Pharmacokinetics I by Marc Imhotep Cray, M.D.

General Principles of Drug Therapy

Integrated Scientific and Clinical Pharmacology

Pharmacokinetics I: ADME Marc Imhotep Cray, M.D. BMS / CK-CS Teacher

http://www.imhotepvirtualmedsch.com/

General Principles of Drug Therapy

Topics Outline ABSORPTION Ionization Molecular Weight Dosage Form Routes of Administration DISTRIBUTION Plasma Protein Binding Selective Distribution

METABOLISM Rates of Metabolism Microsomal P450 Isoenzymes Enzyme Induction and Inhibition ELIMINATION Pharmacokinetic Changes with Aging

General Principles of Drug Therapy

Pharmacokinetics (PK) study of ADME Absorption Distribution Metabolism Excretion

drug in drug out = Elimination

Movement of drug molecules through various physiologic compartments drug deposition Processes that determine drug delivery to (in) and removal from (out) molecular targets Drug concentration-Time relationship 3

General Principles of Drug Therapy

Pharmacokinetics Overview PK what the body does to a drug

Understanding PK parameters, enable design of optimal drug regimens, including : route of administration (RoA), dosage, dosing interval, and duration of Tx

Modified from: Lippincott Illustrated Reviews: Pharmacology. 6e. (2014)

General Principles of Drug Therapy

Pharmacokinetics Overview (2)

Goodman and Gilman's The Pharmacological Basis of Therapeutics 12e, (2011)

Interrelationship of absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action

General Principles of Drug Therapy

Important Properties Affecting Drug Absorption Physiologic variables: Chemical properties gastric motility acid or base pH at the absorption site degree of ionization area of absorbing surface polarity blood flow molecular weight presystemic elimination lipid solubility or...partition coefficient ingestion w/wo food 6

General Principles of Drug Therapy

Routes of Drug Administration (RofA) 

Absorption is how the patient’s body takes in (absorbs) the drug in question RofA:  Enteral, meaning absorbed through intestines: oral and rectal

 Parenteral, meaning absorbed without intestines: intravenous (IV), intramuscular (IM), subcutaneous (SQ ), inhaled, topical, or transdermal Lippincott Illustrated Reviews, Pharmacology. 6e. (2015)

General Principles of Drug Therapy

Enteral Routes of Administration

General Principles of Drug Therapy

 

Bioavailability (F) F is how much of what is ingested makes it into the systemic circulation Drugs administered intravenously bypass absorption, thus have a bioavailability of 1 (100%)



Oral drugs have < 100% bioavailability (< 1) because: 1) not everything is absorbed (incomplete tablet breakdown, barriers to absorption across gut mucosa, gastric acid or enzymatic destruction) 2) after absorption through intestines into portal vein, drug first passes through liver, where some of drug is metabolized before reaching systemic circulation-termed first pass metabolism 9

General Principles of Drug Therapy

First-pass metabolism Any substance absorbed through the intestinal mucosa (except at end of the rectum) will drain into the portal system and be processed by the liver before reaching the systemic circulation

From Brenner GM, Stevens CW. Pharmacology. 3rd ed. Philadelphia: Elsevier; 2009.

General Principles of Drug Therapy

Oral Ingestion â&#x20AC;˘ Governed by: surface area for absorption, blood flow, physical state of drug, concentration occurs via passive process

In theory: weak acids optimally absorbed in stomach, weak bases in intestine In reality: overall rate of absorption of drugs is always greater in intestine (surface area, organ function) 11

General Principles of Drug Therapy

Forms of Oral Drugs Fastest

 liquids: syrups, elixirs  Suspensions  Powders

Slowest

 pills: capsules, tablets

General Principles of Drug Therapy

Rate of Appearance in Blood ď&#x201A;§ Dependent on rate of dissolution ď&#x201A;§ Rate of absorption from GI tract

For example: Timed release capsules dissolve at different rates Enteric coating pills dissolve in alkaline fluid 13

General Principles of Drug Therapy

Effect of Changing Rate of Gastric Emptying Ingestion of a solid dosage form with a glass of cold water will accelerate gastric emptying accelerated presentation of drug to upper intestine significantly increases absorption Ingestion with a fatty meal, acidic drink, or with another drug with anticholinergic properties, will retard gastric emptying Sympathetic output (as in stress) also slows emptying 14

General Principles of Drug Therapy

Sublingual (SL) Administration Absorption from oral mucosa has special significance for certain drugs despite small surface area Nitroglycerin (SL-NTG) - nonionic, very lipid soluble Due to venous drainage into superior vena cava, this route â&#x20AC;&#x153;protectsâ&#x20AC;? from first-pass liver metabolism

General Principles of Drug Therapy

Rectal Administration Advantages: Useful when oral administration is precluded by vomiting or when patient is unconscious Approx. 50% of drug absorbed from rectum will bypass liver, thus reducing influence of first-pass hepatic metabolism Disadvantages: Irregular and incomplete absorption Irritation Patient aversion 16

General Principles of Drug Therapy

Parenteral Routes of Administration

General Principles of Drug Therapy

Subcutaneous  Slow and constant absorption  Slow-release pellet may be implanted

 Drug must not be irritating

General Principles of Drug Therapy

Intramuscular  Rapid rate of absorption from aqueous solution, depending on the muscle

 Perfusion of particular muscle influences rate of absorption: gluteus vs. deltoid  Slow & constant absorption of drug when injected in an oil solution or suspension

General Principles of Drug Therapy

Intra-arterial administration ď&#x201A;§ Occasionally a drug is injected directly into an artery to localize its effect to a particular organ, e.g., for liver tumors, head/neck cancers ď&#x201A;§ Requires great care and should be reserved for those with experience

General Principles of Drug Therapy

Intrathecal administration ď&#x201A;§ Necessary RofA if the blood-brain barrier and blood-CSF barrier impede entrance into CNS

ď&#x201A;§ Injection into spinal subarachnoid space: used for local or rapid effects of drugs on the meninges or cerebrospinal axis, as in spinal anesthesia or acute CNS infections 21

General Principles of Drug Therapy

Intraperitoneal administration  Peritoneal cavity offers a large absorbing surface area from which drug may enter the circulation rapidly

 Seldom used clinically  Infection is always a concern

General Principles of Drug Therapy

Pulmonary Absorption



Inhaled gaseous and volatile drugs are absorbed by the pulmonary epithelium and mucous membranes of respiratory tract  almost instantaneous absorption  avoids first-pass metabolism  local application 23

General Principles of Drug Therapy

Topical Application 

Mucous membranes  Drugs are applied to mucous membranes of conjunctiva, nasopharynx, vagina, colon, urethra, and bladder for local effects  Systemic absorption may occur (e.g. antidiuretic hormone via nasal mucosa)

General Principles of Drug Therapy

Topical Application (2) 

Skin  Few drugs readily penetrate skin  Absorption is proportional to surface area  More rapid through abraded, burned or denuded skin  Inflammation increases cutaneous blood flow and, therefore, absorption  Enhanced by suspension in oily vehicle and rubbing into skin

General Principles of Drug Therapy

Topical Application (3) 

Eye  topically applied ophthalmic drugs are used mainly for their local effects  systemic absorption that results from drainage through nasolacrimal canal is usually undesirable  not subject to first-pass hepatic metabolism

General Principles of Drug Therapy

Routes of Administration Summary Table (1) RofA

ABSORPTION PATTERN

ADVANTAGES

DISADVANTAGES

Oral

• Variable; affected by many factors

• Safest and most common, convenient, and economical RofA

Intravenous

• Absorption not required

• Limited absorption of some drugs • Food may affect absorption • Patient compliance is necessary • Drugs may be metabolized before systemic absorption • Unsuitable for oily substances • Bolus injection may result in adverse effects • Most substances must be slowly injected • Strict aseptic techniques needed

Subcutaneous

Intramuscular

• Can have immediate effects • Ideal if dosed in large volumes • Suitable for irritating substances and complex mixtures • Valuable in emergency situations • Dosage titration permissible • Ideal for high molecular weight proteins and peptide drugs • Depends on drug diluents: • Suitable for slow-release drugs Aqueous solution: prompt • Ideal for some poorly soluble Depot preparations: slow and suspensions sustained • Depends on drug diluents: • Suitable if drug volume is moderate Aqueous solution: prompt • Suitable for oily vehicles and certain Depot preparations: slow and irritating substances sustained • Preferable to intravenous if patient must self-administer

• Pain or necrosis if drug is irritating • Unsuitable for drugs administered in large volumes • Affects certain lab tests (creatine kinase) • Can be painful • Can cause intramuscular hemorrhage (precluded during anticoagulation therapy) 27

General Principles of Drug Therapy

Routes of Administration Summary Table (2)

RofA

ABSORPTION PATTERN

ADVANTAGES

Transdermal (patch)

• Slow and sustained

• Bypasses the first-pass effect • Convenient and painless • Ideal for drugs that are lipophilic and have poor oral bioavailability • Ideal for drugs that are quickly eliminated from the body

Rectal

• Erratic and variable

Inhalation

• Systemic absorption may occur; this is not always desirable

Sublingual

• Depends on the drug: Few drugs (for example, nitroglycerin) have rapid direct systemic absorption Most drugs erratically or incompletely absorbed

• Partially bypasses first-pass effect • Bypasses destruction by stomach acid • Ideal if drug causes vomiting • Ideal in patients who are vomiting, or comatose • Absorption is rapid; can have immediate effects, Ideal for gases • Effective for patients with respiratory Problems, Dose can be titrated • Localized effect to target lungs: lower doses used compared to that with oral or parenteral administration • Fewer systemic side effects • Bypasses first-pass effect • Bypasses destruction by stomach acid • Drug stability maintained because the pH of saliva relatively neutral • May cause immediate pharmacological effects

DISADVANTAGES

• Some patients are allergic to patches, which can cause irritation • Drug must be highly lipophilic • May cause delayed delivery of drug to pharmacological site of action • Limited to drugs that can be taken in small daily doses • Drugs may irritate the rectal mucosa • Not a well-accepted route

• Most addictive route (drug can enter the brain quickly) • Patient may have difficulty regulating dose • Some patients may have difficulty using inhalers

• Limited to certain types of drugs • Limited to drugs that can be taken in small doses • May lose part of the drug dose if swallowed

General Principles of Drug Therapy

Physicochemical Factors In Transfer of Drugs Across Membranes

 Cell Membranes  Passive Properties  Carrier-Mediated Transport

General Principles of Drug Therapy

Facts... 

“ADME of a drug all involve its passage across cell membranes”



Drugs generally pass through cells rather than between them  Thus, the plasma membrane is the common barrier Passive diffusion depends on movement down a concentration gradient



General Principles of Drug Therapy

1. Molecular Size  In general, smaller molecules diffuse more readily across membranes than larger ones because the diffusion coefficient is inversely related to the sq. root of the MW  This applies to passive diffusion but NOT to specialized transport mechanisms (active transport, pinocytosis)  tight junction: MW <200  diffusion through large fenestrations in capillaries: MW 20K30K 31

General Principles of Drug Therapy

2. Lipid-Solubility Oil:Water Partition Coefficient The greater the partition coefficient, the higher the lipid-solubility of the drug, and the greater its diffusion across membranes

A non-ionizable compound (or the non-ionized form of an acid or a base) will reach an equilibrium across the membrane that is proportional to its concentration gradient

General Principles of Drug Therapy

Absorbed from stomach in 1 hour (% of dose) 50

580

Other things (MW, pKa) being equal, absorption of these drugs is proportional to lipid solubility

1 0 barbital (pKa 7.8)

secobarbital (pKa 7.9)

thiopental (pKa 7.6) 33

General Principles of Drug Therapy

3. Ionization â&#x20AC;˘ Most drugs are small (MW < 1000) weak electrolytes (acids/bases) â&#x20AC;˘ This influences passive diffusion since cell membranes are hydrophobic lipid bilayers that are much more permeable to the non-ionized forms of drugs The fraction of drug that is non-ionized depends on its chemical nature, its pKa, and the local biophase pH... 34

General Principles of Drug Therapy

Ionization (2)  You can think of properties this way:  ionized = polar = water-soluble  non-ionized = less polar = more lipid-soluble

 Think of an acid as having a carboxyl: COOH / COO_  Think of a base as having an amino: NH3+ / NH2 *For both acids and bases, pKa = acid dissociation constant, the pH at which 50% of the molecules are ionized.  Example: weak acid = aspirin (pKa 3.5) weak base = morphine (pKa 8.0) 35

General Principles of Drug Therapy

Weak acid H+ HA

A-

AH+

Weak base extracellular pH

H+ BH+

BH+

B intracellular pH

H+

* The pH on each side of the membrane determines the equilibrium on each side 36

General Principles of Drug Therapy

A Useful Concept... Drugs tend to exist in the ionized form when exposed to their “pH-opposite” chemical environment.  Acids are increasingly ionized with increasing pH (basic environment), whereas…  Bases are increasingly ionized with decreasing pH (acidic environment).

General Principles of Drug Therapy

acid

base

cromolyn sodium (2.0)

diazepam (3.3)

furosemide (3.9)

chlordiazepaxide (4.8)

triamterene (6.1) cimetidine (6.8)

sulfamethoxazole (6.0) phenobarbital (7.4)

7.4

phenytoin (8.3)

morphine (8.0)

chlorthalidone (9.4)

amantadine (10.1)

General Principles of Drug Therapy

Henderson-Hasselbalch Eqn. [protonated] log = pKa - pH [unprotonated]

General Principles of Drug Therapy

Problem: What percentage of phenobarbital (weak acid, pKa = 7.4) exists in the ionized form in urine at pH 6.4? pKa - pH = 7.4 - 6.4 = 1 antilog of 1 = 10

take antilog of 1 to get the ratio between non-ionized (HA) and ionized (A-) forms of the drug:

if pH = pKa then HA = Aif pH < pKa, acid form (HA) will always predominate if pH > pKa, the basic form (A-) will always predominate Ratio of HA/A- = 10/1 % ionized = A- / A- + HA X 100 = 1 / (1 + 10) X 100 = 9% ionized 41

General Principles of Drug Therapy

Problem: What percentage of cocaine (weak base, pKa =8 .5) exists in the non-ionized form in the stomach at pH 2.5? pKa - pH = 8.5 - 2.5 = 6 antilog of 6 = 1,000,000

take antilog of 6 to get the ratio between ionized (BH+) and non-ionized (B) Forms of the drug:

if pH = pKa then BH+ = B if pH < pKa, acid form (BH+) will always predominate if pH > pKa, the basic form (B) will always predominate Ratio of BH+/B = 1,000,000/1

% non-ionized = B / (B + BH+) X 100 = 1 X 10-4 % non-ionized or 0.0001% 42

General Principles of Drug Therapy

In a Suspected Overdose...  The most appropriate site for sampling to identify the drug depends on the drug’s chemical nature  Acidic drugs concentrate in plasma, whereas the stomach is a reasonable site for sampling basic drugs  Diffusion of basic drugs into the stomach results in almost complete ionization in that low-pH environment 43

General Principles of Drug Therapy

naproxen (weak acid, pKa 5.0) gastric juice pH 2.0 HA = 1.0 + A- = 0.001

plasma pH 7.4 HA = 1.0 + A- = 251

total HA + A- = 1.001

total HA + A- = 252

morphine (weak base, pKa 8.0) small intestine pH 5.3 HB+ = 501 + B = 1.0

plasma pH 7.4 HB+ = 4 + B = 1.0

total HB + B = 502

total HB + B = 5

General Principles of Drug Therapy

Other aspects….  amphetamine (weak base, pKa 10)  its actions can be prolonged by ingesting bicarbonate to alkalinize the urine...  this will increase the fraction of amphetamine in non-ionized form, which is readily reabsorbed across the luminal surface of the kidney nephron...  in overdose, you may acidify the urine to increase kidney clearance of amphetamine

General Principles of Drug Therapy

Other aspects….  Certain compounds may exist as strong electrolytes  This means they are ionized at all body pH values  They are poorly lipid soluble Examples: strong acid = glucuronic acid derivatives of drugs. strong base = quaternary ammonium compounds such as acetylcholine

General Principles of Drug Therapy

Membrane Transfer passive diffusion

carrier-mediated active

endocytosis

passive

ATP ADP-Pi

General Principles of Drug Therapy

Facilitated Diffusion  This is a carrier-mediated process that does NOT require energy  Movement of substance can NOT be against its concentration gradient  Necessary for transport of endogenous compounds whose rate of movement across membranes by simple diffusion would be too slow Example: Insulin 48

General Principles of Drug Therapy

Special carriers  Substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes  eg, peptides, amino acids, glucose.  These kind of transport, unlike passive diffusion, is saturable and inhabitable Active transport - requirement of energy Facilitated diffusion - needs no energy 49

General Principles of Drug Therapy

Special carriers (2) Carrier-mediated transport is important for some drugs that are chemically related to endogenous substances The transporter proteins also mediate drug efflux ď&#x201A;§ P-glycoprotein /MDR1 ď&#x201A;§ MRP transporters Function as a barrier system to protect cells 50

General Principles of Drug Therapy

MDR1/P-glycoprotein P-glycoprotein: P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette subfamily B member 1 (ABCB1) is an important protein of the cell membrane that pumps many foreign substances out of cells. Produced by the mdr-1 gene (Characterization of the human MDR1 gene. 2005). 51

General Principles of Drug Therapy

Active Transport  Occurrence:  neuronal membranes, choroid plexus, renal tubule cells, hepatocytes  Characteristics:  carrier-mediated  Selectivity  competitive inhibition by congeners  energy requirement *  Saturable  movement against concentration gradient *

*differences from facilitated diffusion 52

General Principles of Drug Therapy

Endocytosis, Exocytosis, Internalization Endocytosis (or pinocytosis): a portion of the plasma membrane invaginates and then pinches off from the surface to form an intracellular vesicle

Example: This is the mechanism by which thyroid follicular cells, in response to TSH, take up thyroglobulin (MW > 500,000).

General Principles of Drug Therapy

Drug Absorption and Bioavailability (F) ď&#x201A;§ Absorption describes the rate and extent at which a drug leaves its site of administration ď&#x201A;§ Bioavailability (F) is the extent to which a drug reaches its site of action, or to a biological fluid (such as plasma) from which the drug has access to its site of action

General Principles of Drug Therapy

Pharmacokinetics Tissue reservoirs

Locus of action “receptors” Bound

Free

Bound

Free

Systemic circulation

Absorption

Free drug

Bound drug

Excretion

Metabolites

Biotransformation 55

General Principles of Drug Therapy

plasma concentration of drug

AUC = area under the curve AUC oral Bioavailability = AUC injected i.v. X 100

AUC injected i.v.

AUC oral

time 56

General Principles of Drug Therapy

Factors Modifying Absorption    

drug solubility (aqueous vs. lipid) local conditions (pH) local circulation (perfusion) surface area

General Principles of Drug Therapy

Bioequivalence ď&#x201A;§ Drugs are pharmaceutical equivalents if they contain the same active ingredients and are identical in dose (quantity of drug), dosage form (e.g., pill formulation), and route of administration ď&#x201A;§ Bioequivalence exists between two such products when the rates and extent of bioavailability of their active ingredient are not significantly different

General Principles of Drug Therapy

Distribution ď&#x201A;§ Once a drug is absorbed into the bloodstream, it may be distributed into interstitial and cellular fluids ď&#x201A;§ The actual pattern of drug distribution reflects various physiological factors and physicochemical properties of the drug

General Principles of Drug Therapy

Phases of Distribution  first phase  reflects cardiac output and regional blood flow  Thus, heart, liver, kidney & brain receive most of the drug during the first few minutes after absorption

 next phase  delivery to muscle, most viscera, skin and adipose is slower, and involves a far larger fraction of the body mass

General Principles of Drug Therapy

Drug Reservoirs  Body compartments where a drug can accumulate are reservoirs  Have dynamic effects on drug availability.

 plasma proteins as reservoirs (bind drug)  cellular reservoirs  Adipose (lipophilic drugs)  Bone (crystal lattice)  Transcellular (ion trapping) 61

General Principles of Drug Therapy

Pharmacokinetics Tissue reservoirs

Locus of action “receptors” Bound

Free

Bound

Free

Systemic circulation

Absorption

Excretion

Free drug

Bound drug

Metabolites

Biotransformation 62

General Principles of Drug Therapy

Protein Binding  Passive movement of drugs across biological membranes is influenced by protein binding  Binding may occur with plasma proteins or with nonspecific tissue proteins in addition to the drug’s receptors ***Only drug that is not bound to proteins (i.e., free or unbound drug) can diffuse across membranes

General Principles of Drug Therapy

Plasma Proteins  albumin - binds many acidic drugs  α1-acid glycoprotein - binds basic drugs  The fraction of total drug in plasma that is bound is determined by 1. its concentration 2. its binding affinity 3. the number of binding sites  At low concentration, binding is a function of Kd (dissociation constant); at high concentration it’s the # of binding sites 64

General Principles of Drug Therapy

Plasma Proteins (2) Example Thyroxine (thyroid hormone T4)  > 99% bound to plasma proteins (PPB)  The main carrier is the acidic glycoprotein thyroxine-binding globulin [Thyroxine Binding Globulin (TBG)]  very slowly eliminated from the body, and has a very long halflife

General Principles of Drug Therapy

Drugs Binding Primarily to Albumin barbiturate benzodiazepines bilirubin digotoxin fatty acids penicillins phenytoin phenylbutazone

probenecid streptomycin sulfonamides tetracycline tolbutamide valproic acid warfarin

General Principles of Drug Therapy

Drugs Binding Primarily to Îą1-Acid Glycoprotein alprenolol bupivicaine desmethylperazine dipyridamole disopyramide etidocaine imipramine

lidocaine methadone prazosin propranolol quinidine verapamil

General Principles of Drug Therapy

Drugs Binding Primarily to Lipoproteins amitriptyline nortriptyline

General Principles of Drug Therapy

Bone Reservoir  Tetracycline antibiotics (and other divalent metal ion-chelating agents) and heavy metals may accumulate in bone  They are adsorbed onto the bone-crystal surface and eventually become incorporated into the crystal lattice

 Bone then can become a reservoir for slow release of toxic agents (e.g., lead, radium) into the blood

General Principles of Drug Therapy

Adipose Reservoir • Many lipid-soluble drugs are stored in fat • In obesity, fat content may be as high as 50%, and in starvation it may still be only as low as 10% of body weight • 70% of a thiopental dose may be found in fat 3 hr. after administration (see next slide)

General Principles of Drug Therapy

Thiopental A highly lipid-soluble i.v. anesthetic  Blood flow to brain is high, so maximal brain concentrations brain are achieved in minutes and quickly decline  Plasma levels drop as diffusion into other tissues (muscle) occurs  Onset and termination of anesthesia is rapid  The third phase represents accumulation in fat (70% after 3 h)  Can store large amounts and maintain anesthesia 71

General Principles of Drug Therapy

Thiopental (2) Graphic Illustration Thiopental concentration (as percent of initial dose)

100

blood

brain muscle

adipose

0 1

100

1000

minutes 72

General Principles of Drug Therapy

GI Tract as Reservoir ď&#x201A;§ Weak bases are passively concentrated in stomach from blood because of large pH differential ď&#x201A;§ Some drugs are excreted in bile in active form or as a conjugate that can be hydrolyzed in intestine and reabsorbed In the above two cases, and when orally administered drugs are slowly absorbed, GI tract serves as a reservoir

General Principles of Drug Therapy

Redistribution ď&#x201A;§ Termination of drug action is normally by biotransformation / excretion, but may also occur as a result of redistribution between various compartments ď&#x201A;§ Particularly true for lipid-soluble drugs that affect brain and heart

General Principles of Drug Therapy

Placental Transfer  Drugs cross the placental barrier primarily by simple passive diffusion  Lipid-soluble, nonionized drugs readily enter fetal bloodstream from maternal circulation  Rates of drug movement across placenta tend to increase towards term as tissue layers between maternal blood and fetal capillaries thin

General Principles of Drug Therapy

Clinical Pharmacokinetics Fundamental hypothesis:  A relationship exists between the pharmacological or toxic response to a drug and the accessible concentration of the drug (e.g., in blood) Important parameters:  volume of distribution (Vd)  clearance (CL)  bioavailability (F) 76

General Principles of Drug Therapy

Volume of Distribution ď&#x201A;§ Volume of distribution (Vd) relates the amount of drug in the body to the plasma concentration of drug (Cp)

**The apparent volume of distribution is a calculated space and does not always conform to any actual anatomic space** Note: Vd is the fluid volume the drug would have to be distributed in if Cp were representative of the drug concentration throughout the body 77

General Principles of Drug Therapy

Total body water extracellular

plasma volume

plasma 3 liters

interstitial volume

15 liters

interstitial volume

intracellular volume intracellular

12 liters

42 liters

27 liters 78

General Principles of Drug Therapy

At steady-state plasma concentration (Css): total drug in body (mg) Vd = -----------------------------plasma conc. (mg/ml)

General Principles of Drug Therapy

Example of Vd • The plasma volume of a 70-kg man ~ 3L, blood volume ~ 5.5L, extracellular fluid volume ~ 12L, and total body water ~ 42L. • Givens: If 500 mg of digoxin were in his body, Cp would be ~ 0.7 ng/ml • Dividing 500 mg by 0.7 ng/ml yields a Vd of 700L, a value 10 times total body volume! Huh? • Digoxin is hydrophobic and distributes preferentially to muscle and fat, leaving very little drug in plasma • The digoxin dose required therapeutically depends on body composition 80

General Principles of Drug Therapy

Clearance (CL) • Clearance is the most important property to consider when a rational regimen for long-term drug administration is designed – The clinician usually wants to maintain steady-state drug concentrations known to be within the therapeutic range – CL = dosing rate / Css – CL = rate of elimination / Css – (volume/time) = (mass of drug/time) / (mass of drug/volume)

General Principles of Drug Therapy

Clearance (2) â&#x20AC;˘ Clearance does not indicate how much drug is removed but, rather, the volume of blood (or plasma) that would have to be completely freed of drug to account for the elimination rate. â&#x20AC;&#x201C; CL is expressed as volume per unit time

General Principles of Drug Therapy

Clearance (3) Sum of all process contributing to disappearance of drug from plasma

Drug in plasma at concentration of 2 mg/ml Remember: CL = dosing rate / Css CL = rate of elimination / Css

CL =

Drug concentration in plasma is less after each pass through elimination / metabolism process

Drug molecules disappearing from plasma at rate of 400 mg/min 400 mg/min = 200 ml/min 2 mg/ml 83

General Principles of Drug Therapy

Clearance (4) Example: cephalexin, CLp = 4.3 ml/min/kg • For a 70-kg man, CLp = 300 ml/min, with renal clearance accounting for 91% of this elimination • So, the kidney is able to excrete cephalexin at a rate such that ~ 273 ml of plasma is cleared of drug per minute • Since clearance is usually assumed to remain constant in a stable patient, the total rate of elimination of cephalexin depends on the concentration of drug in plasma 84

General Principles of Drug Therapy

Clearance (5) Example: propranolol, CLp = 12 ml/min/kg or 840 ml/min in a 70-kg man The drug is cleared almost exclusively by the liver Every minute, the liver is able to remove the amount of drug contained in 840 ml of plasma NB: Clearance of most drugs is constant over a range of concentrations This means that elimination is not saturated and its rate is directly proportional to the drug concentration: this is a description of 1st-order elimination 85

General Principles of Drug Therapy

CL in a given organ CL in a given organ may be defined in terms of blood flow and [drug] Q = blood flow to organ (volume/min) CA = arterial drug conc. (mass/volume) CV = venous drug conc.

rate of elimination = (Q x CA) - (Q x CV) = Q (CA-CV)

General Principles of Drug Therapy

Further study:  eNotes: GP- General Principles of Drug Action  Drug-Receptor Interactions, Morris ZS, Golan DE and (or)  Brody’s Human Pharmacology: Ch.1 Pharmacodynamics- Receptors and Concentration-Response Relationships  Enzyme kinetics Notes  MedPharm Wiki| PK and PD, Pgs. 73-88  Pharmacology Course Website