by Marc Imhotep Cray, M.D. Basic Medical Sciences Professor

Chemotherapy drugs in vials and an IV bottle. (Bill Branson Photographer; image courtesy of National Cancer Institute Visuals Online.)

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Companion Notes IVMS BASIC PHARM General Principles,

Pharmacokinetics and Pharmacodynamics Notes

Pharmacokinetics

“How the body handles a drug over time.”

The Time-Dependent Roles of Drug Absorption, Distribution, and Elimination (Metabolism/Excretion) in Determining Drug Levels in Tissues.

Pharmacokinetics

Locus of action

“receptors” Bound Free

Tissue reservoirs

Bound Free

Absorption Excretion

Biotransformation

Free drug

Systemic circulation

Bound drug Metabolites

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Important Properties Affecting Drug Absorption

• Chemical properties

– acid or base

– degree of ionization

– polarity

– molecular weight

– lipid solubility or...

– partition coefficient

• Physiologic variables

– gastric motility

– pH at the absorption site

– area of absorbing surface

– blood flow

– presystemic elimination

– ingestion w/wo food

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Enteral Routes of Drug Administration

Oral Ingestion

• 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: the overall rate of absorption of drugs is always greater in the intestine (surface area, organ function).

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Effect of Changing Rate of Gastric Emptying

• Ingestion of a solid dosage form with a glass of cold water will accelerate gastric emptying: the accelerated presentation of the drug to the upper intestine will significantly increase 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.

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Sublingual Administration

Absorption from the oral mucosa has special significance for certain drugs despite the small surface area. Nitroglycerin - nonionic, very lipid soluble. Because of venous drainage into the superior vena cava, this route “protects” it from first-pass liver metabolism.

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Rectal Administration

May be useful when oral administration is precluded by vomiting or when the patient is unconscious. Approximately 50% of the drug that is absorbed from the rectum will bypass the liver, thus reducing the influence of first-pass hepatic metabolism. -irregular and incomplete. -irritation.

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Parenteral Routes of Administration

Subcutaneous

• Slow and constant absorption.

• Slow-release pellet may be implanted.

• Drug must not be irritating.

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Intramuscular

• Rapid rate of absorption from aqueous solution, depending on the muscle.

• Perfusion of particular muscle influences the rate of absorption: gluteus vs. deltoid.

• Slow & constant absorption of drug when injected in an oil solution or suspension.

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Intraarterial Administration

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.

Requires great care and should be reserved for experts.

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Intrathecal Administration

Necessary route of administration if the blood-brain barrier and blood-CSF barrier impede entrance into the CNS. Injection into the 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.

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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.

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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

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Topical Application

• mucous membranes

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

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• Skin

• Few drugs readily penetrate the 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.

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

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Physicochemical Factors In Transfer of Drugs Across Membranes

• Cell Membranes

• Passive Properties

• Carrier-Mediated Transport

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Fact...

“The absorption, distribution, biotransformation, and excretion 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.

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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 for diffusion.

large fenestrations in capillaries: MW 20K-30K.

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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.

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Absorbed from stomach in 1 hour (% of dose)

1

52

580

barbital (pKa 7.8)

secobarbital (pKa 7.9)

thiopental (pKa 7.6)

0

10

20

30

40

50

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

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3. Ionization

Most drugs are small (MW < 1000) weak electrolytes (acids/bases). 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...

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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)

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Weak acid Weak base

H+

HA A-

HA

H+

A-

B BH+

H+

H+

B BH+

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

extracellular pH

intracellular pH

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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).

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pH 2 4 6 7.4 8 10

acid cromolyn sodium (2.0) furosemide (3.9) sulfamethoxazole (6.0) phenobarbital (7.4) phenytoin (8.3) chlorthalidone (9.4)

base diazepam (3.3) chlordiazepaxide (4.8) triamterene (6.1) cimetidine (6.8) morphine (8.0) amantadine (10.1) A

-

HA HB+

B

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Henderson-Hasselbalch Eqn.

[protonated] log = pKa - pH

[unprotonated]

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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 take antilog of 1 to get the ratio between non-ionized (HA) and ionized (A-) forms of the drug: antilog of 1 = 10

if pH = pKa then HA = A- if 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 X100 = 1 / (1 + 10) X 100 = 9% ionized

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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 take antilog of 6 to get the ratio between ionized (BH+) and non-ionized (B) formsof the drug: antilog of 6 = 1,000,000

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+) X100 = 1 X 10-4 % non-ionized or 0.0001%

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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.

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naproxen (weak acid, pKa 5.0)

plasma pH 7.4

HA = 1.0 +

A- = 251

total HA + A- = 252

small intestine pH 5.3

HB+ = 501 +

B = 1.0

total HB+ + B = 502

plasma pH 7.4 HB+ = 4

+ B = 1.0

total

HB+ + B = 5

morphine (weak base, pKa 8.0)

gastric juice pH 2.0

HA = 1.0 +

A- = 0.001

total HA + A- = 1.001

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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.

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Certain compounds may exist as strong electrolytes. This means they are ionized at all body pH values. They are poorly lipid soluble.

Ex: strong acid = glucuronic acid derivatives of

drugs. strong base = quarternary ammonium

compounds such as acetylcholine.

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Membrane Transfer

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ATP

ADP-Pi

passive

diffusion carrier-mediated endocytosis

active passive

Facilitated Diffusion

This is a carrier-mediated process that does NOT require energy. In this process, movement of the substance can NOT be against its concentration gradient. Necessary for the transport of endogenous compounds whose rate of movement across membranes by simple diffusion would be too slow.

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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

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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.

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

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Drug Absorption

Absorption describes the rate and extent at which a drug leaves its site of administration. 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.

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Pharmacokinetics

Locus of action

“receptors” Bound Free

Tissue reservoirs

Bound Free

Absorption Excretion

Biotransformation

Free drug

Systemic circulation

Bound drug Metabolites

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AUC injected I.v.

AUC oral

time

pla

sma

con

cen

trat

ion

of

dru

g

Bioavailability =

AUC oral

AUC injected i.v.

X 100

AUC = area under the curve

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Factors Modifying Absorption

• drug solubility (aqueous vs. lipid)

• local conditions (pH)

• local circulation (perfusion)

• surface area

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Bioequivalence

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.

Bioequivalence exists between two such products when the rates and extent of bioavailability of their active ingredient are not significantly different.

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Distribution

Once a drug is absorbed into the bloodstream, it may be distributed into interstitial and cellular fluids. The actual pattern of drug distribution reflects various physiological factors and physicochemical properties of the drug.

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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.

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Pharmacokinetics

Locus of action

“receptors” Bound Free

Tissue reservoirs

Bound Free

Absorption Excretion

Biotransformation

Free drug

Systemic circulation

Bound drug Metabolites

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Drug Reservoirs

Body compartments where a drug can accumulate are reservoirs. They have dynamic effects on drug availability.

• plasma proteins as reservoirs (bind drug)

• cellular reservoirs – Adipose (lipophilic drugs)

– Bone (crystal lattice)

– Transcellular (ion trapping)

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Protein Binding

Passive movement of drugs across biological membranes is influenced by protein binding. Binding may occur with plasma proteins or with non-specific 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.

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Plasma Proteins

• albumin - binds many acidic drugs

• a1-acid glycoprotein for basic drugs The fraction of total drug in plasma that is bound is determined by its concentration, its binding affinity, and the number of binding sites. At low concentration, binding is a function of Kd; at high concentration it’s the # of sites.

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Plasma Proteins

• Thyroxine (thyroid hormone T4)

• > 99% bound to plasma proteins.

• The main carrier is the acidic glycoprotein thyroxine-binding globulin.

• very slowly eliminated from the body, and has a very long half-life.

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Drugs Binding Primarily to Albumin

barbiturate probenecid benzodiazepines streptomycin bilirubin sulfonamides digotoxin tetracycline fatty acids tolbutamide penicillins valproic acid phenytoin warfarin phenylbutazone

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Drugs Binding Primarily to a1-Acid Glycoprotein

alprenolol lidocaine

bupivicaine methadone

desmethylperazine prazosin

dipyridamole propranolol

disopyramide quinidine

etidocaine verapamil

imipramine

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Drugs Binding Primarily to Lipoproteins

amitriptyline

nortriptyline

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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.

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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.

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Thiopental

• A highly lipid-soluble i.v. anesthetic. Blood flow to the 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.

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Thio

pen

tal c

on

cen

trat

ion

(a

s p

erce

nt

of

init

ial d

ose

)

100

50

0

minutes 1 10 100 1000

blood

brain muscle adipose

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GI Tract as Reservoir

Weak bases are passively concentrated in the stomach from the blood because of the large pH differential.

Some drugs are excreted in the bile in active form or as a conjugate that can be hydrolyzed in the intestine and reabsorbed.

In these cases, and when orally administered drugs are slowly absorbed, the GI tract serves as a reservoir.

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Redistribution

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

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Placental Transfer

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

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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).

• volume of distribution (Vd)

• clearance (CL)

• bioavailability (F)

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Volume of Distribution

Volume of distribution (Vd) relates the amount of drug in the body to the plasma concentration of drug (C).

**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.

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Total body water

plasma

interstitial volume

intracellular volume

42 liters

27 liters

15 liters

12 liters

3 liters

plasma volume

interstitial volume

extracellular

intracellular

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At steady-state: total drug in body (mg)

Vd = ------------------------------

plasma conc. (mg/ml)

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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.

If 500 mg of digoxin were in his body, Cplasma 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.

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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)

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Clearance

Clearance does not indicate how much drug is removed but, rather, the volume of blood that would have to be completely freed of drug to account for the elimination rate.

CL is expressed as volume per unit time.

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Sum of all process contributing to dis- appearance of drug

from plasma

Drug in plasma at concentration of 2 mg/ml

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

Drug molecules disappearing from plasma at rate of 400 mg/min

CL = 400 mg/min

2 mg/ml

= 200 ml/min

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Example: cephalexin, CLplasma = 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.

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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.

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• 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.

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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)

76 Source: First Aid for the USMLE Step 1, 2012 pg.259-261

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Source: First Aid for the USMLE Step 1, 2012 pg.259-261

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Source: First Aid for the USMLE Step 1, 2012 pg.259-261

79

Source: First Aid for the USMLE Step 1, 2012 pg.259-261

80

Source: First Aid for the USMLE Step 1, 2012 pg.259-261

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Source: First Aid for the USMLE Step 1, 2012 pg.259-261

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FOR ADDITIONAL STUDY: PHARM2000

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