactive/Toxic/
Rate limiting/ Affected by genetic and environmental factors Active/Inactive/Toxic/ Mutagenic/Carcinogen Phase I Phase II DRUG METABOLITE CONJUGATE Expose or introduce a Conjugate the functional functional group that groups exposed or introduced can be conjugated by during Phase I biotransformation Phase II enzymes Small  in water solubility Large  in water solubility Termination of Pharmacological activity or introduce toxicity The rate and extent to which a drug is metabolized determines the dose of the drug and the duration of the effect of the drug O H O G l u c u r o n i d e

Two-phase biotransformation
Phase I (functionalization) reactions: Oxidation, Reduction, and hydrolytic reactions (makes the drug more polar, but not necessarily inactive) Phase II (conjugation) reactions: Conjugation to polar groups: glucuronidation, sulfation, acetylation (most of these result in drug inactivation) Ultimate effect is to facilitate elimination 144

Phase I introduction of functional group
hydrophilicity increases slightly may inactivate or activate original compound major player is CYP or mixed function oxygenase (MFO) system in conjunction with NAD(P)H location of reactions is smooth endoplasmic reticulum

Phase II conjugation with endogenous molecules
(GSH, glycine, cystein, glucuronic acid) hydrophilicity increases substantially neutralization of active metabolic intermediates facilitation of elimination location of reactions is cytoplasm

Drug Metabolism - Phase II
Conjugation reactions Glucuronidation by UDP-Glucuronosyltransferase: (on -OH, -COOH, -NH2, -SH groups) Sulfation by Sulfotransferase: (on -NH2, -SO2NH2, -OH groups) Acetylation by acetyltransferase: Amino acid conjugation (on -COOH groups) Glutathione conjugation by Glutathione-S-transferase: (to epoxides or organic halides) Fatty acid conjugation (on -OH groups) Condensation reactions

Cytochrome P450 (CYP) Mixed Function Oxidases (MFO)
Located in many tissues but highly in liver ER Human: 16 gene families CYP 1,2,3 perform drug metabolism >48 genes sequenced Key forms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 Highly inducible Alcohol CYP2E1 Dioxin/PCBs CYP1A Barbiturates CYP2B CYP genes have multiple alleles (2D6 has 53, and 2E1 has 13)

METABOLISM (BIOTRANSFORMATION) ------------------------------------
The processes by which foreign molecules (Xenobiotics) are chemically altered by a living organism.

Water soluble metabolites Reduced Biological Half-life
Result Water soluble metabolites Increased Excertion Reduced Biological Half-life Minimum Toxicity

Result ------------ More polar metabolites is formed
Possible Increase in M. wt and Size Excretion & Elimination

Result ------------ Exposure time is shortened
Possibility of accumulation is reduced Probable change in Biological activity Change in the duration of the biological activity

Metabolism the major mechanism for terminating xenobiotic activity, and is frequently the single most important determinant of the duration and intensity of toxic responses to a xenobiotic.

conversion of substance
Enzymatic, chemical, or stereo chemical change to an administered drug; conversion of substance v Active to Less Active or Inactive (Most cases): Hydroxylation of Pentobarbital v Active to Equivalent Activity: Codeine to Morphine v Inactive to Active: Carbon Tetrachloride - carcinogen v

IMPLICATIONS FOR DRUG METABOLISM
1. Termination of drug action 2. Activation of prodrug 3. Bioactivation and toxication 4. Carcinogenesis 5. Teratogenesis

Transformation of Xenobiotics by Biological Systems

Sites of biotransformation
where ever appropriate enzymes occur; plasma, kidney, lung, gut wall and LIVER the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation Skin Blood Brain

Metabolism Amitriptylline is metabolized by CYP1A2
Cimetidine inhibits CYP1A2 Coadministration results in elevated Amitriptylline levels 158

Cimetidine, Ritonavir, amiodarone, diltiazem, ketoconazole
Inhibit CYP3A4 Cimetidine, Fluoxetine, amiodarone Inhibit CYP2D6 Cimetidine, Ketoconazole, Omeprazole Inhibit CYP2C19

Phenobarbital, dexamethasone
Barbiturates, Carbamazepine, Phenytoin, pioglitazone, glucocorticoids, … Induce CYP3A4 & 3A5 Phenobarbital, dexamethasone Induce CYP2A6 & 2B6 & 2C9 Smoking , Omeprazole Induce CYP1A1 &1A2

Aspirin, Ethanol Phenytoin
Metabolism rate is constant

Drug Elimination Kinetics
Most drugs are eliminated according to a First-Order Rate Process: A constant fraction of drug is eliminated per unit of time – rate of elimination is proportional to the plasma concentration Blood concentration declines in linear fashion over time Log Concentration 100 50 25 12.5 6.25 3.13 1.56 0.78 0.39 Time

First order kinetics A constant fraction of drug is eliminated per unit of time. When drug concentration is high, rate of disappearance is high.

First order kinetics

First order kinetics The half life is independent of dose
The rate of elimination is directly proportional to the amount of chemical in the body

Zero order kinetics Rate of elimination is constant. Rate of elimination is independent of drug concentration. Constant amount eliminated per unit of time. Example: Alcohol

Velocity Of Metabolism Of A Drug
Kmx2.pzm

Aspirin, Ethanol Phenytoin
Metabolism rate is constant

Zero order kinetics Why?

Paracetamol Metabolism

Supplies glutathione N-acetylcysteine Side-effects
Dosage for NAC infusion - ADULT (1) 150mg/kg IV infusion in 200ml 5% dextrose over 15 minutes, then (2) 50mg/kg IV infusion in 500ml 5% dextrose over 4 hours, then (3) 100mg/kg IV infusion in 1000ml 5% dextrose over 16 hours Side-effects Flushing, hypotension, wheezing, anaphylactoid reaction Alternative is methionine PO (<12 hours)

What factors can affect
Metabolism What factors can affect metabolism of a drug

Factors affecting drug metabolism
Main site of drug metabolism = LIVER Drug metabolism can be affected by: First pass effect Hepatic blood flow Liver disease Drugs which alter liver enzymes FIRST PASS METABOLISM May render a drug ineffective by mouth e.g. lignocaine, insulin May mean that much higher dose needed orally to produce the same effect e.g. 5mg propranolol IV = 100mg propranolol PO Can use sub-lingual or rectal route e.g GTN get absoprtion directly into systemic circulation and bypass the liver initially LIVER DISEASE The liver has a large capacity and metabolism is only affected in extensive liver disease. Arteriovenous shunting in the absence of much hepatocellular damage can impair drug metabolism e.g. in liver cirrhosis HEPATIC BLOOD FLOW Liver receives blood from the portal vein and the hepatic artery. The hepatic clearance of a drug depends on hepatic blood flow and the hepatic extraction ratio. Free drug (dissociated from plasma proteins or partitioned out of blood cells) passes across hepatocyte membrane and undergoes either biliary excretion or metabolism by an enzyme. Drugs with a high extraction ratio (approaching 1) - none of these processes is slow or rate limiting. Hepatic clearance depends on the rate of hepatic blood flow. Drugs with a low extraction ratio - one of the processes is slow and rate limiting e.g. poor diffusion into hepatic cell, slow diffusion out of blood cell, tight binding to plasma proteins. Drug concentration is almost the same in venous and arterial blood and hepatic clearance is independent of blood flow. 174

“first pass metabolism” and its clinical relevance
The phenomenon of “first pass effect” or “first pass metabolism” and its clinical relevance Some drugs are ineffective when given orally – examples: nitroglycerine, nor-adrenaline, insulin 175

Drug Admin: Formulation
First Pass Effect Blood from the gastrointestinal tract passes through the liver before entering any other organs. During this first pass through the liver, a fraction of the drug (in some cases nearly all) can be metabolized to an inactive or less active derivative. The inactivation of some drugs is so great that the agents are useless when given orally. (e.g.. lidocaine) 176

Factors affecting drug metabolism
Genetic factors e.g acetylation status Other drugs hepatic enzyme inducers hepatic enzyme inhibitors Age Impaired hepatic enzyme activity Elderly Children < 6 months (especially premature babies) 177

Factors affecting biotransformation
age (reduced in aged patients & children) sex (women slower ethanol metabilizers) species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); biotransformation route can change clinical or physiological condition other drug administration (induction (not CYP2D6 ) or inhibition) food (grapefruit juice --CYP3A) first-pass (pre-systemic) metabolism

Factors Influencing Activity and Level of CYP Enzymes
Red indicates enzymes important in drug metabolism

drug metabolizing enzymes
Pharmacogenetics drug transporters drug metabolizing enzymes

Succinylcholine Used during anesthesia to induce muscle paralysis
Paralysis usually lasts minutes, but in some individuals, it may last up to one hour Due to altered kinetics of pseudocholinesterase 181

Isoniazid Used in the treatment of tuberculosis
Observed variation in the amount of unchanged isoniazid in the urine Differences were due to an individuals ability to convert isoniazid to acetylisoniazid. Caused by mutations in the N-acetyltransferase-2 enzyme (NAT2) on chromosome 8 Some individuals develop isoniazid toxicity manifested as peripheral neuropathy 182

Pharmacokinetics.

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