Is the passage of drug from its site of administration to its site of action through cell membranes.

Sites of Administration

Sites of action

Cell membrane

Sites of Administration

Absorption & distribution Elimination

The transport of drugs across membranes occurs through one or more of the following processes:

1. Simple diffusion = passive diffusion.

2. Active transport.3. Facilitated diffusion.4. Pinocytosis (Endocytosis).

water soluble drug (ionized or polar) is readily absorbed via diffusion through aqueous channels or pores in cell membrane.

Lipid soluble drug (nonionized or non polar) is readily absorbed via diffusion through lipid cell membrane itself.

Characters common.Occurs along concentration gradient. Non selective Not saturable Requires no energy No carrier is neededDepends on lipid solubility. Depends on pka of drug - pH of medium.

Drugs exist in two forms ionized (water soluble) nonionized forms (lipid soluble) in equilibrium. Drug ionized form + nonionized

form Only nonionized form is absorbable. Nonionized / ionized fraction is determined by pH and pKaAs general basic drugs are more ionized and less diffusible in a relatively acidic medium, on the contrary basic are more lipid soluble and more diffusible in a relatively alkaline medium

PKa of the drug(Dissociation or ionization constant): pH at which half of the substance is ionized & half is unionized.

The lower the pKa value (pKa < 6) of the acidic drug the stronger the acid e.g aspirin (Pka= 3.0 )

The higher the pKa value (pKa >8) of a basic drug, the stronger the base e.g propranolol ( pKa= 9.4)

PKa of the drug(Dissociation or ionization constant):pH at which half of the substance is ionized & half is unionized.

pH of the medium

Affects ionization of drugs.◦Weak acids best absorbed in stomach.◦Weak bases best absorbed in intestine.

Which one of the following drugs will be best absorbed in stomach (pH=3)?

Aspirin pka=3.0 warfarin pka=5.0

Arrange the following drugs in ascending order from least to greatest in rate of absorption in small intestine (pH=7.8)?

Propranolol pka= 9.4 Aspirin pka=3.0

Relatively unusual.Occurs against concentration gradient.

Requires carrier and energy.Specific Saturable.eg. Sugar, amino acids and Iron absorption.

Uptake of levodopa by brain.

Occurs along concentration gradient.

Requires carriers Selective. Saturable. No energy is required.

Passive transportActive transport

along concentration gradient

(From high to low)

against concentration gradient

(From low to high)

No carriersNeeds carriers

Not saturablesaturable

Not selectiveSelective

No energyenergy is required

Active transportCarrier-mediated facilitated diffusion

Against concentration gradient

(From low to high)

along concentration gradient

(From high to low)

Needs carriersNeeds carriers

saturablesaturable

SelectiveSelective

Energy is requiredNo energy is required

Endocytosis: uptake of membrane-bound particles.

Exocytosis: expulsion of membrane-bound particles.

Phagocytosis occurs for high molecular weight

Drugs or highly lipid insoluble drugs.

OUTINOUT IN

Prof. Hanan HagarDr. Ishfaq Bukhari

Pharmacology Department

By the end of the lectures, students should be able to define the following:

Major body fluid compartments Concept of compartments. Apparent volume of distribution (vd). Plasma protein binding. Tissue binding.

Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action (therapeutic effect)

Bioavailability (F) = AUC (oral) X 100 AUC (I.V.)

I.V. provides 100% bioavailability i.e. F= 1. Subcutaneous, intramuscular, oral, rectal, and other extra vascular routes of administration require that the drug be absorbed first, which can reduce bioavailability.

The bioavailability of a drug after administration by any route is compared to its intravenous standard formulation.

is determined when two products are compared to each other, not to an intravenous standard.

This is commonly calculated in the drug industry to determine that the generic formulation is bioequivalent to another formulation.

e.g Tylenol (paracetamol 500 mg) compared to panadol (paracetamol 500 mg).

is important to get an idea of how different formulations or routes of administration differ in their bioavailability.

dosage adjustment is required when changing formulations or routes of administration.

Two drug products are considered to be bioequivalent when the rates and extents of bioavailability of the two products are not significantly different under suitable test conditions.

Rate and extent means the amount of drugs and the time required reaching the systemic circulation.

Factors affecting bioavailability:

are the same factors controlling drug absorption

GENERAL FACTORS lipid solubility Degree of ionization Drug solubility (aqueous sol better than oily,susp,sol) Dosage forms (depending on particle size and

disintegration) Concentration of drugs Circulation at site of absorption Area of absorbing surface (small intestine has large

surface area) Route of administration.

Is the process by which drugs leave blood

circulation and enters the interstitium

and/or the cells of the tissues.

Sites of Administration

Absorption & distribution Elimination

Total body fluids (70% of body weight in 70-kg individual)

Plasma (4 L)

Interstitial fluids (10 L) Intracellular volume ( 28 L)

Total body Fluids

(42 Liters)

is the ratio of drug amount in the body to the concentration of drug in blood

Vd (L)= Dose of the drug (mg) concentration in blood (mg/L)

Large Vd = means long duration of action

FACTORS AFFECTING DISTRIBUTION

1.Cardiac output and blood flow. 2. Physiochemical properties of the drug.

◦Molecular weight◦Pka.◦Lipid solubility.

3. Capillary Permeability 4. Plasma protein binding 5. Tissue binding.

The greater the blood flow to tissues, the more distribution that occurs from plasma to interstitial fluids.

Drugs distribute more rapidly to brain, liver and kidney > more than skeletal muscles & fat.

Most lipid soluble drugs cross biological membranes

Hydrophilic drugs do not readily cross membranes but go through slit junctions

Drugs with high Vd

Have higher concentrations in tissues

than in plasma.

Relatively lipid soluble.

Distributed intracellularly

Not efficiently removed by

haemodialysis.

e.g. phenytion, morphine, digoxin

Drugs with low Vd confined to plasma & interstitial fluid. distributed in extracellular

compartments. Polar comp or lipid insoluble drugs. e.g.

Carbenicillin, vecuronium, gentamycin. High MW e.g. heparin – insulin. High plasma protein binding e.g. warfarin. Do not cross BBB or placental barriers.

Endothelial cells of capillaries in tissues other than brain have wide slit junctions allowing easy movement & distribution.

Brain has tight junction Blood Brain Barrier (BBB).

Blood brain barrier (BBB): Only lipid soluble drugs or actively

transported drugs can cross BBB. Hydrophilic drugs (ionized or polar drugs)

can not cross BBB. Inflammation as in meningitis increase

permeability to hydrophilic drugs e.g. penicillin & gentamycin

Placental barrier Lipid soluble drugs can cross placental

barrier and enter the fetal blood.

Binding of Drugs

◦Plasma proteins binding.

◦Tissue proteins binding.

Plasma Proteins

Albumin

Has affinity for acidic drugs as warfarin,

phenytoin, aspirin

GlycoproteinHas affinity for basic drugs (cationic) as diazepam, quinidine.

Plasma protein binding

Drugs can bind to plasma proteins (acidic drug bind to albumin while basic drugs bind to glycoprotein)

Drugs exist in two forms bound and unbound forms in equilibrium Unbound drug (free) bound drug

Drugs can bind to specific tissue

Tetracycline bind to bone

Iodides accumulate in salivary & thyroid glands

Bound form of drug

non diffusible form can not combine with receptors inactive not available for metabolism & excretion

has long duration of action (t ½).

Unbound form of drug

diffusible form combine with receptors

active available for metabolism & excretion

has short duration of action (t ½).

Binding of drugs and its effect on drug action

Usually reversible. determines volume of distribution (vd) Slows drug metabolism & excretion. Prolongs duration of drug action (t1/2). Result in clinically important drug

interactions.