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Far Eastern Uni versity – Nicanor Reyes Medical Foundation PHARMA A : PHARMACOKINETICS Dr .

Far Eastern Uni versity – Nicanor Reyes Medical Foundation PHARMA A : PHARMACOKINETICS Dr . Abraham Cruz, MD

By the end of this lecture, the learner should be able to:

- Describe the different phases of drug development

- Describe the physicochemical and physio logic factors that affect absorption, distribution, metabolism, and excretion

- Explain how dose, bioavailability, rate of absorption, volume of distribution, clearance, and half - life affect plasma concentrations after drug administration.

- Compute and adj ust dosage regimens in relation to changes in volume of distribution and clearance.

2 DISCIPLINES OF PHARMACOLOGY

- Pharmacokinetics – drug disposition and the way the body affects the drug with time (i.e., factors that determine its absorption, distribut ion, metabolism, and excretion); BIOLOGIC FATE OF DRUGS

- Pharmacodynamics – effect of the drug on the body

DRUG DEVELOPMENT AND EVALUATION

- Possible therapeutic value à drug development

- DOH - BFAD à FDA

o

Ensure safety and reliability

o

Must undergo pre - clinica l trials and clinical trials (phase I, II, III, IV)

clinica l trials and clinical trials (phase I, II, III, IV) PRE - CLINICAL TRIALS -

PRE - CLINICAL TRIALS

- In vitro and animal studies

- Purpose

o

Evaluate toxicity

o

Determine presumed effects

- Reasons for dropping

o

Lack therapeutic activity

o

Toxic to living animals

o

Teratogenic (adverse effect on fetus)

o

Small or narrow margin of safety

PHASE I

- 20 - 50 HEALTHY volunteers (young men)

- Clinical investigators evaluate:

o

Safety (adverse effects)

o

Pharmacokinetics

o

Therapeutic effects (?)

- Reasons for dropping

o

Lack therapeutic effect

o

Unacceptable adverse effec ts

o

Highly teratogenic

o

Too toxic

PHASE II

- 20 – 300 subjects; patients WITH DISEASE

- Evaluate

o

Efficacy – does it work?

o

Safety

- Reasons for dropping

o Less effective than anticipated

o Too toxic, unacceptable adverse effect

o Low benefit - t0 - risk ratio

o No more effect ive than other available drugs

PHASE III

- Randomized, controlled multicenter trials

- Double blind

- Large patient groups (300 – 3000)

- Patients WITH DISEASE

- Usually compared with “gold standard” and placebo

- Most expensive, time consuming, difficult trials to d esign and run

PHASE IV

- Post marketing surveillance

- Pharmacovigilance

- Detect any rare or long term adverse effects

- Report any untoward or unexpected adverse effect not seen during

- pre - clinical and phases I – III

o

After prolonged use and wide distribution

o

Ri sk of malignancy

o

Thrombotic events

o

Idiosyncratic side effects in special populations

DRUGS WITHDRAWN FROM THE MARKET

- Troglitazone (Rezulin) – liver failure

- Rofecoxib (Vioxx) – thrombotic events

- Dexfenfluramine (Redux) – cardiotoxicity

COMPLIANCE

- extent to which patients follow treatment instructions

- 4 types of NON - COMPLIANCE

o

Failure to obtain medication – no prescription, discharge meds, financial

o

Failure to take the medication as prescribed – due to inadequate communication

o

Patient prematurely discontinues medication – usually due to symptomatic relief

o

Patient (or another person) takes the medication inappropriately

- Patient issues

o

must be taken at regular intervals and for a certain duration to be effective

o

Some forms require inpatient treatment à issues:

transport, work, having young children

- More problematic in pediatrics

o

Parent/guardian: give medication and follow directions

o

Child: cooperate with guardian

- Practical dosage forms à ease of administration à achieve compliance

o

Sugar - coated tablets

o

Elixirs a nd suspensions for children (different colors and flavors)

- Route of administration – may affect compliance;

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o e.g. oral à simpler than parenteral

- Dosing schedule à easier to follow, less frequent

administration à increased compliance

Strategies to Improve C ompliance

- Enhanced communication

- Assessment of personal, social, and economic conditions

- Development of routine

- Systems to assist taking of medications (containers, alarms)

- Mailing of refill reminders

- Instruction about how to understand and monitor effects of medication

§ Protonated form of a weak acid (HA)

§ Unprotonated form of a weak base (B)

o Henderson - Hasselbalch trapping – occurs when a weakly acidic or basic drug equilibrates across a membrane separating regions of different pH

HENDERSON - H ASSELBALCH EQUATION

regions of different pH HENDERSON - H ASSELBALCH EQUATION - Active patient participation REMEMBER: PHARMACOKINETICS
- Active patient participation REMEMBER: PHARMACOKINETICS - neutral à uncharged/unionized/non - polar à more lipid
- Active patient participation
REMEMBER:
PHARMACOKINETICS
- neutral à uncharged/unionized/non - polar à more lipid
soluble
-
drug should reach its site of action; scenarios:
- law of mass action à reactions move to the:
o
Drug is active, lipid soluble, stable à given as such
o
o
Prodrug à absorbed and distributed à converted to
the active drug by metabolic processes
left in an acid environment (low pH, excess protons
available)
o
right in an alkaline environment
o
A pply drug directly to target tissue
o
-
most common scenario: administer drug in one compartment
à move to site of action in another compartment; requires:
the lower the pH rel ative to the pKa , the greater will
be the fraction of drug in the protonated form
o
Permeation
§ Absorption
§ Distribution
o
Elimination

§ Metabolic inactivation/activation

§ Excretion

MOVEMENT OF DRUGS IN THE BODY

- Drugs must cross barriers (intestinal wall, blood - brain barrier) to be absorbed or distributed; via passive diffusion, facilitated diffusion, or active transport

- PASSIVE DIFFUSION – no energy required; no carrier, not saturable; propo rtional to concentration gradient

o

for very small molecules (lithium, alcohols, gases)

o

requires some degree of lipid solubility if across lipid membranes

FICK’S LAW OF DIFFUSION

if across lipid membranes FICK’S LAW OF DIFFUSION Where: - C1 = higher concentration - C2

Where:

- C1 = higher concentration

- C2 = lower concentration

- Area = cross - se ctional area of the diffusion path

- Permeability coefficient = measure of the mobility of the drug molecules in the medium of the diffusion path

- thickness = length of the diffusion path

- lipid diffusion

o lipid: aqueous partition coefficient - major determinan t of drug mobility

partition coefficient - major determinan t of drug mobility - F or a weak base such

- F or a weak base such as hypothetical drug shown (pKa – 7.4), the region with lower pH (greater proton concentration) will trap more drug because the protonated form is less soluble and cannot diffuse back across the membrane

- the Henderson - Hasselbalch equation predicts that if the total concentration of this weak base in the blood at pH 7.4 is 2mg/L (50% neutral, 50% protonated), the equilibrium concentration in the urine at pH 5.4 will be 100 mg/L (1 mg/L unprotonated, 99 mg/l protonated)

- Ionized form of the drug will be trapped in the renal tubules and thus excreted in the urine

HENDERSON - HASSELBALCH TRAPPING

- Used in detoxification of overdosed patients à accelerate excr etion by:

MOVEMENT OF DRUGS IN THE BODY:

o

Acidifying (NH 4 Cl; high - dose vitamin C ) if the patient used a weak base (BH + );

PASSIVE DIFFUSION

- Lipid solubility – partly determined by the electrical charge (structure)

 

§

ex. Amphetamines

o

Alkalinizing (NaHCO 3 ; acetazolamide) if the patient took

- Weak acids and bases – determined by the pH of the medium according to the Henderson - Hasselbalch equation

o Uncha rged, more lipid - soluble form

a weak acid (A - );

§ ex. Aspirin, barbiturates

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MOVEMENTS OF DRUGS IN THE BODY

- FACILITATED DIFFUSION – no energy required; carrier required; saturable

- ACTIVE TRANSPORT – against concentration /

electrical

gradient; requires energy; requires carrier; saturable

o

By carriers – structurally related to endo genous molecules (amino acids, sugars)

o

Endocytos is – very large or very polar (vitamin B12, iron)

à complexe d with proteins and actively transported into cells

- Other factors:

o Drug solubility, drug concentration, drug ionization, surface area, vascularity

DRUG ABSORPTION

- Site of administration à circulati on

o Drugs may be administered directly at their site of action or may be absorbed into the circulation to be distributed to distant sites (review routes of administration above)

- Will be affected by both chemical and physiological factors, since the drugs mu st cross barriers in order to enter cells or to transfer between body compartments

BIOAVAILABILITY

- Considers both absorption and metabolism

- (F) - fraction of the plasma concentration of a drug for any given route of administration compared with the IV ro ute; the fraction of (active) drug that reaches the systemic circulation/site of action after administration by any route

- AUC (area under the plasma - concentration curve) quantitates drug absorption into systemic circulation

F = AUC route (extravascular) /AUC IV (intravascular)

- proportion of the drug that passes into systemic circulation

- 100% (1) after IV injection; variable for oral administration (or any other route for that matter); depends on:

o

Drug

o

Individual

o

Circumstances under which the drug is giv en

- Bioequivalence – comparison of two formulations of the same

compound; have the same bioavailability and same rate of absorption

Cell Membranes

- lipid bilayers à absorption is usually proportional to the lipid solubility of the drug

- Un - ionized molecu les (B)

- more lipid soluble

- Ionized (BH + ) - surrounded by

a

“shell” of water

- + H + ↔ BH +

B

by a “shell” of water - + H + ↔ BH + B LIPID - WATER

LIPID - WATER PARTITION COEFFICIENT

- ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (representing the membrane ); and an aqueous buffer, pH 7.4 (representing the plasma)

- The higher the lipid/water p.c. the greater the rate of transfer across the membrane

p.c. the greater the rate of transfer across the membrane SIZE - Small size = ↑
p.c. the greater the rate of transfer across the membrane SIZE - Small size = ↑

SIZE

-

Small size = ↑ absorption

-

Most drugs are small molecules (molecular weight <1000) à can diffuse across membranes in their uncharged state

pH

-

Most drugs are weak bases, weak acids, or amphoteric

-

Important determinants of drug fraction in the unionized form:

o

pH of the environment in which drugs dissolve

o

pK a value of the drug

§ pH at which 50% of the molecules are in the ionized form; characterized by the Henderson - Hasselbalch equation

REMEMBER THE:

HENDERSON - HASSELBALCH EQUATION

equation REMEMBER THE: HENDERSON - HASSELBALCH EQUATION REMEMBER: - neutral à uncharged/unionized/non - polar

REMEMBER:

- neutral à uncharged/unionized/non - polar à more lipid soluble

- law of mass action à reactions move to the:

o

left in an acid environment (low pH, excess protons available)

o

right in an alkaline environment

o

the lower the pH relative to the pKa , the greater will be the fraction of drug in the protonated form

o the lower the pH relative to the pKa , the greater will be the fraction
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B asic equation: Log (protonated form/unprotona ted form) = pK a - pH - for

B asic equation:

Log (protonated form/unprotona ted form) = pK a - pH

- for acidic molecules: HA ↔ H + + A pK a = pH + log ([HA]/[A])

- for basic molecules: BH + ↔ B + H + pK a = pH + log ([BH + ]/[B])

- drugs will tend to exist in the ionized form when exposed to an environment with a pH opposite to their own state, i.e. ac ids become more ionized with increasing pH (basic medium)

CASE:

- A 12 year old child has bacterial pharyngitis and is to

receive an oral antibiotic. Ampicillin is a weak organic acid with a pKa of 2.5. What percentage of a given dose will be in the lipid soluble form in the duodenum at a pH of 4.5?

o

A. about 1%

o

B. about 10%

o

C. about 50%

o

D. about 90%

o

E. about 99%

EXPLANATION:

Ampicillin is an acid, so it is more ionized in an alkaline pH and less ionized in an acidic pH. The Henderson - Hasselbalch equation predicts that the ratio changes from 50/50 at the pH equa l to the pKa, to 1/10 (protonated/unprotonated) at 1 pH unit more alkaline than the pKa, and 1/100 at 2 pH units more alkaline. For acids, the protonated form is the non - ionized, more lipid - soluble form

COMPUTATION

- log (protonated/unprotonated) = pKa - pH

ION TRAPPING

 

-

Body fluids where a pH difference from blood pH will favor

- substituting the values, we get log (protonated/unprotonated) = 2.5 - 4.5

- log (protonated/unprotonated) = - 2

trapping or reabsorption:

 

o

stomach contents

- to get the actual value of (protonated/unprotonated), you

o

small intestine

need a scientific calculator and get the antilog of - 2

o

breast milk

- if u remember a little bit of calculus, the antilog of - 2 is also

o

aqueous humor (eye)

equal to 10 raised to the exponent of - 2

o

vaginal secretions

- 10 raised to the exponent of - 2 is equal to .01

o

prostatic sec retions

- .01 = 1/100 = 1%

pH

ROUTES OF ADMINISTRATION

-

3 important body compartments in relation to drugs:

 

o

plasma: pH = 7.4

- Topical – drug is placed where it is needed; no need to cross membranes

o

stomach: pH = 2

o

Examples: skin ointments; ear, nose, or eye drops;

o

urine: pH = 8

aerosols inhaled in asthma management

-

Examples and Implications

 

o

Note:

 

o

Aspirin – weak acid (pK a = 3.5); absorption is favored in

§

antacids – elicit their effect in the stomach;

 

the stomach (uncharged); may damage stomach in

 

classified as topical

high doses

o

Some references classify the topical route as a

 

o

Mo rphine – weak base (pK a = 8); highly charged in the

parenteral route

 

- Enteral – drug reaches its target via the gut

stomach, quite charged in the plasma, and half - charged in the urine

o

Least predictable ROA due to:

§

Can cross BBB, but poorly and erratically

§ Liver metabolism

absorbed from the stomach and intestines , and

§ Chemical breakdown

metabolized by the liver à must be given by

§ Possible binding to food

in jection or delayed - release capsules

o

Drugs must cross several barriers

Weak Bases

 

§

May or may not be a problem depending on physicochemical properties (charge, size)

- Quaternary ammonium compounds (e.g.

- Quaternary ammonium compounds (e.g. o HOWEVER, most drugs are administe red ORALLY (because of convenience)

o

HOWEVER, most drugs are administe red ORALLY (because of convenience) unless the drug is:

succinylcholine, tubocurarine)

§ Unstable or rapidly inactivated in the gastrointestinal tract

- always charged (polar) à can not cross membranes

§ Absorption from the gastrointestinal tract is uncertain due to:

(remains in one

 

Metabolism by the liver or intestines

compartment); must be

Vomiting

injected if systemic effect is

A disease that may affect drug absorption

desired)

o

Disadvantage of oral route: absorption is slower and less complete than with other routes

 

o

Buccal or sublingual route

§ Avoids portal circulation à valuable when drug

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is subject to a high degree of first - pass metabolism (unavoidable if taken orally)

§ For potent drugs with agreeable taste (e.g. sublingual nitroglycerin to relieve acute angina attack)

o Rectal route (suppositories)

- inhalation 2 - 3 minutes

- sublingual 3 - 5 minutes

- intramuscular 10 - 20 minutes

- subcutaneous 15 - 30 minutes

- rectal 5 - 30 minutes

- ingestion 30 - 90 minutes

 

§ Less first - pass metabolism by the liver because

venous return from the lower GIT is less compared to that from the up per GIT

- transdermal (topical) variable (minutes to hours)

The ROA is determined by the physical characteristics of the drug, the speed which the drug is absorbed and/ or released, as well as the need to bypass hepatic metabolism and ac hieve high concentration at particular sites.

§ Disadvantage: inconsistent absorption

-

Parenteral Routes

 

o

Intravascular (IV, IA) - placing a drug directly into the blood stream

o

Intramuscular (IM) - drug injected into skeletal muscle

No single method of drug administration is ideal for all drugs in all circumstances.

o

Subcutaneous - Absorption of drugs from the subcutaneous tissues

   
 

o

I nhalation (?) - Absorption through the lungs

DRUG DISTRIBUTION

- Parenteral – drug administration that avoids the gut

- Circulation à tissue binding sites

o

Example: insulin – protein drug; stomach acidity and digestive enzymes destroy the drug

o

small molecular size à leave circulation by capillary filtration à ti ssues

§

SQ or IV (depends on preparation)

o

Can influence onset, intensity, and duration of action

o

Intravenous injection

- Half - life (t ½ ) – can be affected by distribution (2 - compartment

§

Advantages:

model), although mainly affected by elimination

 

- Rate and extent depend on:

Mo st direct route à enters the bloodstream directly; bypasses

o

Blood flow to the tissue

absorption

o

Size of the organ

Drug is distributed in a large volume

o

Binding

and/or acts rapidly

o

Appar ent volume of distribution

o

Important for drugs that must be given continuously by infusion or for drugs that damage tissues

o

Lipid solubility

or for drugs that damage tissues o Lipid solubility BLOOD FLOW TO THE TISSUE - High

BLOOD FLOW TO THE TISSUE

- High blood flow (viscera, brain, muscle) – receive significant amounts of drug in a short time

- Low perfusion (fat, bone) – receive drug more slowly

SIZE OF THE ORGAN

- Large organs (e.g. skeletal muscle) – take up large quantities of the drug if allowed to reach steady state

PERFUSION RATE

- Considers organ size AND blood flow

o

Alternative parenteral route s

- Volume of blood that flows per unit time per unit volume of the tissue (ml/min/ml)

§ Subcutaneous

§ Intramuscular

- Permeability - limited vs perfusi on - limited distribution

§ Epidural or intrathecal injections

§ Epidural or intrathecal injections

§ Transdermal patches – slowly released; used for prolonged action

o

Rate of drug absorption from the site on injection can be decreased by:

§ Binding the drug to a vehicle

§ Co - administering a vasoco nstrictor (usually epinephrine) to reduce blood flow to the site

Special formulations – modify rate of absorption

- IM injection of drugs dissolved in oil à slow absorption; repository form

- Permeability - rate limited when:

o

Drug is ionic/polar/water soluble

- Oral intake of drugs encapsulated in slowly dissolving shells (lipo somses) à slow, continuous absorption

o

The highly selective physiologic barriers restrict the diffusion of drugs to the inside of the cell

- Perfusion - rate limited when:

Time until effect

o

Drug is highly lipophilic

- intravenous 30 - 60 seconds

o

Membrane is highly permeable

- intraosseous 30 - 60 seconds

- endotracheal 2 - 3 minutes

Some Applications:

- Highly lipophilic drugs can cross most selective barrier like

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BBB; Ex. Thiopental

- Highly permeable capillary wall permits passage of almost all drugs (except those

- bound to plasma protein)

- Highly perfused tissues Lung s, Kidneys, Liver, Heart, Brain are rapidly equlibriated with lipid soluble drugs

- Drug distribution in a particular tissue or organ depends upon the size of tissue (Volume) & Tissue/blood partition coefficient

- Ex.Thiopental i.v (liphopillic drug) & high tissue/blood partition coefficient towards

- brain & adipose tissue

- The brain is highly perfused organ à drug is distributed fast and shows rapid onset of action on the CNS than poorly perfused adipose tissue

factor which is normally excreted by kidney

- Determinants of alpha1 - acid glycoprot ein level

o may increase in response to: surgery, chronic pain, acute MI

- Alpha1 - acid glycoprotein levels are low in neonates

o Decreased protein binding of diazepam, propanolol, sufentanil, lidocaine

- May possibly increase the risk of toxicity because the plasm a concentration of the active drug has been increased, yet depending on the drug à increase in free fraction may actually increase its metabolism because more drug is available to metabolizing enzymes

o Example: aspirin can displace diazepam from albumin

PERMEATION, BLOOD FLOW, AND PROTEIN BINDING

- Perfusion - Rate Limitation

BINDING

o

Membrane offers no resistance

- Bulk transfer in the blood à very fast (instantaneous)

o

Drug in the blood leaving the tissue is in equilibrium

- Drugs exist either dissolved in blood or bound to plasma proteins

with that of the tissue à blood and tissue viewed as one à equilibrium achieved instantaneously

- Plasma proteins:

o

Alteration in protein content is NOT expected to affect

o

Albumin – most important circulating protein for

rate of transport at a given concentration

binding many acidic drugs

- Permeability - Rate Limitation

o

Globulin/α1 - glycoprotein – bind basic drugs; increases

o

Membrane resistance to drug movement is high

with age

o

Movement is slow and insensitive to changes in

- Bound drug - confined to the vascular system is unable to exert its actions

perfusion à equilibrium is not achieved by the time the blood leaves tissue à view blood and tissue as

o

Becomes a problem if more than 80% of the drug is

separate

bound

o

Altered protein - binding influences rate of transport by

o

Drug interaction: one drug may displace another à free fract ion of one drug may increase

affecting unbound concentration

- Importance: Only free (i.e. unbound) fraction is able to cross cell membrane

APPARENT VOLUME OF DISTRIBUTION (V d )

-

calculated pharmacokinetic space into which a drug is distributed; the apparent volume in the body available to contain the drug; NOT a physiologic value; not absolute for any given drug

- When protein binding is high

o

Drugs kept in plasma

o

Plasma concentration is high

o

Calculated Vd is lower

- Only unbound fraction can enter hepatocytes and cross Glomerulus

o undergo hepatic metabolism and glomerular filtration

- Changes in protein binding

o Especially important for drugs which are: highly protein - bound, with narrow therapeutic index, distributed primarily in the plasma

§ Small changes in binding à Large changes in free fraction

§ e.g. propanolol, phenytoin, diazepam

- General determinants of protein binding

o

Lipid solubility à parallels protein - binding

o

Plasma concentration of the drug

§

Low plasma concentration is more likely to be highly protein bound

o

Nu mber of available binding sites (plasma protein)

- Plasma albumin binding is non - selective à drugs can compete

with each other

o Ex. Sulfonamides can displace uncon jugated bilirubin from albumin à bilirubin encephalopathy in neonates (kernicterus)

- Protein bin ding and renal failure

o Protein - bound fraction of a drug decreases (despite normal plasma protein level); possible causes:

alteration of protein, displacement by a metabolic

V d = dose administered (or amount of drug in the body) / initial apparent plasma concentration

VOLUME DISTRI BUTION

/ initial apparent plasma concentration VOLUME DISTRI BUTION APPARENT VOLUME OF DISTRIBUTION (V d ) -

APPARENT VOLUME OF DISTRIBUTION (V d )

- V d values that amount to less than a certain body compartment volume indicate that the drug is contained within that compartment; examples

o

< 3 L = plasma

o

< 5 L = vasculature/blood

o

< 15 L = extracellular f luid

o

> 15 L = total body water (TBW); 42 L [average 70 kg man x 60%; for women, 50% of body weight in kg is body water due to lower lean muscle mass and higher fat content (adipose tissue)]

- Some important volumes and proportions

o

Intracellular volume (ICV ) = 2/3 of TBW

o

Extracellular volume (ECV) = 1/3 of TBW

o

Interstitial volume = 2/3 of ECV

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o Plasma volume = 1/3 of ECV

- Some drugs (usually basic) have a volume of distribution that

exceeds body weight à (+) tissue binding à these drugs tend to be contained outside the circulation and may accumulate in certain tissues:

o

Lead – bone

o

Quinacrine – nucleic acids; concentrates in the liver 200 times more than in the plasma

LIPID SOLUBILITY

- Very lipid - soluble substances (e.g. thiopental) – adipose tissue and brai n

o

Reach higher concentrations in tissues with high fat content

o

Half - life will be much longer in obese patients*

- *Plasma half - life is generally directly proportional to a drug’s duration of action, but not always.

Some Applications – Sedative Hypnotics

Absorption and Distribution

- Most are lipid - soluble and are absorbed well from the GIT with good distribution to the CNS

- highest lipid solubility (eg. Thiopental) enter the CNS rapidly à determine

- onset of action à use as induction agents in anesthesia

o CNS effects are terminated by rapid redistribution from the brain to other highly perfused tissues

- Other drugs with rapid onset of action – eszopiclone, zaleplon, zolpidem

Benzodiazepine Chemistry and Lipid Solubility

- Variations in lipid solubility and pKa a ffect whether or not they are quickly absorbed

- and effective shortly after administration (ONSET)

- List of some BZDs and their pKa

Bromazepam - 11.0

Clonazepam - 10.5 (1 - position); 1.5 (4 - position)

Diazepam - 3.3

Flunitrazepam - 1.8

Flurazepam - 8.2

Lorazepa m - 11.5

Medazepam - 6.2

Nitrazepam - 10.8

Oxazepam - 1.8

Prazepam - 3.0

DRUG METABOLISM

- Most drugs are metabolized prior to excretion

- A small number of drugs are fully ionized at physiologic pH

(7.4) à highly polar à metabolized only to a minor extent, if at all à excreted unchanged

- Sequential metabolic reactions: phase 1 and 2

- Liver – major site ; other sites:

o Kidneys, lungs, gastrointestinal tract

PHARMACOGENOMICS:

o Kidneys, lungs, gastrointestinal tract PHARMACOGENOMICS: FIRST - PASS METABOLISM - Especially relevant for orally
o Kidneys, lungs, gastrointestinal tract PHARMACOGENOMICS: FIRST - PASS METABOLISM - Especially relevant for orally

FIRST - PASS METABOLISM

- Especially relevant for orally administered drugs

- Intest inal absorption à portal circulation (portal vein) à liver metabolism à less drug reaches systemic circulation à bioavailability

- Implications:

o

o

Higher doses of drug must be given

Individual variation à drug effects can be unpredictable

- If it occurs to a high degree (lidocaine, nitroglycerin) à give by another route

degree (lidocaine, nitroglycerin) à give by another route - Magnitude of first pass hepatic effect: Extract

- Magnitude of first pass hepatic effect: Extract ion ratio (ER) ER = CL liver / Q where Q is hepatic blood flow (usually about 90 L per hour)

- Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER):

F = f x (1 - ER)

PHASE 1 METABOLIC REACTIONS

- Oxidation, reduction, hydrolysis

- Make the drug more reactive and capable of combining with polar conjugating groups

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o ↑ water solubility à ↑elimination

- Introduce a functional group ( - OH, - NH 2 , - SH, or COOH):

o

increases polarity of the drug molecule

o

provides a site for phase 2 reactions

- Drug activity may or may not change à potentially dangerous

- Activity decreases with age

OXIDATION

dangerous - Activity decreases with age OXIDATION - Loss of electron or gain of oxygen -

- Loss of electron or gain of oxygen

- most common and important

- catalyzed by the microsomal mixed function oxidase system

o

o

located on the SER

consists of a number of enzymes known as cytochromes P450 (CYP enzymes/CYT P450)

- CYP enzymes : most impor tant of the phase 1 enzymes

o

Found in the SERs mainly in hepatocytes, and in the GIT, kidney, and lungs

o

require oxygen, reduced nicotinamide adenine dinucleotide

o

phosphate (NADPH), and NADPH cytochrome P450 reductase

o

over 50 isoforms in humans – constituti ve or inducible in response to certain signals

§ Substrate specificities tend to be low and can overlap à many drugs can be oxidized by one or more isoforms

Major human P450 families involved in phase 1 metabolism

- CYP1A2 (caffeine ciprofloxacin, theophylli ne, R - warfarin)

- CYP2C9 (ibuprofen, naproxen, phenytoin, S - warfarin)

- CYP2D6 (codeine, dextromethorphan, fluoxetine, haloperidol, loratadine, metoprolol, paroxetine, risperidone, thioridazine, venlafaxine),

- CYP2E1 (ethanol, INH, acetaminophen [at high doses ])

- CYP3A4 (responsible for metabolism of the largest proportion of drugs [50 – 60%]; alprazolam, carbamazepine, cyclosporine, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, lidocaine, lovastatin, midazolam, nifedipine, quinidine, sim vastatin, tacrolimus, verapamil)

OXIDATION

- Usually result in drug inactivation

- sometimes produce a pharmacologically active metabolite à duration of action may exceed the original drug (prodrug)

duration of action may exceed the original drug (prodrug) OTHER PHASE 1 METABOLIC REACTIONS REDUCTION -

OTHER PHASE 1 METABOLIC REACTIONS

REDUCTION

- invol ve microsomal enzymes; less common than oxidation reactions

- Examples:

Prednisone (prodrug) – reduced to the active glucocorticoid prednisolone

Warfarin (anticoagulant) – inactivated by the transformation of a ketone group to a hydroxyl group

HYDROLYSIS

- Not restricted to the liver

- Example: aspirin à spontaneously hydrolyzed to salicylic acid in moisture

PHASE 2 METABOLIC REACTIONS

- Drugs with a suitable site

- (present before phase 1 or

result of a phase 1 reaction)

à susceptible to phase 2

reacti ons

o Conjugation – the

attachment of a large chemical (polar) group to a functional group à ↑ hydrophilicity à easily excreted

§ Main: liver, and other tissues

à easily excreted § Main: liver, and other tissues Chemical Groups Involved - Glucuronic acid -

Chemical Groups Involved

- Glucuronic acid

- Sulphate

- Methyl and acetyl groups

- Glutathione

- Amides

PHASE 2 METABOLIC REACTIONS

- Conjugating enzymes exist in many isoforms, and show relative substrate and metabolite specificity

- Conjugates are almost invariably inactive

o Important exception:

are almost invariably inactive o Important exception: morphin e à morphine - 6 - glucuronide (analgesic

morphin e à morphine - 6 - glucuronide (analgesic effect lasts lo nger than parent molecule)

FACTORS AFFECTING METABOLISM

ENZYME INDUCTION

- increased synthesis or decreased degradation of enzymes;

occurs as a result of the presence of an exogenous substance

- Some drugs can increase the activity of certain CYP isoforms

à increase their own metabolism as well as that of other

drugs

o Ex. Phenobarbital, rifampin, phenytoin, carbamazepine, St. John’s wort, chronic ethanol consumption

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- Smoking - increases metabolism of certain drugs because of CYP1A2 induction by nicotine

of certain drugs because of CYP1A2 induction by nicotine ENZY ME INHIBITION - two drugs competing

ENZY ME INHIBITION

- two drugs competing for a metabolic enzyme à decreased metabolism of one or both

- Grapefruit juice – potent inhibitor of CYP3A4

- Other drugs: erythromycin, ketoconazole, ciprofloxacin, quinidine, cimetidine, omeprazole, ritonavir, chloramphen icol, acute alcohol intoxication

DIET

- *Diet may also affect drug metabolizing enzymes – ratio of protein and carbohydrate, flavonoids in vegetables, polycyclic aromatic hydrocarbons in barbecued foods

polycyclic aromatic hydrocarbons in barbecued foods Acetaminophen Poisoning - example of a drug that can be
polycyclic aromatic hydrocarbons in barbecued foods Acetaminophen Poisoning - example of a drug that can be
polycyclic aromatic hydrocarbons in barbecued foods Acetaminophen Poisoning - example of a drug that can be
polycyclic aromatic hydrocarbons in barbecued foods Acetaminophen Poisoning - example of a drug that can be

Acetaminophen Poisoning

- example of a drug that can be lethal at high doses (203 times the maximum therapeutic dose) due to accumulation of metabolites

- conjugated with glucuronic acid and sulphate in phase 2 metabolic process

o

saturation occurs in high doses à metabolism by mixed function oxida ses occurs à forms the toxic metabolite N - acetyl - p - benzoquinone (NAP1I; metabolized by glutathione) à glutathione depletion à NAPQI binds to nucleophilic constituents of the cell à liver and kidney necrosis

o

N - Acetyl or methionine: used as antidote

o

Increase s liver glutathione formation and conjugation reactions, respectively

DRUG EXCRETION

- Occurs in a variety of ways

- Kidneys (urine), GIT (bile and feces), lungs (exhaled air), breastmilk, sweat

- Clearance rate = volume of plasma cleared of drug per unit

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RENAL EXCRETION/CLEARANCE

- Determinants of extent of renal drug excretion

o

o

o

o

Glomerular filtration

Tubular reabsorption

(passive

and active)

Tubular secretion

GLOMERULAR CAPILLARIES

and active) Tubular secretion GLOMERULAR CAPILLARIES - Allow passage of molecules with MW < 20,000 à

- Allow passage of molecules with MW < 20,000 à glomerular filtrate contains most of the substances

- Corpuscular membrane:

o negatively charged à repels negatively charged molecules, including plasma proteins à drugs bound to plasma proteins will not be filtered

à drugs bound to plasma proteins will not be filtered RENAL EXCRETION/CLEARANCE - if there is

RENAL EXCRETION/CLEARANCE

- if there is no active secretion or reabsorption, renal cl earance is equal to glomerular filtration rate

- if drug is protein bound, renal clearance = GFR x free fraction of drug

- renal disease affects excretion of certain drugs

PERITUBULAR CAPILLARIES

o

24 - hr creatinine clearance – measures extent of renal

- Most of the drug in the blood does not pass into the

excretion

glomerular filtrate (because of protein binding) but passes into the peritubular capillaries in the proximal tubule

o

Cockcroft - Gault Formula – estimation of creatinine clearance; overestimate of GFR

- Drug may be transported into the lumen by either of 2 mechanisms

o

Tubular secretion

o

Tubular reabsorption

TUBULAR SECRETION

- responsib le for most renal excretion; allows clearance of drugs bound to plasma proteins

- separate systems for weak organic acids and bases (organic anionic and cationic transporters)

o

Competition between drugs that share the same transport mechanism à reduced excretion

o

Ex. Probenecid competes with penicillin for excretion à penicillin duration of action is increased

excretion à penicillin duration of action is increased TUBULAR REABSORPTION - depends on the fraction of

TUBULAR REABSORPTION

- depends on the fraction of molecules in the ionized state à depends on urine pH and pK a of drug (recall the H enderson - Hasselbalch equation)

- ex. Aspirin overdose (note: weak acid, pK a = 3.5)

o bicarbonate à urine alkalinization à ionizes aspirin à less prone to reabsorption

§ Prediction based on age, sex, creatinine, lean body weight

CrCl (ml/min) = [(140 – age) x Lean Body Weight (kg)] / [Serum Creatinine (mg/dL) x 72] x f f = 1 if male; f = 0.85 if female

COCKROFT - GAULT EQUATION*

f = 1 if male; f = 0.85 if female COCKROFT - GAULT EQUATION* MDRD (MODIFICATION

MDRD (MODIFICATION OF DIET IN RENAL D ISEASE) EQUATION*

MDRD (MODIFICATION OF DIET IN RENAL D ISEASE) EQUATION* GASTROINTESTINAL EXCRETION - Enterohepatic circulation” o
MDRD (MODIFICATION OF DIET IN RENAL D ISEASE) EQUATION* GASTROINTESTINAL EXCRETION - Enterohepatic circulation” o

GASTROINTESTINAL EXCRETION

- Enterohepatic circulation”

o

drug conjugate excretion into the bile à release into the intestines à hydrolyzed back into parent compound à reabsorbed

o

Prolo ngs the effect of th e drug

à hydrolyzed back into parent compound à reabsorbed o Prolo ngs the effect of th e
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SOME APPLICATIONS – METABOLISM AND EXCRETION

Benzodiazepine Cl assification (based on half - life )

Benzodiazepine Cl assification (based on half - life ) PHARMACOKINETICS OF BENZODIAZEPINES - Liver metabolized to
Benzodiazepine Cl assification (based on half - life ) PHARMACOKINETICS OF BENZODIAZEPINES - Liver metabolized to

PHARMACOKINETICS OF BENZODIAZEPINES

- Liver metabolized to active compounds EXCEPT oxazepam, temazepam, lorazepam (immediately conjugated)

- Variable half lives and durations of action

o Midazolam < oxazepam < temazepam < alprazolam < lorazepam < diazepam

CATEGORIES OF DRUGS ACTIVE AT THE BENZODIAZEPINE RECEPTOR

- based on elimination half - lives:

o

ultra - short - acting benzodiazepines: few minutes

o

short - acting agents

o

< 6 hours

o

Triazolam, midazo lam

o

nonbenzodiazepine zolpidem (half - life approximately 2 hours)

o

zopiclone (half - life 5 to 6 hours)

- intermediate - acting agents

o

6 to 24 hours

o

estazolam and temazepam

- long - acting agents

o

> 24 hours

o

flurazepam, diazepam, and quazepam

Short - acting (< 12 hr)

Intermediate - acting (12 - 24 hrs)

Long - acting ( > 24 hrs)

Triazolam (Halcion) – 1.5 to 5.5 hrs Midazolam –

Lorazepam (Ativan) – 12hrs mean (r=9 to 16 hrs, n= unknown) Tmax = 2hrs

Temazepam – 8 to

Nitrazepam – 16 to 38 hrs Clonazepam (Klonopin) – 18 to 50 hrs Quazepam (Doral) – 39 hrs Diazepam (Valium)

1.8

to 6.4 hrs Brotizolam –

4.4

hrs

Oxazepam – 4 to 14 hrs Loprazolam (Triazulenone) – 6 to 12 hrs Lormetazepam – 10 to 12 hrs Alprazolam (Xanax) – 11.2 hrs (r=6.3 to 15.8)

20

hrs

20

to 100 hrs

Estazolam – 10 to

Phenazepam – 60 hrs

24

hrs

Medazepam

Bromazepam – 12 to 20 hrs Chlordiazepoxide (Librium) – 5 to 30 hrs Clobazam – 18 hrs Nimetazepam (Erimin) – 20 hrs Flunitrazepam (Rohypnol) – 18 to 26 hrs

(Nobrium) – 36 to 150 hrs Prazepam – 36 to

 

200

hrs

Ultrashort – less than 6 hours – midazolam, triazolam

Flurazepam – 40 to

250

hrs

Clorazepate – 48 hrs Nordazepam (Nordiazepam, Desmethyldiazepam) –

 

50

to 120 hrs

MATHEMATICAL ASPECTS OF PHAR MACOKINETICS

KINETIC ORDER

- Related to plasma concentration of a drug; describes the rate at which a drug leaves the body

- 2 types:

o

Zero - order kinetics

o

First - order kinetics

ZERO - ORDER KINETICS

- Decrease in drug levels in the body is independent of the plasm a concentration

- Rate of elimination is held constant ( fixed amount ) by a limiting factor (e.g., availability of an enzyme cofactor)

- Plot of plasma concentration against time – straight line

- Only 3 clinically important drugs: ethanol, high dose phenyt oin, high dose aspirin

drugs: ethanol, high dose phenyt oin, high dose aspirin Plasma concentration vs. time plot for a

Plasma concentration vs. time plot for a drug displaying zero - order kinetics

FIRST ORDER KINETICS

- Majority of drugs

- Decrease in drug levels in the body is dependent on the plasma concentration (i.e., rate of elimination is proporti onate [ fixed fraction/percentage ] to plasma concentration), since the concentration of the substrate (drug) is the rate - limiting factor

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- Plot of plasma concentration against time – exponential

- Plot of plasma concentration against time – exponential Plasma concentration vs. Time plot for a

Plasma concentration vs. Time plot for a drug displaying first - order kinetics

vs. Time plot for a drug displaying first - order kinetics First order vs. Zero -
vs. Time plot for a drug displaying first - order kinetics First order vs. Zero -

First order vs. Zero - order elimination

COMPARTMENT MODELS

ONE - COMPARTMENT MODEL

- Widely used to determine the dose of the drug to be administered

- Considers the body as a single compartment à drug is absorbed, immediately distributed, an d subsequently eliminated by metabolism and excretion

- If the volume of the compartment is V d and the dose administered is D, then the initial drug concentration will be:

C 0 = D/V d

- Half - life – time taken for the plasma concentration to fall to half ( a pplicable only to drugs undergoing first - order elimination ) after complete absorption and distribution

- Decline in concentration may be exponential, but expressed graphically as a straight line when the log plasma concentration is plotted against the time after an intravenous dose

- Half - life

o related to the elimination rate constant (K el ) by the following equation:

t ½ x K el = natural log 2 (ln2)

t ½ = 0.693 x (V d / Cl) or t ½ = (0.693 x V d )/ Cl t ½ = 0.693 / K el

- related to V d , but does not determine t he ability of the body to remove the drug from the

- circulation, since both V d and half - life change in the same direction

- can also be derived from graphs of plasma concentration versus time (see discussion of half- life in the section in the two - compartmen t model)

half- life in the section in the two - compartmen t model) Log plasma concertation vs.

Log plasma concertation vs. Time plot compatible with one - compartment open pharmacokinetic model for drag disposition after a parenteral dose, assuming first - order kinetics (K el = elimination rate constant, C 0 = initial drug concentrat ion, t 1/2 = half life)

HALF - LIFE
HALF - LIFE

ONE - COMPARTMENT MODEL

- Clearance – the body’s ability to remove a drug from the blood; constant for individual drugs

o Volume of blood cleared of the drug per unit time

Cl p = V d x K el

Where K el is the elimination cons tant

Cl = rate of elimination of drug /plasma drug concentration

Total Body Cl = Cl hepatic + Cl renal + Cl pulmonary + Cl other

CLEARANCE

renal + C l pulmonary + C l other CLEARANCE If the drug is not administered

If the drug is not administered parenterally, plotting the log plasma drug concentration against time will requ ire the consideration of both absorption and elimination from the compartment

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12

Log plasma drug concentration vs. plot of a drug compatible with the one - compartment

Log plasma drug concentration vs. plot of a drug compatible with the one - compartment pharmacokinetic model for drug disposition after an oral dose (K el = elimination rate constant, C 0 = initial drug concentration, t 1/2 = half life)

TWO - COMP ARTMENT MODEL

- Drug distribution between the peripheral compartment (tissues) and the central compartment (plasma) occurs at varying rates (rapid à insignificant)

MODEL - INDEPENDENT APPROACH

- C ss = plasma concentration of the drug at steady state (for drugs displaying first - order kinetics) à the level of th e drug in the body increases until it is equal to the level excreted

- Rate of drug influx into the body = rate of drug elimination out of the body

into the body = rate of drug elimination out of the body Log plasma concentration vs.

Log plasma concentration vs. time plot for a drug administered by mouth every 6 hours when term inal dispo si tion half - life is 6 hours

- Curvilninear rel ationship between the log of plasma concentration and time (2 phases)

- During constant infusion, steady state

half - life =

% of

o

α - phase – early, rapid; represents the redistribution of the drug to the peripheral compartment and a modest component of elimination

o

• 1 – 50

o

• 2 – 75

o

β - phase – later, slower; combination of elimination and return of the drug from the peripheral compartment to the central compartment, in which the drug distributes rapidly

o

• 3 – 87.5

o

• 4 – 94

- amount of drug in the body at steady - state will depend on the frequency of drug administration

- state will depend on the frequency of drug administration Log plasma concentration vs. time plot

Log plasma concentration vs. time plot that requires a two - compartment open model to account for its disposition after a parenteral dose. (K el = elimination rate constant)

Half - life may also be derived from this model using graphs of plasma concentration versus time (see Figure 9) by measuring the time for a 50% decrease in the elimination phase

the time for a 50% decrease in the elimination phase Typical dru g plasma concentration vs.

Typical dru g plasma concentration vs. time curve after intravenous injection (note: concentration axis is logarithmic)

o

greater frequency à g reater amount of drug à less variation between peak and trough plasma concentration

o

accumulation of the drug will occur if the frequency of administration is greater than the half- life

o

if infusion rate/dosing interval is doubled, steady state concentra tion is also doubled because dose and concentration are directly proportional (linear kinetics); C ss x

- Loading dose – can be calculated according to the desired plasma concentration at steady - state (C ss ) and the volume of distribution (V d ) of the drug

Loading dose (mg/kg) = V d (L/kg) x C ss (mg/L)

Therefore, V d = Loading dose / steady - state plasma concentration

PHARMACOKINETIC INTERACTIONS

- absorption, distribution, metabolism, and excretion all affect pharmacokinetic properties of drugs; any drug tha t interferes with these processes will be altering the effect of other drugs

Dosage Regimens

- Calculations require target therapeutic plasma concentration and PK parameters of the drug

- Loading dose - fill the volume of distribution to achieve target plasm a concentration;

o Stays the same despite impaired renal and hepatic function

Loading dose = (V d x C p [target])/F F = 1 if 100% oral bioavailability

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LOADING DOSE

LOADING DOSE Dosage Regimens - Maintenance dose (rate; mg/hr) - replace the drug that is being

Dosage Regimens

-

Maintenance dose (rate; mg/hr) - replace the drug that is

being eliminated by the body over time to maintain a steady target plasma concentration (involves clearance)

o decreases with impaired renal or hepatic function

Maintenance dose = (Cl x C p [target])/F

For IV infusion:

infusion rate ( k 0 ) =rate of elimination (at steady state)

k 0 = Cl x C ss

For oral administration :

Maintenance dose = (Cl x C ss x τ)/F

where τ (tao) = dosing interval (hours)

-

MAINTENANCE DOSAGE

τ (tao) = dosing interval (hours) - MAINTENANCE DOSAGE Dosage Regimens - Dosing interval for maintenance

Dosage Regimens

- Dosing interval for maintenance dosing is based on t ½ such that peak and trough concentrations do not vary excessively form target C p

- Most oral drugs are given one or mo re times a day but rarely more than 4 times a day

- Drugs with short t ½ may have to be given by a different route (IV) or in the form of slow - or extended - release oral formulations

Correction for Dosage Regimens

- May be necessary to account for variations in PK

- Clearance may be significantly affected by disease (renal or hepatic failure)

- Volume of distribution is rarely changed significantly by disease

significant

- if partly cleared partly by the kidney and partly by other

routes, equation should be applied to the part of the dose that is eliminated by the kidney

o

ex. Drug is 50% cleared by kidneys, 50% by the liver; normal dosage: 200 mg/d; therefore, hepatic and renal elimination rates are each 100 mg/d.

o

if the patient’s creatinine clearance of 20 mL/min:

Dosage = 100 mg/d (liver) + [100 mg/d x (20 ml/min / 100 ml/min)] (kidney)

Dosage = 100 mg/d + 20 mg/d = 120 mg/d

CORRECTED DOSAGE

Dosage = 100 mg/d + 20 mg/d = 120 mg/d CORRECTED DOSAGE Further Drug Classification 


Further Drug Classification

- Pregnancy Category

o A, B, C, D, X

- Controlled drugs

o

Closely monitored by the Dangerous Drugs Board of the DOH

o

Need S - 2 license

o

Prescription in triplicate

FDA Pregnancy Categories

- A - Adequate studies in pregnant, no risk

- B - Animal studies show no fetal risk, but human studies are not adequate OR Animal toxicity but human studies show no risk

- C - Animal studies show toxicity, human studies inadequate but benefit of use m ay exceed risk

- D - Evidence of human risk, but benefits outweigh risks

- X - Fetal abnormalities in humans, risk greater than benefit

ADJUSTMENT OF DOSAGE WHEN ELIMINATION IS ALTERED BY DISEASE

- Renal disease or reduced cardiac output à reduce s the clearance of drugs that depend on renal function

- Less common - alteration of clearance by liver disease

o occurs (for high extraction drugs) in the following states:

§ reduced liver blood flow (i.e., heart failure)

§ severe cirrhosis and other forms of liv er failure

CORRECTION OF DOSAGE IN A PATIENT WITH RENAL IMPAIRMENT

- average dosage for a normal person multiplied by the ratio of the patient’s altered creatinine clearance (CLcr) to normal creatinine clearance (approximately 100 mL/min, or 6 L/h)

Correc ted dosage =Average dosage x (Patient’s Cl Cr )/(100 ml/min)

Notes from Lecture PPT, and Manual ONLY

- limitation: ignores non - renal routes of clearance that may be

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