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.