biopharm review1

HONEYLENE B. PALOMA, RPH.

INTRODUCTION TO BIOPHARMACEUTICS AND

PHARMACOKINETICS

BASIC TERMINOLOGIES

Drug any substance that interacts with a molecule or protein that plays a regulatory role in living systems.

Introduction to biopharmaceutics:

Biopharmaceutics: the study of how the physicochemical properties of drugs, dosage forms and routes of administration affect the rate and extent of the drug absorption.

Thus, biopharmaceutics involves factors that influence the:

1) protection and stability of the drug within the product;

2) the rate of drug release from the product; 3) the rate of dissolution of the drug at the

absorption site; and 4) the availability of the drug at its site of

action .

Generally, the GOAL of biopharmaceutical studies is to develop a dosage form that will

provide consistent bioavailability at a desirable rate.

Pharmacokinetics – “what the body DOES to the drug”. This phase of drug delivery system involves ADME

Pharmacodynamics – “what the drug DOES to the body”; the biochemical & physical effects of drugs on the body & the mechanism of drug action.

Pharmacotherapeutics – the use of drugs to prevent and treat diseases.

BASIC TERMINOLOGIES

Pharmacokinetics vs Pharmacodynamics…concept

Fluoxetine increases plasma concentrations of amitriptyline. This is a pharmacokinetic drug interaction.

Fluoxetine inhibits the metabolism of amitriptyline and increases the plasma concentration of amitriptytline.

Pharmacokinetics vs Pharmacodynamics…concept

If Fluoxetine is given with Tramadol, serotonin syndrome can result. This is a pharmacodynamic drug interaction.

Fluoxetine and Tramadol both increase availability of serotonin leading to the possibility of “serotonin overload” This happens without a change in the concentration of either drug.

9

Dynamic Relationship

Drug release and

dissolution

Drug in Systemic circulation

Pharmacologic or clinical response

Excretion and metabolism

Drug in tissues Absorption

Elimination

Relationship between the drug, the drug product and the pharmacologic effect

BIOPHARMACEUTICSPK PD

Applications of Pharmacokinetic studies:

1. Pharmacological testing – assess the relationship bet the drug C and pharmacological activities. This is important to determine how much and how often the drug should be given.

2. Toxicological testing – assess tissue accumulation of drugs and how it is related to drug toxicity.

Applications of Pharmacokinetic studies:

3. Evaluation of Organ Function – evaluate the function of eliminating organs.

4. Dosage Regimen Design – design the dosing regimen (dose and dosing interval of a specific drug) that can achieve the maximum therapeutic effect w/ minimal toxicity.

WHAT ARE THESE ELIMINATING ORGANS? 12

3

4

5

6

Bioavailability: The rate and extent of drug absorption.

Bioavailable dose: The fraction of an administered dose of a particular drug that reaches the systemic circulation intact.

Plasma level-time curve:

The plasma level-time curve is generated by measuring the drug concentration in plasma samples taken at various time intervals after a drug product is administered.

The concentration of drug in each plasma sample is plotted against the corresponding time at which the plasma sample was removed.

Drug Product Performance Parameters:1- Minimum effective concentration (MEC): The

minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect.

2- Minimum toxic concentration (MTC): The drug concentration needed to just produce a toxic effect.

3- Onset time: The time required for the drug to reach the MEC.

4- Duration of action: The difference between the onset time and the time for the drug to decline back to the MEC.

5- The time of peak plasma level: The time of maximum drug concentration in the plasma and is proportional to the rate of drug absorption.

6- The peak plasma level: The maximum drug concentration, usually related to the dose and the rate constants for absorption and elimination of the drug.

7- Area under the curve: It is related to the amount of drug absorbed systemically.

• chemical nature of a drug• Inert excipients• method of manufacture• physicochemical properties of drug such as pKa, particle size, partition coefficient, polymorphism etc.

Factors influencing the BIOAVAILABILITY of a Drug

Route of Administration Determines Bioavailability

(AUC)

WHY ARE DRUG CONCENTRATION

SAMPLES TAKEN FROM THE BLOOD / PLASMA?

Drug Concentration In Tissues

Tissue biopsies used for verification of malignancy.

Small sample is removed, hence measurement of drug concentration difficult.

Used to ascertain if the drug reached the tissue & reached the proper concentration within the tissues.

Drug Concentrations in Urine & Feces

It is an indirect method to ascertain the bioavailability of a drug.

The rate & extent of drug excreted in urine reflects the rate & extent of systemic drug absorption.

Measurement of drug in feces may reflect drug that has not been absorbed after an oral dose or may reflect drug that has been expelled by biliary secretion after systemic absorption.

Used for TDM because only free drug diffuse into the saliva, saliva drug levels tend to approximate free drug rather than total plasma drug conc.

The ratio of saliva/plasma drug concentration ratio less than 1 for many drugs.

It is influenced by pKa of a drug & pH of the saliva.

Drug Concentration in Saliva

2 General Classifications of Drugs

BASIC TERMINOLOGIES

1. Endogenous

2. Exogenous

1. Hormones

2. Neurotransmitters

3. Mediators

3 groups of endogenous chemical messengers/drugs

that target receptors

1. Hormones - produced by endocrine tissue and carried in the blood to their receptor targets.

e.g. adrenaline, insulin, ADH-vasopressin and aldosterone2. Neurotransmitters - released by neuron terminals; chemical messengers bind to receptors on neurons and other cells, either stimulating or inhibiting activity in those cells.

e.g. noradrenaline, acetylcholine and serotonin (5-HT)

Neurotransmitters

3. Mediators - locally acting chemical messengers released by cells and having an effect on adjacent cells.

e.g.

histamineleukotriene

s

PHARMACOKINETIC PRINCIPLESRoutes of administration are determined by:1.Properties of the drug2.Therapeutic objectives 2 major routes of administration:1.Enteral (extravascular) - administering the

drug by mouth; the simplest and most common2.Parenteral (intravascular)- introduces drugs

directly across the body’s barrier defenses into the systemic circulation or other vascular tissue.

3.Others

Routes of Administration

Injection is the most common parenteral route.

Enteral has advantages:~ Can be self administered~ Limits systemic infections that

could complicate treatment~ Toxicities or overdose may be

overcome with antidotes.

The Universal Antidote is a mixture that

contains activated charcoal, magnesium

oxide, and tannic acid.

Enteral can be further classified into:

A. Oral

B. Sublingual

C. Buccal

D. Sublabial E. Perlingual

Parenteral has AdvantagesFast: 15–30sec for IV, 3–5 mins for IM and

SC100% bioavailabilitysuitable for drugs not absorbed by the

digestive system or those that are too irritant

One injection can be formulated to last days or even months, e.g. Depo-Provera

IV can deliver continuous medication, e.g., morphine for patients in continuous pain, or saline drip for people needing fluids

Other Routes

Inhalation

Intranasal

Intrathecal/intraventricul

ar

Rectal

Transdermal

Topical local effect, substance is applied directly where its action is desired; applied to a localized area of the body or to the surface of a body part or through mucous membranes in the body.

epicutaneous

enemas

eye drops

ear drops

ORGANIZATION OF THE HUMAN BODY

TISSUES AND THEIR MAIN LOCATION

MembranesTypes of Membranes:Cell Membranes: This barrier is permeable to

many drug molecules but not to others, depending on their lipid solubility. Small pores, 8 angstroms, permit small molecules such as alcohol and water to pass through.

Walls of Capillaries: Pores between the cells are larger than most drug molecules, allowing them to pass freely, without lipid solubility being a factor.

Blood/Brain Barrier: This barrier provides a protective environment for the brain. Speed of transport across this barrier is limited by the lipid solubility of the psychoactive molecule.

Placental Barrier: This barrier separates two distinct human beings but is very permeable to lipid soluble drugs.

THEORIES ON CELL STRUCTURE

Unit membrane theory

Fluid Mosaic Model

Modified Fluid Mosaic Model

LADMER Processes can be divided into two classes: a. drug input b. drug output

INPUT PROCESSES are:

L = Liberation, the release of the drug from it's dosage form.A = Absorption, the movement of drug from the site of administration to the blood circulation.

FACTORS AFFECTING LIBERATION

1. Surface area“the larger the surface area

exposed to the solvent, the faster the dissolution rate.”

2. SolubilityFor weakly acidic drugs, solubility increases w/ an increasing pH of the solvent.For basic drugs, solubility increases with decreasing pH.

Despite the effect of pH on the intrinsic solubility of the drug compound, there are cases of compounds with poor aqueous solubility. In such cases, the solubility of the drug in water is sometimes enhanced by the formation of salts.

“salts of the weak acids and salts of weak bases generally have much better aqueous solubility than the corresponding free acid

or free base.”

FACTORS AFFECTING LIBERATION

3. Crystal or Amorphous Form“the amorphous form is more soluble than the crystalline form.”

4. Agitation5. State of hydration

“Anhydrous form of the drug is more readily soluble than the hydrated one.”

6. Drug Design

INPUT PROCESSES

Bioavailability describes the rate and extent of drug input. The fraction of administered drug that reaches systemic circulation.

IV route drugs 100% bioavailability.

ABSOLUTE BIOAVAILABILITY

Is the measurement of a test formulation dose against an IV reference dose the bioavailability of which is 100% by definition.

Absolute Bioavailabilit

y %=

AUC test / Dose test

X 100AUC IV / Dose IV

RELATIVE BIOAVAILABILITY

Is the measurement of a test formulation dose against a reference formulation. The two formulations are may be considered bioequivalent if the range of the ratio of their AUCS is 0.8 to 1.25.

Relative Bioavailabilit

y %=

AUC test / Dose test X 100

AUC reference / Dose reference

FACTORS THAT INFLUENCES BIOAVAILABILITY (additional):

a.First-pass hepatic metabolismb.Solubility of the drugs“for a drug to be readily absorbed, it should be largely hydrophobic, yet have some solubility in aqueous solutions.”c. Chemical instabilityd. Nature of drug formulation

BIOEQUIVALENCE If 2 related drugs show comparable bioavailability and similar times to achieve peak blood concentrations.

THERAPEUTIC EQUIVALENCE 2 similar drugs are therapeutically equivalent if they have comparable efficacy and safety.

OUTPUT PROCESSES

D = Distribution, process by w/c a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues.

Drug Distribution Dependent upon its route of administration and target area,

every drug has to be absorbed, by diffusion, through a variety of bodily tissue.

Tissue is composed of cells which are encompassed within membranes, consisting of 3 layers, 2 layers of water-soluble complex lipid molecules (phospholipid) and a layer of liquid lipid, sandwiched within these layers. Suspended within the layers are large proteins, with some, such as receptors, transversing all 3 layers.

The permeability of a cell membrane, for a specific drug, depends on a ratio of its water to lipid solubility. Within the body, drugs may exist as a mixture of two interchangeable forms, either water (ionized-charged) or lipid (non-ionized) soluble. The concentration of two forms depends on characteristics of the drug molecule (pKa, pH at which 50% of the drug is ionized) and the pH of fluid in which it is dissolved.

In water soluble form, drugs cannot pass through lipid membranes, but to reach their target area, they must permeate a variety of types of membranes.

M = Metabolism, the chemical conversion or transformation of drugs into compounds which are easier to eliminate.

E = Excretion, the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes.

R = Response, the action of the body to the drug administered

OUTPUT PROCESSES

Presystemic metabolism:

Definition:The metabolism of orally administered drugs by gastrointestinal and hepatic enzymes, resulting in a significant reduction of the amount of unmetabolized drug reaching the systemic circulation.

Gut wall metabolism- This effect is known as first-pass metabolism by

the intestine.- Cytochrome P450 enzyme, CYP3A, that is present

in the liver and responsible for the hepatic metabolism of many drugs, is present in the intestinal mucosa and that intestinal metabolism may be important for substrates of this enzyme e.g. cyclosporin.

-

Presystemic metabolism:Hepatic metabolism- After a drug is swallowed, it is absorbed by the

digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body.

- The liver metabolizes many drugs (e.g. propranolol), sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system.

- This first pass through the liver thus greatly reduces the bioavailability of the drug.

Presystemic metabolism (Cont.)

Hepatic metabolism (Cont.)

PORTAL CIRCULATIONWhen the drug is taken orally, absorption will most probably happen in the small intestine.

The drug is considered absorbed when it is transported from the lumen of the small intestine into the blood stream. Blood drained from the small intestine is first passed on to the liver through the portal vein before being released into the systemic circulation.

Drugs that are absorbed through the portal vein may be subjected to liver activity before being released into the systemic circulation.

portal circulation refers to the circulation of the blood from the small intestine to

the liver, via the portal vein. Blood flow to the liver is unique in that it receives

oxygenated and de-oxygenated blood.

FIRST PASS EFFECTFirst pass effect is the inactivation of drugs by the liver immediately after absorption through the portal circulation.

The liver metabolizes many drugs altering the concentration of the active drug that will eventually be released into the systemic circulation.

First pass effect may greatly reduce bioavailability of a drug.

The dose of propranolol administered

intravenously is less than that administered orally.

Why is this so?

Examine the schematic diagram of the different

routes of drug administration showing potential for first pass effect and how it can affect bioavailability.

In your lesson plan, discuss the schematic diagram and

answer the following questions:

1.Give 2 enteral and 2 topical routes of administration that bypass first pass effect.

2.If you want to insert a box for percutaneous administration in the above illustration. Where will you put it?

AbsorptionMain factors affecting oral absorption:I Physiological factors. II Physical-chemical factors. III Formulation factors.

I Physiological factors affecting oral absorption:1- Membrane physiology.2- Passage of drugs across membranes.3- Gastrointestinal physiology.

I. Characteristics of GIT physiology and drug absorption II. Gastric emptying time and motilityIII. Effect of food on drug absorption

Physiological factors influencing bioavailability:

1- Membrane physiology:

http://library.thinkquest.org/C004535/media/cell_membrane.gif

1- Membrane physiology (Cont.):- The cell membrane is the barrier that separates

the inside of the cell from the outside. - The cell membrane is made up of phospholipids,

proteins, and other macromolecules.

- The phosopholipids make up a bilayer. It contains hydrophilic and hydrophobic molecules.

- The proteins in the cell membrane are located

within the phospholipid bilayer.

- So, the biologic membrane is mainly lipid in nature but contains small aqueous channels or pores.

2-Passage of drugs across membranes:

DRUG TRANSPORT:

1. PASSIVE DIFFUSION2. CARRIER-MEDIATED

2.1 FACILITATED DIFFUSION2.2 ACTIVE TRANSPORT

3. PORE, CONVECTIVE, PARACELLULAR4. VESICULAR TRANSPORT

4.1 ENDOCYTOSIS4.1.1 PHAGOCYTOSIS4.1.2 PINOCYTOSIS

4.2 EXOCYTOSIS5. ION PAIR FORMATION6. TRANSPORTER PROTEIN EFFLUX

1. Passive diffusion: - Most drugs cross biologic membranes by passive

diffusion. - Diffusion occurs when the drug concentration on

one side of the membrane is higher than that on the other side.

- The process is passive because no external energy is expended.

- The driving force for passive diffusion is the difference in drug concentrations on either side of the cell membrane.

ABSORPTION OF DRUGS

2. CARRIER- MEDIATED2.1 Facilitated diffusion:

- Play a very minor role in absorption.- A drug carrier is required but no energy is

necessary. e.g. vitamin B12 transport. - Saturable if not enough carrier and structurally

selective for the drug and shows competition kinetics for drugs of similar structure.

- No transport against a concentration gradient only downhill but faster.

involves specific carrier proteins that span a membraneenergy dependent driven by the hydrolysis of ATPcapable of moving drugs against a concentration gradient – that is, from a region of low concentration to one of higher drug concentration.

2.2 ACTIVE TRANSPORT

BOTH DOESN’T REQUIRE ENERGYThe rate of passive transport depends on the permeability of the cell membrane

SIMILARITIES

DIFFERENCES

> involves a carrier, transmembrane proteins> can be saturated

> doesn’t involve a carrier> not saturable > shows a low structural specificity

http://en.wikipedia.org/wiki/Semipermeable_membrane

Fick’s First Law of Diffusion

The amount, M, of material flowing through a unit cross section, X, of a barrier in unit time, t, is known as the flux, J.

The flux, in turn, is proportional to the concentration gradient, dC/dt.

“Diffusion will stop when the concentration gradient no longer exists.”

Diagram of Passive Transport with a Concentration Gradient

-The rate of transport of drug across the membrane can be described by Fick's first law of diffusion:-

Fick's First Law, Rate of Diffusion

The negative sign of equation signifies that diffusion occurs in a direction

opposite to that of increasing concentration.

Diffusion occurs in the direction of decreasing concentration of diffusant.

DRUG TRANSPORT

3- Pore (convective) transport:

- A certain type of protein called transport protein may form an open channel across the lipid membrane of the cell.

- Very small molecules, such as urea, water and sugars are able to rapidly cross the cell membrane through these pores.

4- Vesicular transport:

drug delivery that transports exceptionally large size drugs across the

cell membrane.

Exocytosis: reverse of Endocytosis. Used by cells to secrete or discharge many substances by a similar vesicle formation process.

Endocytosis: engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug-filled vesicle.

cell-eating

cell-drinking

2 TYPES OF ENDOCYTOSIS

5- Ion pair formation:-Strong electrolyte drugs are highly ionized or charged molecules, such as quaternary nitrogen compounds.-These drugs penetrate membranes poorly. When linked up with an oppositely charged ion, an ion pair is formed in which the overall charge of the pair is neutral. This neutral complex diffuses more easily across the membrane.- e.g. the formation of an ion pair for propranolol (basic drug) with oleic acid.

6. Transporter Protein EffluxDrug transport proteins can be grouped into two major classes:

a. the solute carriers (SLC) (facilitate the cellular uptake or influx of substrates, either by facilitated diffusion)

b. ATP-binding cassette (ABC) transporters.

Over 380 unique SLC sequences have been obtained from the human genome, which can be divided into48 subfamilies.

ABC transporters are by definition efflux transporters because they use energy derived from ATP hydrolysis to mediate the primary active export of drugs from the intracellular to the extracellular milieu, often against a steep diffusion gradient.

3- Gastrointestinal (GI) Physiology:

- The gastrointestinal tract is a muscular tube approximately 6 m in length with varying diameters.

- It stretches from the mouth to the anus and consists of four main anatomical areas: the oesophagus, the stomach, the small intestine and the large intestine or colon.

- The majority of the gastrointestinal epithelium is covered by a layer of mucous. This is a viscoelastic translucent aqueous gel that is secreted through out the GIT, acting as a protective layer and a mechanical barrier.

Gastrointestinal (GI) Physiology (Cont.):

Gastrointestinal (GI) Physiology (Cont.):I. Characteristics of GI physiology and

Drug Absorption:

Organs pH Membrane Blood Supply

Surface Area

Transit Time

By-pass liver

Buccal approx 6

thin Good, fast absorption

with low dose

small Short unless

controlled

yes

Oesophagus 5-6 Very thick no

absorption

- small short, typically a

few seconds, except for

some coated tablets

-

I. Characteristics of GI physiology and Drug Absorption (cont.):


Surface Area

Transit Time

By-pass liver

Stomach 1.7-3.5 normal good small 30 min (liquid) - 120 min

(solid food)

no

Duodenum 5 - 7 normal good Very large

very short, no



Surface Area

Transit Time

By-pass liver

Small

Intestine 6 – 7.5 normal good Very

largeAbout 3 hours

no

Large intestine

6.8 - 7 - good Not very large

long, up to 24 hours

Lower colon, rectum

yes

The environment within the lumen:Gastrointestinal pH- As we observed from the previous tables, the pH of fluids

varies along the length of the GIT.- The gastrointestinal pH may influence the absorption of

drugs in a variety of ways:A- It may affect the chemical stability of the drug in the lumen

e.g. penicillin G, erythromycinB- affect the drug dissolution or absorption e.g. weak

electrolyte drugLuminal enzymes- The primary enzyme found in gastric juice is pepsin. Lipases,

amylases and proteases are secreted from the pancreas into the small intestine.

- Pepsins and proteases are responsible for the digestion of protein and peptide drugs in the lumen.


- The lipases may affect the release of drugs from fat / oil – containing dosage forms.

- Bacteria which are localized within the colonic region of the GIT secrete enzymes which are capable of a range of reactions.

- e.g. Sulphasalazine which is a prodrug used to target the colon.

Sulphasalazine active drug

(5-aminosalicylic acid)

treat inflammatory bowel disease


Bacterial enzymes

Disease state and physiological disorders- Local diseases can cause alterations in gastric pH

that can affect the stability , dissolution and absorption of the drug.

- Partial or total gastrectomy results in drugs reaching the duodenum more rapidly than in normal individuals. This may result in an increased overall rate of absorption of drugs that are absorbed in the small intestine.

- However, drugs that require a period of time in the stomach to facilitate their dissolution may show reduced bioavailability in such patients.


The unstirred water layer- It is a more or less stagnant layer of water and

mucous adjacent to the intestinal wall.- This layer can provide a diffusion barrier to drugs.- Some drugs (antibiotics e.g. tetracycline) are

capable of complexing with mucous, thereby reducing their availability for absorption.


II Gastric emptying and motility:

- The time a dosage form takes to traverse the stomach is usually termed: the gastric residence time, gastric emptying time or gastric emptying rate.

- - Generally drugs are better absorbed in the small intestine (because of the larger surface area) than in the stomach, therefore quicker stomach emptying will increase drug absorption. - For example, a good correlation has been found between stomach emptying time and peak plasma concentration for acetaminophen. The quicker the stomach emptying (shorter stomach emptying time) the higher the plasma concentration. - Also slower stomach emptying can cause increased degradation of drugs in the stomach's lower pH; e.g. L-dopa.


Dependence of peak acetaminophen plasma concentration as a function of stomach emptying half-life

II Gastric emptying and motility:Factors Affecting Gastric Emptying


Factors Affecting Gastric EmptyingViscosity Rate of emptying is greater for less viscous

solutionsEmotional states - Stressful emotional states increase

stomach contraction and emptying rate- Depression reduces stomach contraction and emptying

Disease states -Rate of emptying is reduced in: Some diabetic patients, hypothyrodism-Rate of emptying is increased in:hyperthyrodism

Exercise Reduce emptying rate

III Effect of Food:- The presence of food in the GIT can influence the

rate and extent of absorption, either directly or indirectly via a range of mechanisms.

A- Complexation of drugs with components in the diet

e.g.Tetracycline forms non-absorable complexes with calcium and iron, and thus it is advised that patients do not take products containing calcium or iron, such as milk, iron preparations or indigestion remedies, at the same time of day as the tetracycline.

B- Alteration of pHFood tends to increase stomach pH by acting as a

buffer. This liable to decrease the rate of dissolution and absorption of a weakly basic drug and increase that of a weakly acidic one.

III Effect of Food (cont.):C- Alteration of gastric emptyingFats and some drugs tend to reduce gastric

emptying and thus delay the onset of action of certain drugs.

D- Stimulation of gastrointestinal secretions- Gastrointestinal secretions (e.g. pepsin) produced

in response to food may result in the degradation of drugs that are susceptible to enzymatic metabolism, and hence a reduction in their bioavailability.

- Fats stimulate the secretion of bile. Bile salts are surface active agents which increase the dissolution of poorly soluble drugs (griseofulvin).

Bile salts can form insoluble and non-absorbable complexes with some drugs, such as neomycin and kanamycin.

III Effect of Food (cont.):E-Competition between food components and drugs

for specialized absorption mechanismsThere is a possibility of competitive inhibition of

drug absorption in case of drugs that have a chemical structure similar to nutrients required by the body for which specialized absorption mechanisms exist.

F- Increased viscosity of gastrointestinal contentsThe presence of food in the GIT provides a viscous

environment which may result in:- Reduction in the rate of drug dissolution- Reduction in the rate of diffusion of drug in

solution from the lumen to the absorbing membrane lining the GIT.

Hence, there is reduction in drug bioavailability.

G- Food-induced changes in presystemic metabolism- Certain foods may increase the bioavailability of drugs that

are susceptible to presystemic intestinal metabolism by interacting with the metabolic process.

- E.g. Grapefruit juice is capable of inhibiting the intestinal cytochrome P450 (CYP3A) and thus taken with drugs that are susceptible to CYP3A metabolism which result in increase of their bioavailability.

H- Food-induced changes in blood flow- Food serve to increase the bioavailability of some drugs (e.g.

propranolol) that are susceptible to first-pass metaolism.- Blood flow to the GIT and liver increases after a meal. The

faster the rate of drug presentation to the liver; the larger the fraction of drug that escapes first-pass metabolism. This is because the enzyme systems become saturated.

III Effect of Food (cont.):

III Effect of Food (cont.):

Effect of Fasting versus Fed on Propranolol Concentrations

Double peak phenomena:- Some drugs such as cimetidine and rantidine,

after oral administration produce a blood concentration curve consisting of two peaks.

- The presence of double peaks has been attributed to variability in stomach emptying, variable intestinal motility, presence of food, enterohepatic cycle or failure of a tablet dosage form.

II Physical-Chemical Factors Affecting Oral Absorption:

Physical-chemical factors affecting oral absorption include: A- pH-partition theory B- Lipid solubility of drugsC- Dissolution and pHD- Drug stability and hydrolysis in GITE- ComplexationF- Adsorption

A. pH - Partition Theory:- According to the pH-partition hypothesis, the

gastrointestinal epithelia acts as a lipid barrier towards drugs which are absorbed by passive diffusion, and those that are lipid soluble will pass across the barrier.

- As most drugs are weak electrolytes, the unionized form of weakly acidic or basic drugs (the lipid-soluble form) will pass across the gastrointestinal epithelia, whereas the gastrointestinal epithelia is impermeable to the ionized (poorly-lipid soluble) form of such drugs.

- Consequently, the absorption of a weak electrolyte will be determined by the extent to which the drug exists in its unionized form at the site of absorption.

A. pH - Partition Theory (Cont.):

Diagram Showing Transfer Across Membrane

ABSORPTION OF DRUGSEffect of pH. Most drugs are weak acids and

weak bases.

A. pH - Partition Theory (Cont.):- The extent to which a weakly acidic or basic drug

ionizes in solution in the gastrointestinal fluid may be calculated using Henderson - Hasselbach equation.

** Weak acids (e.g. aspirin):

Dissociation Constant equation - Weak Acids

taking the negative log of both sides

A. pH - Partition Theory (Cont.):

Rearranging gives the following equation:

Henderson - Hasselbach Equation - Weak Acids

A. pH - Partition Theory (Cont.):**Weak Bases:

Henderson - Hasselbach Equation - Weak Bases

Limitations of the pH-partition hypothesis:-Despite their high degree of ionization, weak acids are highly absorbed from the small intestine and this may be due to:1- The large surface area that is available for absorption in the small intestine.2- A longer small intestine residence time.

A. pH - Partition Theory (Cont.):3- A microclimate pH, that exists on the

surface of intestinal mucosa and is lower than that of the luminal pH of the small intestine.

ABSORPTION OF DRUGSPhysical Factors affecting Absorption.

1. Blood flow to the absorption site2. Total Surface area available for absorption3. Contact time at the absorption surface.

Absorption from the intestine is more favorable.

Parasympathetic input increases gastric emptying while sympathetic

input prolongs gastric emptying.

B. Lipid solubility of drugs:

- Some drugs are poorly absorbed after oral administration even though they are non-ionized in small intestine. Low lipid solubility of them may be the reason.

- The best parameter to correlate between water and lipid solubility is partition coefficient.

Partition coefficient (p) = [ L] conc / [W] conc

where, [ L] conc is the concentration of the drug in lipid phase.

[W] conc is the concentration of the drug in aqueous phase.

- The higher p value, the more absorption is observed.

C. Drug Dissolution:- Many drugs are given in solid dosage forms and

therefore must dissolve before absorption can take place.

- If dissolution is the slow, it will be the rate determining step (the step controlling the overall rate of absorption) then factors affecting dissolution will control the overall process.

C. Drug Dissolution (cont.):- Drug dissolution is considered to be diffusion

controlled process through a stagnant layer surrounding each solid particle.

Diagram Representing Diffusion Through the Stagnant Layer

C. Drug Dissolution (cont.):- The dissolution of drugs can be described by the

Noyes-Whitney equation:

- Where D is the diffusion coefficient, A the surface area, Cs the solubility of the drug, Cb the concentration of drug in the bulk solution, and h the thickness of the stagnant layer. -If Cb is much smaller than Cs then we have so-called "Sink Conditions" and the equation reduces to

C. Drug Dissolution (cont.):Factors affecting drug dissolution in the GIT:I Physiological factors affecting the dissolution

rate of drugs:- The environment of the GIT can affect the

parameters of the Noyes-Whitney equation and hence the dissolution rate of a drug.

A- Diffusion coefficient, D: - Presence of food in the GIT increase the

viscosity of the gastrointestinal fluids reducing the rate of diffusion of the drug molecules away from the diffusion layer surrounding each undissolved drug particles (↓ D)

decrease in dissolution rate of a drug.

C. Drug Dissolution (cont.):B- Drug surface area, A:Surfactants in gastric juice and bile salts

increase the wettability of the drug increase the drug solubility via micellization.

C. The thickness of diffusion layer, h:An increase in gastric and/or intestinal motility

decrease the thickness of diffusion layer around each drug particle increase the dissolution rate of a drug.

D. The concentration, C, of drug in solution in the bulk of the gastrointestinal fluids:

C. Drug Dissolution (cont.):Increasing the rate of removal of dissolved drug by

absorption through the gastrointestinal-blood barrier and increasing the intake of fluid in the diet will decrease in C rapid dissolution of the drug.

II Physicochemical factors affecting the dissolution rate of drugs:

A- Surface area, A:- The smaller the particle size the greater

the effective surface area of drug particle the higher the dissolution rate.

C. Drug Dissolution (cont.):- Methods of particle size reduction include: mortar

and pestle, mechanical grinders, mills, solid dispersions in readily soluble materials (PEG's).

- However very small particles can clump together. Therefore a wetting agent such as Tween 80 can have a beneficial effect on the overall absorption.

C. Drug Dissolution (cont.):B-Diffusion coefficient, D:The value of D depends on the size of the

molecule and the viscosity of the dissolution medium.

C- Solubility in the diffusion layer, Cs:- The dissolution rate of a drug is directly

proportional to its intrinsic solubility in the diffusion layer surrounding each dissolving drug particle.

C. Drug Dissolution (cont.):D- Salts:- Salts of weak acids and weak bases

generally have much higher aqueous solubility than the free acid or base.

- The dissolution rate of a weakly acidic drug in gastric fluid (pH 1 – 3.5) will be relatively low.

- If the pH in the diffusion layer increased, the solubility, Cs, of the acidic drug in this layer, and hence its dissolution rate in gastric fluids would be increased.

C. Drug Dissolution (cont.):- The pH of the diffusion layer would be increased if

the chemical nature of the weakly acidic drug was changed from that of the free acid to a basic salt (the sodium or potassium form of the free acid.)

- The pH of the diffusion layer would be higher (5-6) than the low bulk pH (1-3.5) of the gastric fluids because of the neutralizing action of the strong (Na+, K+ ) ions present in the diffusion layer.

- The drug particles will dissolve at a faster rate and diffuse out of the diffusion layer into the bulk of the gastric fluid, where a lower bulk pH.

C. Drug Dissolution (cont.):- Thus the free acid form of the drug in solution, will

precipitate out , leaving a saturated solution of free acid in gastric fluid.

This precipitated free acid will be in the form of:

- very fine, - non-ionized,- wetted particles which have a very large surface

area in contact with gastric fluids, facilitating rapid redissolution when additional gastric fluid is available.

Drug Dissolution (cont.):

Dissolution process of a salt form of a weakly acidic drug in gastric fluid.

Drug Dissolution (cont.):- One example is the dissolution and bioavailability profiles

of Penicillin V with various salts.

These results might support the use of the benzathine or procaine salts for IM depot use and the potassium salt for better

absorption orally.

Drug Dissolution (cont.):E- Crystal form:1- Polymorphism:- Some drugs exist in a number of crystal forms or

polymorphs. These different forms may have different solubility properties and thus different dissolution characteristics.

- Chloramphenicol palmitate is one example which exists in three crystalline forms A, B and C.

A is the stable polymorphB is the metastable polymorph (more

soluble)C is the unstable polymorph- The plasma profiles of chloramphenicol from oral

suspensions containing different proportions of

Drug Dissolution (cont.):Polymorphic forms A and B were investigated.-The extent of absorption of Chloramphnicol increases as theProportion of the polymorphic formB is increased in each suspension.This is attributed to the more rapidDissolution of the metastablePolymorphic form B.

- Shelf-life could be a problem as the more soluble (less stable) form may transform into the less soluble form (more stable).

Drug Dissolution (cont.):2- Amorphous solid:- The amorphous form dissolves more rapidly than

the corresponding crystalline form.- The more soluble and rapidly dissolving

amorphous form of novobiocin antibiotic was readily absorbed following oral administration of an aqueous suspension to humans. However, the less soluble and slower-dissolving crystalline form of novobiocin was not absorbed (therapeutically ineffective).

- The amorphous form of novobiocin slowly converts to the more stable crystalline form, with loss of therapeutic effectiveness.

Drug Dissolution (cont.):

3- Solvates:

Solvates: If the drug is able to associate with solvent molecules to produce crystalline forms known as solvates.

Hydrates: drug associates with water molecules.- The greater the solvation of the crystal, the lower

are the solubility and dissolution rate in a solvent identical to the solvation molecules.

Drug Dissolution (cont.):- The faster-dissolving anhydrous form of ampicillin

was absorbed to a greater extent from both hard gelatin capsules and an aqueous suspension than was the slower-dissolving trihydrate form.

D- Drug stability and hydrolysis in GIT:- Drugs that are susceptible to acidic or enzymatic

hydrolysis in the GIT, suffer from reduced bioavailability.

- How to protect drugs (erythromycin) from degradation in gastric fluid ??

1- Preparing enteric coated tablets containing the free base of erythromycin. The enteric coating resists gastric fluid but disrupts or dissolves at the less acid pH range of the small intestine.

2- The administration of chemical derivatives of the parent drug. These prodrugs (erythromycin stearate) exhibit limited solubility in gastric fluid, but liberate the drug in the small intestine to be absorbed.

E- Complexation:- Complexation of a drug may occur within the

dosage form and/or in the gastrointestinal fluids, and can be benefecial or deterimental to absorption.

1- Intestinal mucosa (mucin) + Streptomycin =

poorly absorbed complex

2- Calcium + Tetracycline = poorly absorbed complex (Food-drug interaction)

3- Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed complex (tablet additive – drug interaction)

4- Lipid soluble drug + water soluble complexing agent = well-absorbed water soluble complex ( cyclodextrin)

F- Adsorption:- Certain insoluble susbstances may adsorbed co-

administrated drugs leading to poor absorption. Charcoal (antidote in drug intoxication).Kaolin (antidiarrhoeal mixtures)Talc (in tablets as glidant)

III Formulation Factors Affecting Oral Absorption:

- The role of the drug formulation in the delivery of drug to the site of action should not be ignored.

- Since a drug must be in solution to be absorbed efficiently from the G-I tract, you may expect the bioavailability of a drug to decrease in the order solution > suspension > capsule > tablet > coated tablet.

A. Solution dosage forms:- In most cases absorption from an oral solution is

rapid and complete, compared with administration in any other oral dosage form.

III Formulation Factors Affecting Oral Absorption (Cont.):

- Some drugs which are poorly soluble in water may be:

1- dissolved in mixed water/alcohol or glycerol solvents (cosolvency),

2- given in the form of a salt (in case of acidic drugs)

3- An oily emulsion or soft gelatin capsules have been used for some compounds with lower aqueous solubility to produce improved bioavailability.


B. Suspension dosage forms:- A well formulated suspension is second to a

solution in terms of superior bioavailability.

- A suspension of a finely divided powder will maximize the potential for rapid dissolution.

- A good correlation can be seen for particle size and absorption rate.

- The addition of a surface active agent will improve the absorption of very fine particle size suspensions.


Absorption of drugs from aqueous suspensions


C. Capsule dosage forms:- The hard gelatin shell should disrupt rapidly and

allow the contents to be mixed with the G-I tract contents.

- If a drug is hydrophobic a dispersing agent should be added to the capsule formulation. These diluents will work to disperse the powder, minimize aggregation and maximize the surface area of the powder.

- Tightly packed capsules may have reduced dissolution and bioavailability.


D. Tablet dosage forms:

Blood


- The tablet is the most commonly used oral dosage form.

- It is also quite complex in nature.

1-IngredientsDrug : may be poorly soluble, hydrophobic Lubricant : usually quite hydrophobic Granulating agent : tends to stick the ingredients

togetherFiller: may interact with the drug, etc., should be

water soluble Wetting agent : helps the penetration of water into

the tablet Disintegration agent: helps to break the tablet

apart


- Coated tablets are used to mask an unpleasant taste, to protect the tablet ingredients during storage, or to improve the tablets appearance.

This coating can add another barrier between the solid drug and drug in solution. This barrier must break down quickly or it may hinder a drug's bioavailability.

- Sustained release tablet Another form of coating is enteric coated tablets

which are coated with a material which will dissolve in the intestine but remain intact in the stomach.

DRUG DISTRIBUTION

Factors Affecting Drug Distribution:1. Blood Flow 2. Capillary permeability; determined by:

capillary structure. In the brain, we also have the Blood Brain Barrier (BBB) - barrier between brain tissues and circulating blood

chemical nature of the drug3. Binding of drugs to plasma proteins

Plasma Albumin is the major drug binding protein.

“Bound drugs are pharmacologically inactive; only the free, unbound drug can act on the target sites in the tissues, elicit a biologic response, and be available

to the process of elimination”

BINDING OF DRUGS TO PLASMA PROTEINS

VOLUME OF DISTRIBUTION

:A hypothetical volume

of fluid into w/c a

drug is dispersed. This is the relative size of

various distribution volumes within a 70-kg individual (42

Liters)

How do we determine the Vd in 4 scenarios?

Apparent Volume of Distribution or Vd

~ The volume into w/c drugs distribute.

Apparent Volume of Distribution

1. Absence of Elimination. Assuming that the drug distributes and is not

eliminated.

Vd = D D = the total amount of drug in the body

C C = the plasma concentration of the drug

Ex. If 25mg of a drug are administered and the plasma conc is 1mg/L, what will be its volume of distribution?

Vd = 25mg 1mg/L

Vd = 25L


2. Elimination is present. The rate at w/c the drug is eliminated is usually proportional to the concentration of

drug, C.If C is equal to 1mg/mL, it is the same

amount of drug eliminated in the body.

Drug concentrations in serum after a single injection of drug at time = 0.

Assume that the drug distributes and is subsequently eliminated.


3. Distribution is instantaneous. Assuming that the elimination process began at the time of injection and continued throughout the distribution phase.

C, plasma concentration of the drug, can be extrapolated back to time zero (time of injection) to determine C0.

C0 = the concentration of drug that would have been achieved if the distribution phase had occurred instantly.

Ex. If 10mg of drug are injected into a patient and the plasma concentration is extrapolated to time zero, the concentration is C0 = 1mg/L, what will be its volume of distribution? Vd = 10mg

1mg/L Vd = 10L


4. Uneven distribution between compartments.

Ex. Assume the arrhythmia of a cardiac patient is not well controlled due to inadequate plasma levels of digitalis. Suppose the concentration of drug in the plasma is C1 and the desired level of digitalis is a higher concentration, C2. The clinician needs to know how much additional drug should be administered to bring the circulating level of the drug from C1 to C2:(Vd)(C1) = amount of drug initially in the body(Vd)(C2) = amount of drug in the body needed to achieve the desired plasma concentration.

The difference between the two values is the additional dosage needed, w/c equals Vd(C2 - C1).

Effect of a large Vd on the half-life of a drug:

“If the Vd for a drug is large, most of the drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, any factor that increases the volume of distribution can lead to an increase in the half-life and extend the duration of action of the drug.”

METABOLISM

Kinetics of Metabolism

1. First-order Kinetics – a constant fraction of drug is metabolized per unit time.

The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis-Menten kinetics.

“The rate of drug metabolism is directly proportional to the concentration of free drug”.


2. Zero-order Kinetics – a constant amount of drug is metabolized per unit time.

“The enzyme is saturated by a high free-drug concentration, and the rate of drug metabolism remains constant over time.”


Effect of drug dose on the rate of metabolism.

First order kinetics means the amount of excretion depends on the amount

of drug present.

Zero order kinetics means that the amount of excretion is independent of

the amount of drug present.

BIOTRANSFORMATION OF DRUGS

ELIMINATION

Most important route in removal of a drug from the body is through the kidney (major organ of excretion) into the urine. Other routes include the bile, intestine, lung or milk in nursing mothers.

Drug elimination by

the kidney

Pharmacodynamic Principles

BASIC TERMINOLOGIES

Receptor a specific molecule, usu. a protein that interacts with a specific chemical that then causes a change in the specific molecule causing a change in regulatory function.Ligand Any substance (e.g. hormone, drug, etc.) that binds specifically and reversibly to another chemical entity to form a larger complex; a signal triggering molecule, binding to a site on a target protein.

may function as agonist or antagonist.

From Latin ligandus, rootword is ligare meaning ‘to bind’.

Receptors as targets for drugs:

over 10,000 different proteins in the body which means there are potentially over 10,000 different targets

Different tissues express different proteins so that drugs can target specific proteins on the heart, blood vessels, bronchioles etc.

Proteins have important functions in the body so they make worthwhile targets

- lipid structure - resistant to the entry of most non-lipid substances, including proteins and ions

Some drugs can cross the membrane and bind to internal cell receptors whilst others cannot, therefore, those that cannot bind to receptors

on the outside of the cell in order to exert their effect on the cell.

Regions of the Cell:Intracellular region - means inside the cell.Extracellular region - means outside of the cell

Drug Receptor Interactions

Receptors have a specific shape that allows the messenger to dock with that receptor, rather like a

lock that allows only one key to open it. In addition to shape, receptors and messengers bind via tiny electro-

magnetic forces such as van de Waals forces and hydrogen bonds.

Major Receptor Families

1. Ligand-gated ion channels - these involves the movement of ions across cell membrane through opening of an ion channel. These channels can open or close, allowing control over the movement of ions.

For example, acetylcholine binding to a cholinergic receptor in the

neuromuscular junction opens sodium channels and promotes contraction in the muscle cell.

2. G-Protein Coupled Receptors

G-Protein Coupled Receptors

3. Enzyme-linked receptors

also known as a catalytic receptor - is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic

activity on the intracellular side.

4. Intracellular receptors

the ligand w/c is lipid

soluble must

penetrate into the cell to

interact with the receptor.

Some characteristics of Receptors

SPARE RECEPTORS- Ability to amplify signal duration and

intensity- Exhibited by Insulin receptors

Has an immense functional reserve that ensures adequate amounts of glucose enter the cell

- Only 5 to 10% of the total beta-adrenoceptors of the heart are spare. “Most receptors must be occupied to

obtain maximal contractility”

Desensitization of ReceptorsRepeated or continuous administration of an agonist/antagonist may lead to changes in the responsiveness of the receptors. TACHYPHYLAXISE.g. Voltage-

gated channel receptor, require a finite time (rest period) following

stimulation before they can

be activated again.

Importance of the Receptor ConceptMost Drugs interact with receptors that will determine selective therapeutic and toxic effects of the drug. Receptors largely determine the quantitative relations bet. dose of a drug and its pharmacologic

effect.

AGONISM

Agonist – any drug (a ligand) that binds to a receptor and activates the receptor.

Once the agonist comes in contact with a protein receptor, there’ll be a chemical reaction that will occur causing a change inside the cell. This chemical rxn is a natural process by the body.

In many receptors, agonist leaving the binding site deactivates the receptor. In other receptors, agonist permanently activates the receptor until that receptor has been broken down by the body.

Pharmacologic Antagonist

any drug that binds to a receptor and prevents the activation of the receptor or decrease the

action of another drug.

Types of Pharmacologic Antagonist

Competitive (reversible) antagonist - it fits into the lock but doesn’t activate it. It competes with the agonist at the agonist binding site.

Ex. Atropine is the competitive antagonist of Acetylcholine at the muscarinic receptors.

Non Competitive (irreversible) antagonist – any antagonist that binds to a site on the receptor other than the agonist binding site.Ex. ketamine is a non-competitive antagonist at the NMDA-glutamate receptor

Chemical Antagonist

any drug that binds directly to an agonist and deactivates the agonist.Common ex. Protamine is the chemical antagonist of Heparin, a blood thinner.

Physiological/Functional Antagonist

a drug that opposes or reverses the effect of an agonist by binding to a different receptor and producing the opposite physiological effects. Common ex. Effect of Adrenaline (epinephrine) during anaphylactic shock.

Drug Effectiveness

Dose-response (DR) curve: Depicts the relation between drug dose and magnitude of drug effect

Drugs can have more than one effect

Drugs vary in effectiveness Different sites of action Different affinities for

receptorsThe effectiveness of a

drug is considered relative to its safety (therapeutic index)

DOSE-RESPONSE RELATIONSHIPGraded dose-response relations“As the concentration of a drug increases, the magnitude

of its pharmacologic effect also increases”.

Measure of the amount of drug necessary toproduce an effect of a given magnitude

EFFICACYThe ability of a drug to illicit a

physiologic response when it interacts with a receptor.

POTENCY

Dose-Effect Curves

QUANTAL DOSE-RESPONSE RELATIONSHIP

Quantal D-R Curves plot the percentage of a population responding to a specified drug effect versus dose or log dose.

They permit estimations of the median effective dose (ED50)(e.g., effective dose in 50% of a population)

This is a figure of two different dose response curves. You can obtain a different dose response curve for any system that the drug effects. When you vary the drug, this is the Independent variable, what you are measuring is the % of individuals responding to the drug. Here we see the drugs effects on hypnosis and death. Notice that the effective dose for 50 % of the people is 100 mg and if you double the dose to 200 mg then 1 % of your subjects die. Thus, if you want to use this drug to hypnotize 99 % of your subjects, in the process you will kill 2-3 % of your subjects.

Drug Safety and Effectiveness

Not all people respond to a similar dose of a drug in the exact same manner, this variability is based upon individual differences and is associated with toxicity. This variability is thought to be caused by: Pharmacokinetic factors contribute to

differing concentrations of the drug at the target area.

Pharmacodynamic factors contribute to differing physiological responses to the same drug concentration.

Unusual, idiosyncratic, genetically determined or allergic, immunologically sensitized responses.

Definitions you should know

Pharmacokinetics, intravascular,extravascular

Absorption ; process by which a drug proceeds from the site of administration to the site of measurement within the body.

Disposition ; all the processes that occur subsequent to the absorption of a drug

Distribution ; reversible transfer of a drug to and from the site of measurement.

Metabolism; irreversible conversion to another chemical species.

Excretion; irreversible loss of the chemically unchanged drug

Definitions you should knowAccumulation; the increase of drug concentration

in blood and tissue upon multiple dosing until steady state is reached

Steady state; the level of drug accumulation in blood and tissue upon multiple dosing when input and output are at equilibrium .

Biophase ; the actual site of action of drug in the body.

A receptor; a site in the biophase to which drug molecules can be bound

A compartment in pharmacokinetics; an entity which can be described by adefinite volume and concentration of drug contained in that volume. In pharmacokinetics , experimental data are explained by fitting them to compartmental models.

Definitions you should knowCentral compartment; the sum of all body

regions( organs and tissue) in which the drug concentration is in instantaneous equilibrium with that in blood or plasma. The blood or plasma is always part of the central compartment

Peripheral compartment; the sum of all body regions to which a drug is eventually distributes but is not in instantaneous equilibrium.

Feathering ; refers to a graphical method for separation of exponents such as separating the absorption rate constant from the elimination rate constant. ( residual method)

Biliary recycling; the phenomenon that drugs emptied via bile in to the small intestine can be reabsorbed from the intestinal lumen in to systemic circulation.

Definitions you should knowApparent partition coefficient; the ratio of the

concentration at equilibrium between a lipoid phase (n, octane) and an aqueous phase ( buffer ph 7.4).

Area under the curve; the integral of drug level over time from zero to infinity, and is a measure of the quantity of drug absorbed in the body.

Clearance rate; the volume of blood in ml which is completely cleared of the drug per unit time (minute) by urinary excretion or metabolism.

Renal clearance; the hypothetical plasma volume (volume of plasma volume (volume of of unmetabolized drug which is cleared in one minute via the kidney.

Hepatic clearance; the hypothetical plasma volume (volume of distribution) in ml of the metabolized drug which is cleared in one minute via the liver

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