Basic PrinciplesIntroduction

the body of knowledge concerned with the action of chemicals (drugs) on biologic systems

Medical Pharmacology – use of drugs in the prevention, diagnosis, and treatment of disease, especially in humans

Toxicology – undesirable effects of drugs on biologic systems

Pharmacology

Commonly include: inorganic ions nonpeptide organic molecules small peptides and proteins nucleic acids lipids Carbohydrates

Often found in plants and animals Many partially or completely synthetic

THE NATURE OF DRUGS

Vary from MW 7 (Li) to over MW 50,000 (thrombolytic enzymes)

Majority have MW 100-1000

A. Size and MW

Very strong covalent bonds

Weaker electrostatic bonds

Much weaker interactions (H-bonds, van der Waals, hydrophobic bonds)

B. Drug-Receptor Bonds

1. AQUEOUS DIFFUSION – passive movement through the extracellular and intracellular spaces (usually through water-filled pores)

2. LIPID DIFFUSION – passive movement through membranes

MOVEMENT OF DRUGS IN THE BODY (PERMEATION)

3. FACILITATED DIFFUSION – transport by special carriers across barriers

- capacity-limited - may be inhibited

4. ENDOCYTOSIS, PINOCYTOSIS – permit transport of very large (peptides) or very lipid-insoluble molecules or complexes (small, polar molecules combined to special proteins)

MOVEMENT OF DRUGS IN THE BODY (PERMEATION)

Predicts the rate of movement of molecules across a barrier

Rate = (C1 – C2) x Permeability coefficient x Area

Thickness

FICK’S LAW OF DIFFUSION

Weak bases – ionize when protonated; more water-soluble

RNH3+ ⇋ RNH2 + H+

Water-sol. Lipid-sol.

Weak acids – do not ionize when protonated; more lipid-soluble

RCOOH ⇋ RCOO- + H+

Lipid-sol. Water-sol.

IONIZATION OF WEAK ACIDS AND BASES

can predict the fraction of molecules in the ionized state (water-soluble) if the pKa of the drug and the pH of the medium are known

pKa - pH = log Protonated form Unprotonated form

Clinically important when it is necessary to estimate or alter the partition of drugs between compartments of differing pH

HENDERSON-HASSELBALCH EQUATION

“Trapping” is a method for accelerating excretion of drugs.

Nonionized form diffuses readily across the lipid barriers of the nephron

Protonation will occur within the blood and urine

Example: Pyrimethamine – pKa 7.0 >

NH3

NH4+NH4+

NH3

BloodpH 7.4

UrinepH 6.0

Membranes of the nephron

Lipid diffusion

H+

H+

ROUTES OF ADMINISTRATION

Rate and efficiency of absorption differ depending on a (1) drug’s route of administration, (2) blood flow, (3) concentration of drug at site of administration

Bioavailability = The amount absorbed into systemic circulation divided by the amount of drug administered

Oral (swallowed) maximum convenience slower absorption and less complete drugs are subject to first-pass effect (a

significant amount is metabolized in the gut wall, portal circulation, and liver before reaching systemic circulation)

ROUTES OF ADMINISTRATION

Intravenous

Instantaneous and complete absorption Potentially more dangerous if administration

is too rapid (high blood levels is reached)

ROUTES OF ADMINISTRATION

Intramuscular

Often faster and more complete than oral Large volumes may be given if drug is not

too irritating First-pass metabolism is avoided NOT applicable to anticoagulants (heparin)

as this may cause bleeding

ROUTES OF ADMINISTRATION

Subcutaneous

Slower absorption than intramuscular First-pass metabolism is avoided Large-volume bolus doses are less feasible Applicable to heparin

ROUTES OF ADMINISTRATION

Buccal and sublingual

Permits direct absorption into systemic venous circulation

Bypasses hepatic portal circulation and first-pass metabolism

Fast or slow depending on physical formulation of drug

ROUTES OF ADMINISTRATION

Rectal (suppository)

Partial avoidance of first-pass effect (absorption from this location is partially into portal circulation)

May cause significant irritation Drugs with unpleasant tastes may be

administered rectally

ROUTES OF ADMINISTRATION

Inhalation

Offers delivery closest to the target tissue (respiratory diseases)

Rapid absorption Convenient for drugs that are gases at room

temperature (NO, N2O) or easily volatilized (anesthetics)

ROUTES OF ADMINISTRATION

Topical

Application to skin or mucous membrane of the eye, nose, throat, airway, or vagina for local effect

Rate of absorption varies with area of application and drug’s formulation

Usually slower than any of the previous routes listed

ROUTES OF ADMINISTRATION

Transdermal

Involves application to the skin for systemic effect

Absorption usually occurs very slowly First-pass effect is avoided

ROUTES OF ADMINISTRATION

SIZE OF THE ORGAN – determines the concentration gradient between blood and the organ

- larger organs can take up more (eg. muscles)

DETERMINANTS OF DRUG DISTRIBUTION

BLOOD FLOW – determines the rate of uptake, although it may not affect the steady-state amount of drug in the tissue

- well-perfused tissues (eg. brain, heart, kidneys, splanchnic organs) will often achieve high tissue concentrations sooner than poorly-perfused tissues (eg. fat, bone)

DETERMINANTS OF DRUG DISTRIBUTION

SOLUBILITY – influences the concentration of the drug in the extracellular fluid surrounding the blood

- example: some organs (like brain) have a high-lipid content; thus, very lipid-soluble anesthetic will diffuse into the brain tissue more rapidly and to a greater extent than a drug with low lipid-solubility

DETERMINANTS OF DRUG DISTRIBUTION

BINDING – binding of a drug to macromolecules in blood or tissue compartment will tend to increase its concentration in that compartment

DETERMINANTS OF DRUG DISTRIBUTION

Occurs primarily in the liver

Conversion to a metabolite terminates drug action (a form of elimination)

Prodrugs ( eg. Levodopa, minoxidil) are metabolized to become active

Some drugs are not metabolized and continue to act until they are excreted

METABOLISM OF DRUGS

Not the same as drug excretion Excretion is primarily by way of the kidneys,

except anesthetic gases (lungs) Some drugs (diazepam) have active

metabolites For drugs that are not metabolized, excretion

is the mode of elimination A few drugs combine irreversibly with

receptors, so disappearance from the bloodstream is not equivalent to termination of action

ELIMINATION OF DRUGS

FIRST-ORDER ELIMINATION

Rate of elimination is proportionate to concentration

Plasma concentration decreases exponentially with time

Drugs have a characteristic half-life

ELIMINATION OF DRUGS

FIRST-ORDER ELIMINATION

ELIMINATION OF DRUGS

ZERO-ORDER ELIMINATION

Rate is constant regardless of concentration Plasma concentration decreases linearly Typical of ethanol and aspirin at toxic levels

ZER0-ORDER ELIMINATION

PHARMACODYNAMICS Deals with effects of drugs on biologic

systems

RECEPTOR – specific molecules in the biologic system to which a drug binds to bring about change in function of the system

AGONIST – drug that activates its receptor upon binding

EFFECTOR – channel or enzyme that accomplishes the effect after activation by the receptor

INERT BINDING SITE – component to which a drug binds without changing any function

ANTAGONIST – drug that binds to receptor without activating it

PHARMACODYNAMICS

1. Competitive – can be overcome by increasing the dose of the agonist

2. Irreversible – cannot be overcome by increasing the dose of the agonist

3. Physiologic – counters the effects of another by binding to a different receptor and causing opposing effects

4. Chemical - counters the effects of another by binding the drug and preventing its action

5. Partial – binds to its receptor but produces a smaller effect at full dosage than a full agonist

Antagonists

Maximal efficacy (Emax)

The maximum effect an agonist can bring about regardless of dose

Determined mainly by the nature of the receptor and its associated effector system

Efficacy

Dose or concentration required to bring about 50% of a drug’s maximal effect (EC50) – in graded-dose response

Determined mainly by affinity of the receptor for the drug

Typical variables in *quantal dose-response:ED50 – median effectiveTD50 – median toxicLD50 – median lethal

*minimum dose required to produce a specific response in each member of the population

Potency

THERAPEUTIC WINDOW

index of safety

Dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose.

Eg. Theophylline: 8 – 18 mg/mL

Distribution - the process by which a drug diffuses or is transferred from intravascular space to extravascular space (body tissues). These spaces are described mathematically as volume(s) of distribution.

Volume of distribution is that volume of bodily fluid into which a drug dose is dissolved

PHARMACOKINETICS

The body is usually divided into two spaces, a central and a tissue compartment.

Central volume (Vc) = blood in vessels and tissues which are highly perfused by blood.

Vc = Dose / Peak serum level

Peak = Dose / Vc

DISTRIBUTION

Peripheral volume (Vt) = sum of all tissue spaces outside the central compartment

Vc + Vt = Vd

Distribution volumes are important for estimating: Amount of drug in the body, Peak serum levels, and Clearance

DISTRIBUTION

Volume of distribution (Vd)

Vd = Amount of drug in the body

Plasma drug concentration

Clearance (CL)

CL = Rate of elimination of drug Plasma drug concentration

DISTRIBUTION

PHASE I REACTIONS- oxidation, reduction, deamination, and

hydrolysis

PHASE II REACTIONS - synthetic reactions that involve addition (conjugation) of subgroups to –OH, -NH2, and –SH on the drug molecule;

- subgroups include glucoronate, acetate, glutathione, glycine, sulfate, and methyl groups

DRUG METABOLISM: Types

Liver

Kidneys

Other tissues (blood, intestinal wall)

DRUG METABOLISM: Sites