Principles Pharmacology

Assist Prof
Mohammad T. Naqi
Definition of Basic Terms
Drug
• Simply – a drug is a chemical or substance that causes changes in the
structure or function of living organisms
• Medicine
• A medicine is the vehicle for administration of the drug (active
ingredient) to the human or animal e.g. tablet, capsule, injection,
ointment, inhaler, suppository etc.
• Does This Apply to Foods/Minerals etc.? Obviously, they are not
‘drugs’ in the conventional use of the term however, from a
prescribing perspective, many are regarded as ‘medicines’
• In addition, all prescribers should have a general understanding of
pharmacology and pharmacokinetics as their patients will be on a
range of medications
• Pharmacology:-Simply: the science of drug actions and uses
• Pharmacodynamics: - Mechanisms of action (“what the drug
does to the body”)
• Pharmacokinetics:-Literally, movement of the drug within
the body (“what the body does to the drug”)
• Toxicology:-Manifestation of the harmful effects of the drug
after exposure to high levels (“intoxication” or “poisoning”)
• Therapeutics:-Use of drugs for intended clinical benefits –
cure of a disease, relief of symptoms etc.
Sources of Drugs

1. Plant sources e.g. morphine, atropine, some vitamins

2. Animal sources e.g. thyroxine, insulin
3. Mineral sources e.g. lithium, magnesium
4. Microorganisms e.g. penicillins, cephalosporins
5. Synthetic e.g. benzodiazepines, phenothiazines, some vitamins
6. Bioengineered (recombinant DNA technology) e.g. human insulin,
human growth hormone
Drug name
• 1-Chemical name
• Standardized internationally chemically e.g. salicylic acid
• 2-Generic name
• Standardized internationally recognized name for a drug e.g. ferrous
sulfate, metoprolol, omeprazole, ibuprofen etc. (Some exceptions in
US e.g. paracetamol = acetaminophen)
• 3-Trade or Brand name
• Name given by the manufacturer e.g. Ferrogradumet (ferrous sulfate),
Ventolin® (salbutamol)
Pharmacodynamics
Basic Principles
• Mechanism of action of drugs: - Specific molecular
processes by which drugs work, e.g. inhibition of an enzyme
or stimulation of a receptor sub-type
• Mode of action of drugs: - General description of the type of
action: e.g. supplements, antihypertensive, analgesics
• Site of action of drugs:-Specific organs, tissues or cells
affected by the drug: e.g. sensory neurons; myocardium,
bronchi, etc.
• How Do Drugs Work (Mechanism of Action)?
• Fundamental premise of pharmacodynamics is ‘drug-
receptor interactions’ within the organs of the body
are specific receptors with which specific drugs can
interact
• The analogy often used is ‘lock and key’: only drugs
(chemicals) with the ‘correct’ molecular shape can
interact with a particular receptor
Receptor sites

• Where are receptors (drug targets) found?

1. Cell membranes – usually associated with ion channels, transducer
proteins or enzymes
2. Cell nucleus
3. Enzymes (many vitamins are co-factors)
4. Carrier molecules
Drug Receptors and Pharmacodynamics
• The action of a drug on the body, including receptor
interactions, dose-response phenomena, and
mechanisms of therapeutic and toxic action.
• Many drugs inhibit enzymes control a number of metabolic
processes
A. A very common mode of action of many drugs
B. In the patient (ACE inhibitors)
C. In microbes (sulfas, penicillins)

• Some drugs bind to:

A. Proteins (in patient, or microbes)
B. The genome (cyclophosphamide)
• Most drugs act (bind) on receptors
A. In or on cells
B. Form tight bonds with the ligand
C. Exacting requirements (size, shape,
stereospecificity)
D. Can be agonists (salbutamol), or antagonists
(propranolol)
E. Receptors have signal transduction methods
Types of Protein Receptors
1. Regulatory – change the activity of cellular enzymes
2. Enzymes – may be inhibited or activated
3. Transport – e.g. Na+ /K+ ATP’ase
4. Structural – these form cell parts
Agonists and Antagonists
• Agonists stimulate receptors For example, salbutamol
(Ventolin®) is a beta-receptor stimulant; stimulation of
beta-receptors in the lungs causes bronchodilation
Agonists and Antagonists
• Antagonist (‘blocker’); blockade of beta-receptors in
the heart will slow rate and be ‘cardiprotective’. Note
that by blocking the beta-receptors in the lungs ‘beta-
blockers’ can cause bronchoconstriction in asthmatics
etc.
Partial Agonist
 Mechanism of Action of
Minerals/Vitamins/Supplements

• Not classic Agonists/Antagonists at specific receptors

Generally, they are replacing or supplementing body stores,
or enhancing effects in certain diseases and disorders
Generally, they are co-factors or essential elements in normal
metabolic and physiological processes You will already have
much more knowledge than us of specific actions and effects
Affinity and Efficacy
• Affinity refers to the drug’s forces that cause a
substance to bind its receptor

• Efficacy refers to a drug's ability to effectively activate

the receptor once it has bound to it
Pharmacokinetics
“What the body does to the drug”
Usually described by the acronym ADME:
• 1. Absorption
• 2. Distribution
• 3. Metabolism
• 4. Excretion
Absorption
• Refers to the processes whereby the drug reaches the
bloodstream (systemic circulation) Other than by the
intravenous route, or for agents designed to have a
direct local effect, drugs must first be absorbed into
the circulation before they can be distributed to the
site of action
Absorption
• Requires the drug to pass through cells and cell membranes
to reach the bloodstream (e.g. in G.I.T. tract, across the skin,
across mucous membranes etc.) Cell membranes are
comprised of phospholipids and are essentially lipid (fatty)
sheets
• In general, drugs must be in a lipid-soluble form in order to
be absorbed (there are exceptions including minerals and
some vitamins
Absorption

Factors Influencing Oral Absorption

• The concentrate on oral absorption because it is the
main route of drug delivery, but the same basic
principles apply to other routes
Drug Absorption (Gastrointestinal Tract)
methods
1-Passive diffusion (major mechanism): lipid-soluble drugs will
passively diffuse across membranes on concentration gradient
e.g. fat-soluble vitamins A, D, E, and K
2-Active transport: for a small number of drugs using carrier
molecules in the membrane – can work against a
concentration gradient (for example Vitamin B12, iron)
3-Filtration through pores (especially for small water-soluble
molecules such as glucose, ions such as sodium, magnesium
etc.)
1-Passive diffusion
2-Active transport
3-Filtration through pores
First Pass Effect
• Extent of metabolism that occurs before drug enters the
systemic circulation. Includes metabolism in the gut lumen,
gut wall, and lungs; main site, however, is the liver
• All blood from G.I.T. tract drains through the portal vein to
liver before it reaches systemic circulation (‘first-pass’)
• First-pass and other pre-systemic metabolism is a very
important determinant of oral bioavailability especially for
lipid soluble drugs
First Pass Effect
Drug Distribution
• Distribution describes the reversible transfer of drug from the
bloodstream to the various other tissues and organs of the body

• Water-soluble vitamins and minerals will rapidly distribute to the

extracellular fluid and be taken up by cells.
• Lipid-soluble vitamins will follow passive diffusion (as for absorption)
• Like absorption, most drugs follow passive diffusion along a
concentration gradient
Drug Distribution
• Diffusion as reversible: when tissue levels of the drug exceed those in
ECF and circulation, then the drug will passively diffuse back to the
bloodstream Extent of distribution also depends on:

• 1- The perfusion of the tissue (circulation) – well perfused tissues

generally no problems with distribution
• 2- The existence of any ‘special’ physiological barriers (e.g. blood-
brain barrier)
Distribution: Special Barriers
• 1-‘Blood-brain barrier’ excludes a number of drugs, esp. more water
soluble e.g. dopamine, atenolol, some water soluble-vitamins BBB not
a discrete anatomical structure but specialized collection of cells in
CNS with ‘tight junctions’ that exclude certain substances Highly Lipid-
soluble drugs penetrate BBB readily Cerebrospinal fluid (CSF) normally
impenetrable to antibiotics (e.g. penicillins) – except when inflamed
• 2-Some tissues have poor perfusion e.g. bone and nails – for example
very difficult to treat infections
Metabolism (Biotransformation)
• Alteration of a drug by the body to one or more chemically different
molecules termed metabolites
• Regulated by enzymes in many tissues e.g. gut, skin, lungs, but
predominant organ of metabolism is the liver
• Main purpose of metabolism is to prepare the molecule for excretion
(i.e. make it more water-soluble) for minerals and water-soluble
vitamins metabolism may not be required, they are excreted
unchanged
Metabolism (Biotransformation)
• Phase I Metabolism
• Chemical conversion to a metabolite by hydrolysis, reduction,
oxidation etc.
• Most metabolites are inactive pharmacologically, however some
drugs may produce active metabolites, some inactive drugs may
produce an active metabolite (known as ‘pro-drugs’)
Phase I Metabolism
Metabolism (Biotransformation)
• Phase II Metabolism
• Addition of another chemical structure by conjugation (joining
together) e.g. glucuronic acid, sulphate (example morphine
glucuronide)
• These conjugates are very water-soluble Conjugation increases the
water solubility of the drug and prepares it for excretion
Phase II Metabolism
Metabolism (Biotransformation)
• Most drugs undergo both Phase 1 and Phase 2 metabolism to
produce a range of metabolites; however, some may undergo only
Phase 1 or Phase 2
• Some drugs may be excreted unchanged (i.e. without
biotransformation) – especially if they are already water-soluble e.g.
atenolol and of course many vitamins (e.g. Vitamin C) and minerals
Excretion (Kidney)
Some drugs excreted via lungs, skin etc., but main
organ of excretion is the kidney
Three phases of drug removal from the blood via
the kidney:
• 1. Filtration at the glomerulus
• 2. Active secretion into the proximal tubule
• 3. Passive diffusion (reabsorption) from urine
back to blood along the length of the renal
tubule
 Most drugs and metabolites are filtered at the
glomerulus and enter the filtrate in the nephron, Some
drugs are not filtered but may meet the requirements
for active secretion from the arterioles into the
nephron at the proximal tubule If filtered drug or
metabolite is lipid soluble, it is reabsorbed back into
the bloodstream by passive diffusion; if it is water
soluble it is excreted in urine