1

Basic principles of Pharmacology

&Pharmacokinetics

Memy H. Hassan, PhD Associate Professor of

Pharmacology &Toxicology

College of Pharmacy,

Taibah University

Manar Nader, PhD Associate Professor of

Pharmacology &Toxicology

College of Pharmacy,

Taibah University

Lecture ILOs • To demonstrate basic knowledge of

pharmacology principles

• To demonstrate basic knowledge of drug

pharmacokinetics

• TOPICS COVERED IN THIS LECTURE

• Basic principles of pharmacology.

• Basic principles of pharmacokinetics

• Clinical Pharmacokinetics

INTRODUCTION • Pharmacology : Studying drugs & their effect on living systems.

• Drug is a chemical substance of known structure when

administered to a living organism, produces a biological effect.

• Drug is used in treatment, prevention, diagnosis or amelioration of

diseases.

• Drugs can be stimulatory or inhibitory

• A drug is the active ingredient in a medicine

• A medicine is a chemical preparation (tablete, capsule, or ……..),

which usually but not necessarily contains one or more drugs,

administered with the intention of producing a therapeutic effect.

DRUG NOMENCLATURE

1.The full chemical name. It describes the compound for

chemists. It is unsuitable for prescription

2. A nonproprietary (official, approved, generic)

name. this is given by an official (pharmacopoeia) such

as WHO.

3. The proprietary name is a trade mark applied to a

particular formulation(s) of a particular substance by a

particular manufacturer.

● one drug three names

TYPES OF DRUG REGULATIONs

1. OVER THE COUNTER (OTC):

•These are drugs which are available at pharmacies with out the

prescription of a doctor eg. Paracetamol

2. PRESCRIPTION DRUGS:

•Drugs which can be available only with the written order by the

qualified/registered medical practitioner e.g. antihypetensive drug like

atenolol

3. CONTROLLED DRUGS:

•only available in special cases, which are only written by specialists

(consultants) doctors who are allowed to e.g Opioid derivatives like

morphine; Tranquilizers like diazepam

Pharmacodynamics • Is what the drug does to the body.

• Study of biochemical and physiological effects of drugs and their mode of action ( MOA).

See previous lecture

Pharmacokinetics

(ADME) • Is what the body does to the drug Including:

1. Absorption

2. Distribution

3. Metabolism

4. Execration

Pharmacokinetics I- Drug absorption

• Defined as the passage of a drug from its site of

administration into the plasma.

• Important for all routes of administration, except

intravenous injection.

• The movement of drug molecules across cell barriers occurs by:

1. Diffusing directly through the lipid

2. Diffusing through aqueous pores

3. Aid of carrier protein

4. Pinocytosis

Oral administration • Drug absorption from the intestine mainly

• For local effect (minor) or systemic effect (major)

• Advantages

– Convenient - can be self- administered, pain free, easy to take

– Absorption - takes place along the whole length of the GI tract

– Cheap - compared to most other parenteral routes

• Disadvantages – Sometimes inefficient - only part of the drug may be absorbed

– First-pass effect

– Irritation to gastric mucosa - nausea and vomiting

– Destruction of drugs by gastric acid and digestive juices

– Effect too slow for emergencies

– Unpleasant taste of some drugs

– Unable to use in unconscious patient

Sublingual administration • Placing medicine beneath the tongue

• Glyceryl trinitrate is an example

• Advantages – Rapid absorption

– Drug stability

– Avoid first-pass effect

– Toxicity could be prevented easily

• Disadvantages – inconvenient

– small doses

– unpleasant taste of some drugs

Rectal administration

• To produce a local effect or systemic effects

• Unreliable absorption

• May escape first pass metabolism

• Avoid destruction by stomach juice

• Useful in patients who are vomiting or are uncooperative

Application to epithelial surfaces

• Cutaneous administration: local on the skin

Transdermal: drug is incorporated in a stick-on

patch applied to the skin e.g. oestrogen .

• Nasal sprays: Absorption takes place through

mucosa overlying nasal-associated lymphoid tissue.

• Eye drops: relying on absorption through the

epithelium of the conjunctival sac for example,

dorzolamide.

Administration by inhalation

• The lung serving as the route of both administration and

elimination.

• Usually as an aerosol.

• Advantage :

• Rapid onset of action due to rapid access to circulation

• High local concentrations in the lung while minimizing

systemic side effects e.g. Glucocorticoids and

bronchodilators

Administration by injection • A. Intravenous injection (I.V.) is the fastest and

most certain route of drug administration.

• Absorption phase is bypassed (100% bioavailability)

1.Precise, accurate and almost immediate onset of action,

2. Large quantities can be given, fairly pain free

3. Greater risk of adverse effects

B- Intramuscular (IM):Very rapid absorption of drugs in aqueous

solution

•Storage and slow release preparations

•Pain at injection sites for certain drugs OOH MY GOD

C- Subcutaneous (SC): slower than the IV &IM injection,

minimizes the risks associated with intravascular injection

D- Intrathecal injection :

Injection of a drug into the subarachnoid space via a lumbar

puncture needle is used for some specialized purposes such as

regional anesthesia with bupivacaine

• intravenous 30-60 seconds

• inhalation 2-3 minutes

• sublingual 3-5 minutes

• rectal 5-30 minutes

• intramuscular 10-20 minutes

• subcutaneous 15-30 minutes

• ingestion 30-90 minutes

• transdermal (topical) variable (minutes to hours)

Route for administration

-Time until effect-

Bioavailability (F) • Is used to indicate the fraction of an administered dose that

reaches the systemic circulation as intact (unchanged) drug.

• taking into account both absorption and local metabolic

degradation.

• the fraction absorbed following an intravenous dose is 1 by

definition (100%)

• F is measured by determining the plasma drug concentration

versus time curves

• The areas under the plasma concentration time curves (AUC)

are used to estimate F

intravascular (intravenous or intra-arterial), intramuscular, and subcutaneous (see Figure 1.2). Each route has advantages and drawbacks.

Bioequivalence

• Two related drugs are bioequivalent if they show comparable

bioavailability and similar times to achieve peak blood

concentrations.

Therapeutic equivalence

• Two similar drugs are therapeutically equivalent if they have

comparable efficacy and safety.

• The pattern of distribution depends on:

1. Permeability across tissue barriers

2. Binding within compartments such as plasma protein

3. pH partition 4. Fat: water partition

5. Blood flow

•Lipid-soluble drugs reach all compartments and may accumulate in

fat.

•Lipid-insoluble drugs can not pass the barriers and mainly confined to

plasma and interstitial fluids .

• is the process by which a drug reversibly leaves the bloodstream

and enters the interstitium (extracellular fluid) and/or the cells of

the tissues.

II- Distribution of drugs in the body

Drug distribution •Volume of distribution (Vd): is a hypothetical volume of

fluid into which a drug is dispersed.

•useful to compare the distribution of drugs

•For drugs that accumulate outside the plasma compartment

(e.g. in fat or by being bound to tissues), Vd is very high and

may exceed total body volume.

Binding of drugs to plasma proteins

• Reversible

• relatively nonselective

• Pharmacologically inactive

• Plasma albumin is the major drug-binding protein

• May act as a drug reservoir maintains the free-drug concentration

• Site for drug interaction

• Sequesters drugs in a non diffusible form and slows their transfer

out of the vascular compartment.

• Binding is Takes place at sites on the protein to which endogenous

compounds, such as bilirubin, normally attach.

• By two processes: metabolism and excretion.

• Metabolism (Biotransformation) involves enzymic

conversion of one chemical entity to another within the

body. It occurs mainly in liver

• Excretion consists of elimination of chemically

unchanged drug or its metabolites from the body mainly

via

1. The kidneys

2. The hepatobiliary system

3. The lungs

III- Elimination

The irreversible loss of drug.

Drug metabolism • The process of metabolism transforms lipophilic drugs into

more polar readily excreatable products.

• The liver is the major site for drug metabolism, by many

hepatic drug-metabolizing enzymes, including CYP enzymes

• Specific drugs may undergo biotransformation in other

tissues, such as

1. Plasma (e.g. hydrolysis of suxamethonium by plasma

cholinesterase

2. Lung e.g. various prostanoids

3. Gut e.g. tyramine, salbutamol

• Includes : phase I and phase II reactions

Drug metabolism contd. • Phase I reactions are catabolic (e.g. oxidation, reduction or

hydrolysis)

• Convert lipophilic molecules into more polar molecules by

introducing or unmasking a polar functional group, such as “OH or

“NH2.

• Phase I metabolism may increase, decrease, or leave unaltered the

drug's pharmacologic activity

Implications for drug phase I metabolism

1. Termination of drug action (Inactivation) (main effect)

2. Modification of Pharmacological actions:Terfenadine H1

receptors & cardiac potassium channels . Its pharmacologically

active metabolite (fexofenadine) blocks H1 but not cardiac

potassium channels

3. Activation of prodrug: Prodrugs: ex. azathioprine , is

metabolised to mercaptopurine

4. Bioactivation and toxication . e.g metabolite of paracetamol

5. Carcinogenesis: Benzo -A- pyren

5. Tetratogenesis

Phase II Metabolism

D+ENDOX DX+ENDO

• Phase II reactions are synthetic ('anabolic') and involve

conjugation, which usually results in almost always

pharmacologically inactive and less lipid-soluble than its

precursor, and is excreted in urine or bile

• A molecule endogenous to the body donates a portion of

itself to the foreign molecule

PHASE II REACTIONS Glucuronidation, Sulfate Conjugation, Acetylation,

Glycine Conjugation, Methylation, Transulfuration,

Glutathione Conjugation, Mercapturic Acid

Synthesis

Patterns of Drug Metabolism

• Some drugs are not metabolized, for example, gallamine and

atracurium undergoe spontaneous hydrolysis.

Factor affecting drug metabolism • Age

• Genetic factor

• Enzyme induction and inhibition: drugs such as

ketoconazole causing inhibition leading to higher

blood levels and the potential to increase therapeutic

and/or toxic effects of the drugs .A number of drugs,

such as rifampicin, and carbamazepine induce the

activity of microsomal oxidase resulting in lower

blood levels and the potential to decrease therapeutic

and/or toxic effects of the parent drugs

• Liver health

Biliary excretion and enterohepatic circulation

• Various hydrophilic drug conjugates (particularly

glucuronides) are concentrated in bile and delivered to

the intestine, where the glucuronide is usually

hydrolysed, releasing active drug once more; free drug

can then be reabsorbed and the cycle repeated

(enterohepatic circulation).

• The effect of this is to create a 'reservoir' of recirculating

drug and prolongs drug action.

• Examples where this is important include morphine

First-pass (presystemic) metabolism

• Is the removal ( extraction) of some drugs by the

liver or gut wall hence the amount reaching the

systemic circulation is considerably less than the

amount absorbed.

• first-pass or presystemic metabolism reduces

bioavailability even when a drug is well

absorbed from the gut.

• A much larger dose of the drug is needed

specially by mouth

DRUG EXECRETION

• Excretion consists of elimination from the body of

chemically unchanged drug or its metabolites

mainly via

1.The kidneys

2.The hepatobiliary system

3.The lungs

4.Minor routes ex. Mother milk, seweeting

Renal excretion of drugs and drug metabolites

• Three fundamental processes account for renal

drug excretion:

1. Glomerular filtration : allow non plasma protein

bound drug molecules of molecular weight below

about 20000 to diffuse into the glomerular filtrate.

2. Active tubular secretion: using non-selective

carrier systems.

3. Passive diffusion across tubular epithelium

(reabsorbtion).

Tubular secretion • Two independent and relatively non-selective carrier systems.

1. One transports acidic drugs (as well as various endogenous

acids, such as uric acid),

2. The other handles organic bases.

• Transport drug molecules against an electrochemical gradient

• the most effective mechanism of renal drug elimination.

• even when most of the drug is bound to plasma protein e.g.

Penicillin.

• Many drugs compete for the same transport system, leading to

drug interactions. For example, probenecid inhibits penicillin

secretion.

Renal clearance, total body clearance& half life

• Renal clearance (CLr) : Defined as the volume of plasma

containing the amount of substance that is removed by the

kidney in unit time

• The total body (systemic) clearance, CLtotal or CLt, is the

sum of the clearances from the various drug-metabolizing

and drug-eliminating organs.

• Drug half-life (tl/2): is the time required to reduce the

plasma concentration of drug to half the initial

concentration (the time for 50% elimination).

LECTURE RESOURCES

• Harvey R. A. (2012). Lippincott's Illustrated Reviews: Pharmacology. 6th ed., Philadelphia, PA, USA, Lippincott Williams& Wilkins. Unite 1; chapter 1.

• Katzung B.G. (2015), Basic and Clinical Pharmacology, 13th ed., New York, USA, McGraw-Hill Medical. Section I; chapters 3-4.