Pharmacology and Therapeutics

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Pharmacology and Therapeutics

Introduction 1
UNIT I: Introduction to Pharmacology and Therapeutics

This is an introductory unit to understanding pharmacology and therapeutics.
It gives an overview of the definitions of terms in pharmacology, and considers some of the general principles and concepts in pharmacology and therapeutics

Unit Objectives
By the end of this unit, you will have achieved the following objectives;
1.Definitions of terminologies, 2.Sources of drugs,
3.General principles and concepts in pharmacology and therapeutics,
4.Formulations/preparations of drugs,
5.Classification and naming of drugs,
6.Routes of drug administration,
7.The concept of essential drugs and rational use of drugs,
8.Pharmacy and Poisons Act & Dangerous Drugs Act,
9.Principles of drug prescribing.

Definition of terms and concepts
Pharmacology and therapeutics 4 Definitions
 

Pharmacology

The science that deals with drugs. i.e. the study of drugs.
The study of substances that interact with living systems through chemical processes especially by binding to regulatory molecules and activating or inhibiting body processes
Definitions…   

Drug

Is any substance that brings about a change in biologic function through its chemical actions. WHO definition: a drug is any substance or product that is used or intended to e used to modify or explore physiological systems or pathological states for the benefit of the recipient. A drug is any chemical compound that may be used as a medicament to prevent or cure disease.
Definitions…   

Therapeutics

The branch of medicine concerned with the cure of disease or relief of symptoms, and includes drug treatment.

Pharmacy

The science concerned with identification, selection, preservation, standardization, compounding and dispensing of medicinal substances.

Pharmacognosy

This is the science of identification of drugs Definitions…
   

Pharmacokinetics

Is the study of the processes whereby drug concentrations at effecter sites are achieved, maintained, and diminished. i.e. the study of the absorption, distribution, metabolism, and excretion of drugs. It deals with what the body does to drugs. Pharmacodynamics Is the study of the biological and therapeutic effects of drugs on the body. i.e. actions upon cells, tissues or organs. What the drugs do to the body. Definitions…
 

Pharmacogenomics (pharmacogenetics)

Is the study of the genetic variations that cause differences in drug response among individuals. The scientific study of the relationship between genetic factors and the nature of response to drugs. Definitions…

 

Pharmacology and genetics…

Individuals with inherited diseases have a heritable abnormality in their DNA. It is possible to correct abnormality by gene therapy i.e. insertion of an appropriate healthy gene into somatic cells. Some patients respond to certain drugs with greater than usual sensitivity to standard doses. Increased sensitivity is due to a very small genetic modification that results in decreased activity of a particular enzyme responsible for eliminating that drug.

1 Definitions … 

Chemotherapy

This is the use of a specific chemical agent to arrest or eradicate microorganisms and parasites living and multiplying in a living organism without causing irreversible injury to healthy tissues. It also includes the treatment (therapy) of cancer. 1 Definitions…    
▪ ▪ ▪

Pharmacopoeia

An official code containing a selected list of the established drugs and medicinal preparations with descriptions of their physical properties and tests for their identity, purity and potency. It defines the standards that these preparations must meet, and their average doses for an adult. Every pharmacopoeia also includes a list of drugs added in that particular edition and a list of deleted drugs.
Examples of pharmacopoeias:
British Pharmacopoeia (B.P)
Indian Pharmacopoeia (I.P)
United States Pharmacopoeia (U.S.P)
1 Definitions…  

Toxicology

Is the branch of pharmacology which deals with the undesirable effects of chemicals on the living systems from individual cells to complex ecosystems. The science of poisons. Includes measurement and detection of poisons, as well as treatment of poisoning. Many drugs in larger doses act as poisons. 1 Definitions…

Receptor
- specific molecules in biologic system that interact with drug molecule

Hormones
-drugs synthesized within the body and released into circulation acting far away from their place of origin

Xenobiotics
- drugs/chemicals synthesized outside the body. Chemical substances foreign to animal life, e.g. plant constituents, drugs, pesticides, etc. (xeno =foreign, biotic =pertaining to life)

Poisons
- are drugs that have almost exclusively harmful effects

Toxins
- are poisons of biologic origin i.e. synthesized by plants or animal Definitions…

 

Metabolism of drugs

The process of chemical alteration of drugs in the body.

Biological lag

This is the time between the administration of a drug and the development of response. Definitions…   

Bioavailability of a drug

This is the fraction of the drug dose that reaches the systemic circulation.

Biological half-life of a drug

This is the time required to reduce the concentration of a drug in the body compartments by 50%.

Drug interactions

The actions of one drug upon the effectiveness or toxicity of another or others.

NB: A drug is a single chemical substance that forms the active ingredient of a medicine ( a substance or mixture of substances used in restoring or preserving health)

A medicine may contain many other substances to deliver the drug in a stable form, acceptable and convenient to the patient.

The terms are often used interchangeably for convenience.
The end. Thank you
D.OUMA.OTIENO 18
Sources of Drugs
Drugs are obtained from six major sources:

1.Plant sources
2.Animal sources
3.Mineral sources
4.Microbiological sources (microorganisms)
5. synthetic sources/ Synthetic sources
6.Recombinant DNA technology

Plant Sources

Plant source is the oldest source of drugs.
Most of the drugs in ancient times were derived from plants.
Almost all parts of the plants are used i.e.

leaves,
stem,
bark,
fruits and
roots.

Leaves:
a. The leaves ofDigitalis Purpurea are the source of Digitoxin and Digoxin, which are cardiac glycosides.

b. Leaves of Eucalyptus give oil of Eucalyptus, which is important component of cough syrup.

c. Tobacco leaves give nicotine.

d. Atropa belladonna gives atropine

Flowers:
Poppy papaver somniferum gives morphine (opioid)
Vinca rosea gives vincristine and vinblastine
Rose gives rose water used as tonic.

Fruits:
Senna pod gives anthracine, which is a purgative (used in constipation)
Calabar beans give physostigmine, which is cholinomimetic agent.
Seeds: Seeds of Nux Vomica give strychnine, which is a CNS stimulant.
Castor oil seeds give castor oil.
Calabar beans give Physostigmine, which is a cholinomimetic drug

Roots: Ipecacuanha root gives Emetine, used to induce vomiting as in accidental poisoning. It also has amoebicidal properties.
Rauwolfia serpentina gives reserpine, a hypotensive agent. Reserpine was used for hypertension treatment.

Bark:
Cinchona bark gives quinine and quinidine, which are antimalarial drugs. Quinidine also has antiarrythmic properties.
Atropa belladonna gives atropine, which is anticholinergic.
Hyoscyamus Niger gives Hyosine, which is also anticholinergic.

Stem:
Chondrodendron tomentosum gives tubocurarine, which is skeletal muscle relaxant used in general anesthesia

Pharmacologically active principles in plants
The pharmacologically active principles in plants include:

Alkaloids

Glycosides

Oils

Resins

Oleoresins

Gums

Tannins

Alkaloids

These are basic substances containing cyclic nitrogen, which are insoluble in water but combine with acids to form well-defined, water-soluble salts, e.g. morphine, atropine, emetine. 1

Glycosides

Are ether-like combinations of sugars with other organic structures.
A glycoside does not form salts with acids but when heated with mineral acids it is hydrolysed to a sugar and a non-sugar component called aglycone or genin e.g. digoxigenin.
A glycoside which yields glucose on acid hydrolysis is called a glucoside.

Oils

Fixed oils are glycerides of oleic, palmitic and stearic acids. They are fats and may have food value, e.g. peanut oil, coconut oil, and olive oil. Castor oil acts as a purgative.

Volatile oils are volatilized by heat and possess aromas. Chemically, they are not fats and have no caloric value. They contain the hydrocarbon terpene or some polymer of it, which serves as a diluent or solvent for a more active compound, e.g. menthol in peppermint oil.



Volatile oils are used as:
Carminatives – for expulsion of gas from the stomach e.g. oil of eucalyptus, ginger.
Antiseptics – in mouth wash, pastes.
Counter-irritants – e.g. turpentine oil
Flavoring agents – e.g. oil of peppermint
Pain relieving agents – e.g. oil of clove in toothache

1
Animal Sources

Pancreas is a source of Insulin, used in treatment of Diabetes.
Urine of pregnant women gives human chorionic gonadotropin (hCG) used for the treatment of infertility. Sheep thyroid is a source of thyroxin. Cod liver is used as a source of vitamin A and D. Blood of animals is used in preparation of vaccines

Mineral Sources
Metallic and Non metallic sources:

Iron is used in treatment of iron deficiency anemia.
Zinc is used as zinc supplement. Zinc oxide paste is used in wounds and in eczema.
Iodine is antiseptic. Iodine supplements are also used.
Gold salts are used in the treatment of rheumatoid arthritis.
Mineral sources

Miscellaneous Sources:

Fluorine has antiseptic properties.
Borax has antiseptic properties as well.
Selenium as selenium sulphide is used in anti dandruff shampoos.
Petroleum is used in preparation of liquid paraffin.

Synthetic/ Semi synthetic Sources

Synthetic Sources:
When the nucleus of the drug from natural source as well as its chemical structure is altered, we call it synthetic.
Examples include Aspirin, Sulphonamides, Procaine, and Corticosteroids.
Most of the drugs used nowadays are synthetic forms. …

Semi Synthetic Source:

When the nucleus of a drug obtained from natural source is retained but the chemical structure is altered, we call it semi-synthetic. Examples include Apomorphine, Diacetyl morphine, Ethinyl Estradiol, Homatropine, Ampicillin and Methyl testosterone.

Microbiological Sources

Bacteria and fungi isolated from the soil are important sources of antibacterial substances (antibiotics)
Penicillium notatum is a fungus which gives penicillin. (AlsoPenicillium chrysogenum )
Streptomyces griseus gives Streptomycin. Aminoglycosides such as tobramycin and gentamicin are obtained from Streptomyces andMicromonosporas respectively.

Recombinant DNA technology

Recombinant DNA technology involves cleavage of DNA by enzyme restriction endonucleases.
The desired gene is coupled to rapidly replicating DNA (viral, bacterial or plasmid)
The new genetic combination is inserted into the bacterial cultures which allow production of vast amount of genetic material.
E.g. human chorionic gonadotropin (usually got from urine of pregnant women or pregnant mares) can be extracted from cultures of genetically modified microbes with recombinant DNA.
Recombinant DNA technology

Advantages:

Huge amounts of drugs can be produced.
Drug can be obtained in pure form.
It is less antigenic.
Disadvantages:
Well equipped lab is required.
Highly trained staff is required.
It is a complex and complicated techniqu The end.
Thanks.

Classification and naming of drugs
D.ouma otieno Classification 1.      
Drugs may be classified by:

Therapeutic use

2.Antibacterial
3.Antidiabetic
4.Antihypertensive
5.Analgesic
6.Antifungal
7.Antimalaria
8.Classification… 2.

Mode or site of action

Molecular interaction
Receptor blockers - e.g. beta blockers
Enzyme inhibitors – e.g. reverse transcriptase inhibitors
Cellular site
Loop diuretic
Catecholamine uptake inhibitor (imipramine)
Classification… 3. br/>

Molecular structure

Glycoside
Alkaloid
Steroid
Tetracycline
Macrolides

Nomenclature (Names)

Any drug may have names in all three of the following classes/ categories:
The full chemical name
A nonproprietary (official, approved, generic) name
A proprietary (brand) name
Nomenclature (Names)

Example: one drug – 3 names
1. 3-(10,11-dihydro-5H-dibenz [b,f]-azepin-5- yl) propyl-dimethylamine
2. Imipramine
3. Tofranil (UK), Prodepress, Surplix, Deprinol, etc. (various countries)

The full chemical name describes the compound for chemists. It is obviously unsuitable for prescribin Nonproprietary name

A nonproprietary name
is given by an official agency, e.g. WHO.
A prescription for a generic drug formulation may be filled by any officially licensed product that the dispensing pharmacy has chosen to purchase.
The principal reasons for advocating the habitual use of nonproprietary (generic) names in prescribing are
Nonproprietary name…

    Clarity:
Because it gives information about the class of the drug, e.g.: -
.Diazepam, nitrazepam, flurazepam are all benzodiazepines. Their proprietary names are valium, mogadon, and dalmane respectively.
.Names ending in –olol are adrenoceptor blockers
.Names ending in –floxacin are quinolone antimicrobials
.Nortriptyline and amitriptyline are plainly related, but their proprietary names are allegron and laroxyl (lentizol)
Nonproprietary name…

Economy:
Drugs sold under nonproprietary names are usually, but not always, cheaper than those sold under proprietary names.

Convenience:
..Pharmacists may supply whatever version they stock whereas if a proprietary name is used they are normally obliged to supply that preparation alone.
..International travelers with chronic illnesses will be grateful for recommended international nonproprietary names (rINN)
Proprietary name

The proprietary name
is a trade mark applied to particular formulations of a particular substance by a particular manufacturer.
Manufacture is confined to the owner of the trade mark or to others licensed by the owner.
The principal noncommercial reason for advocating the use of proprietary names in prescribing is consistency. of the product, so that problems of quality, especially of bioavailability, are reduced
Proprietary name
When a prescription is written for a proprietary product pharmacists must, under law, dispense that product only, unless they persuade the doctor to alter the prescription, or under law, they have the right to substitute a generic product (generic substitution), or a drug of different molecular structure deemed to be pharmacologically and therapeutically equivalent (therapeutic substitution) The End.

Routes of Administration of Drugs

Learning objectives

1.Describe the various routes of drug administration
2.Explain the advantages and disadvantages of each route of drug administration
4.Select a suitable route of drug administration

Main routes of drug administration

Drugs can be administered:

1.Locally
2.Orally or enterally
3.Parenterally
(a)By injection
(b)By inhalation
Selection of a suitable route

Selection of a suitable route is dictated by considerations as follows:
1.Convenience for the patient
2.The patient’s condition – degree of illness, type of illness
3.Action required – quick action, local action, systemic action
4.Achievement and maintenance of an adequate drug concentration at the requisite site, e.g. getting the right concentration of a drug in the meninges.
5.Drug formulation that is available

Local application of drugs

This is when a drug is administered directly at the site where it is to produce effects, e.g. of dusting powder, paste, lotion, cream, drops, ointment, vaginal pessaries

Advantages of local application
1.Convenient to the patient
2.Encouraging to the patient
3.Easy to apply
4.Does not require skill
5.Acts at site of application
6.Self-application is possible
7.No gastric irritation

Disadvantages of local application
May be absorbed and produce adverse systemic effects, especially solutions applied to mucus membranes.
Eye drops

Nasal sprays

May be messy on the skin, some might dirty the clothes

Oral or Enteral route
This means taking drugs into the body via the alimentary tract.
It is the most commonly used route of drug administration.
It includes:

Swallowing drugs (oral administration)

Sub-lingual administration of drugs

Rectal administration of drugs
br/>br/> Oral administration
IDrugs are taken by mouth for absorption in the gastrointestinal tract
Advantages of oral administration
ISafe
IConvenient to the patient: - selfadministered at home
IEconomical
IEasy to administer
IComplications of parenteral therapy are avoided

Disadvantages of oral administration
IThe onset of drug action is slow
IIrritant and unpalatable drugs cannot be administered by this route
IRoute may not be useful in the presence of vomiting
IThe route cannot be employed in unconscious patients
IThe route cannot be used in uncooperative patients
It Can produce gastric irritation
IDrugs likely to be destroyed by digestive juices cannot be administered by this route (e. g. insulin)
Sub-lingual administration of drugs
A tablet containing a medicament is placed under the tongue and allowed to dissolve in the mouth.
The active ingredient thus gets absorbed through the buccal mucous membrane directly into the systemic circulation

Advantages of sublingual administration
IRapid onset of action
IQuick termination of drug effect by Ispitting the tablet
IDegradation of the drug in the stomach is avoided

Disadvantages IInconvenience if use has to be frequent
IIrritation of mucous membrane and excessive salivation which promotes swallowing, so losing the advantages of bypassing pre-systemic elimination.

Examples of drugs given sublingually
INitro-glycerine tablet in angina pectoris
IIsoprenaline sulphate in bronchial asthma
INifedipine in hypertension
IErgotamine in migraine

Rectal administration of drugs
The rectum has a rich blood and lymph supply and drugs can cross the rectal mucosa like the other lipid membranes, thus, un-ionized and lipid soluble substances are readily absorbed from the rectum.br/> The portion absorbed from the upper rectal mucosa is carried by the superior haemorrhoidal vein into the portal circulation.br/> The portion absorbed from the lower rectum enters directly into the systemic circulation via the middle and inferior haemorrhoidal veins

Advantages of rectal route
Gastric irritation is avoided
By using a suitable solvent the duration of action can be controlled.
It is a convenient route to use in the long term care of geriatric and terminally ill patients
Administration of a rectal suppository or a capsule is a simple procedure, which can be undertaken by the unskilled personnel and the patient himself.
Suitable in vomiting and motion sickness Suitable for emergency when intravenous line cannot be quickly established

Disadvantages

Rectal inflammation may occur in repeated use
Absorption may be unreliable if the rectum is full of faeces
Psychological embarrassment

Examples of drugs that can be given rectally

Indomethacin in rheumatoid arthritis
Aminophylline for bronchospasm
Chlorpromazine for vomiting
Diazepam for convuls

Enemata
Administration of a medicament in a liquid form into the rectum is called enema.
Enemata are of two types:
Evacuant enema
Retention enema

Evacuant enema

The aim is to remove faecal matter and flatus.
In soap and water enema, the water stimulates the rectum by distension while the soap acts as a lubricant.
The quantity of fluid administered at a time is about 600ml. An evacuant enema is often administered before delivery, surgical operation, and radiological investigation of the gastrointestinal tract

Retention enema

Here the drug incorporated into the enema may act locally or may act systemically after absorption through the mucous membrane.
The quantity of fluid administered in retention enema is usually 100-120ml. It can be used for diagnostic purposes e.g. barium enema

Enteric coating of pills and tablets

Sometimes pills and tablets are coated with keratin, salol, or cellulose acid phosphate.
These substances are not dissolved by the acid juice of the stomach but are dissolved by the intestinal alkaline juices.
Enteric coating is done:
To prevent gastric irritation and alteration of the drug in the stomach
To get the desired concentration of the drug in the small intestine
To retard the absorption of the drug

Parenteral routes

These are routes of administration other than the alimentary tract (enteron)
Advantages:
They can be employed in an unconscious or uncooperative patient
Useful in cases of vomiting and diarrhoea
Useful when the patient is unable to swallow
They avoid drug modification by alimentary juices and liver enzymes
Drugs that might irritate the stomach or which are not absorbed in the small intestine s can be administered
Rapid action and economy of dose are Parenteral routes…

Disadvantages:
They are less safe
More expensive
Inconvenient for the patient
Self-medication difficult
Dangers of infection if proper care is not exercised
Skill is required in administering
Injections are painfull

Inhalation

By this method drugs are inhaled into the respiratory system.

Drugs may be administered as: 1.Solid particles
2.Nebulized particles from solutions (fine spray)
3.In the form of vapours (e.g. steam inhalation)
4.Fine droplets (aerosols), sprayed and 5.deposited over the mucous membranes, 6.producing local effects.
7.Gases e.g. volatile general anaesthetics
Inhalation…

Advantages:
Quick absorption
Produce rapid local and systemic effects
Blood levels of volatile general anaesthetics can be conveniently controlled by the law of gases.
Self administration is practicable
Inhalation…

Disadvantages:
Drugs go directly into the left side of the heart through the pulmonary veins and may produce cardiac toxicity
Local irritation may result in an increase in the respiratory tract secretions
Obstructed bronchi may cause failure of therapy (mucus plugs in asthma)

Injections

Can be administered:
Intradermally
Subcutaneously
Intramuscularly
Intravenously
Intra-arterially
Intrathecally
Intraperitoneally
Intramedullary
intraarticularly

Intradermal injection:

Given in the layers of the skin, e.g. BCG vaccine.
Only a small quantity can be administered by this route
The injection is painful
The route is also employed for studying drug all

Subcutaneous (S/C) injection:

Drug is injected into the subcutaneous tissue
Drug absorption is slower than I.M. or I.V. routes

Advantages:
1.The action is sustained and uniform
2.The route is acceptable for self-administration

Disadvantages:
Only non-irritant substances can be injected by this route
Poor absorption in peripheral circulatory failure
Repeated injections in the same area can cause lipoatrophy, leading to erratic absorption

Intramuscular (I.M.) injection:

The drug is injected into the muscles

Advantages:
In addition to soluble substances, mild irritants, suspensions and colloids can be injected by this route.
Absorption rate is relatively uniform Onset of action is rapid
Depot preparations can be used at monthly or longer periods

I.M. injection…

Disadvantages:
Causes local pain
May cause abscess
May cause nerve irritation or damage if injected very near to or into a nerve causing severe pain or paresis of muscles supplied.
NB: the volume of injection should not exceed 10 ml

Intravenous (I.V. ) Injection

Drugs are given directly into a vein
Advantages:
Allows rapid modification of dose, i.e. immediate cessation of drug administration is possible if unwanted effects occur during administration.
Produce rapid action
The desired blood concentration can be obtained with a well-defined dose.
Large quantities of solution can be administered by this route.
Useful for certain irritant and hypertonic solution (e. g. mannitol and iron) as they are rapidly diluted by blood

Intravenous (I.V. ) Injection…

Disadvantages:
Once a drug has been administered by this route its action cannot be halted
Local irritation can lead to venous thrombosis Leakage of the drug outside the vein can produce severe irritation e.g. intravenous iron. Self medication is difficult
Infection of the intravenous catheter and the small thrombi on its tip are a risk during prolonged infusions

I.V. injection:…
Precautions:

Before injecting ensure that the needle is in the vein
The injection should be given slowly in the case of certain drugs such as iron and aminophylline, as sudden high blood concentrations may be dangerous.
Only the minimum quantity required to elicit a particular effect should be injected


Intra-arterial injection

In this route a drug is administered through an artery.
Danger:
Produces a sudden high concentration in arterial blood and hence, may be harmful locally or dangerous to tissues supplied by the artery

Intra-arterial injection…
Used in
Some diagnostic studies such as angiography
Treatment of peripheral vascular disorders
Treatment of certain localized malignancies where certain anti-malignancy compounds are administered by intra-arterial perfusion

Intra-thecal injection:

This involves the introduction of drugs such as spinal anaesthetics into the subarachnoid space. The drugs act directly on the central nervous system.
This route is convenient for producing local action on the meninges (e.g. certain antibiotics and corticosteroids)
Strict aseptic precautions must be observed

Intra-peritoneal injection:

This route is useful in infants for giving fluids like dextrose saline, as the peritoneum offers a large surface from which they are readily absorbed

Intramedullary injection:

This is the introduction of drugs into the bone marrow. It is rare.

Intra-articular injection:

A drug is administered directly into a joint for local treatment.
It ensures high local concentration of the drug

The end. Thank you.

THE CONCEPT OF ESSENTIAL MEDICINES AND RATIONAL USE OF MEDICINES

learning objectives

State the WHO definition of essential medicines
Explain the importance of the concept of essential medicines
State the criteria for selection of essential medicines
State questions to be considered before inclusion of a new drug in the essential medicines list
Explain the importance of rational drug use State the effect of advertising and promotion on rational drug use
Define first-line treatment
David ouma otieno
 Essential medicines have been defined by the World Health Organization (WHO) as “those that satisfy the healthcare needs of the population” in a particular country.
The concept appeared in in the mid-1970s when there was inequitable distribution of resources for health in developing countries.
The selection of essential drugs should depend on the health as well as the structure and development of the health services of each country.
Essential drugs are selected with due regard to their public health relevance, evidence on efficacy and safety, and comparative costeffectiveness.
Essential medicines are intended to be available within the context of functioning health systems at all times and in adequate amounts.
The list of essential drugs should be drawn up locally and reviewed and updated periodically by experts in public health, medicine, pharmacology, pharmacy, and drug management.
It has been realized that only a handful of medicines out of the multitude available can meet the health care needs of majority of the people in any country.
Also, many well tested and cheaper medicines are of equal or better efficacy and comparable safety as their newer more expensive counterparts.
For optimum utilization of resources, governments in developing countries should concentrate on these medicines by identifying them as essential medicines.
The concept of essential medicines has not only become recognized as a useful tool for selecting drugs according to needs, but it has also provided a rational basis for drug procurement and for establishing drug requirements in national health care systems.
Advances in drug therapy or new experiences from current practice should form the basis for the revision of the essential drugs list.
The decision to include a new product in the list should consider the following questions:
◦Is the medicine more effective than existing ones on the list?
◦Does the medicine induce lesser side effects than similar medicines currently on the list?
◦Does the medicine have a wider spectrum of action than the listed product it is intended to replace?
◦Is it cheaper than similar existing medicines on the list?

Criteria for selection of essential medicines

In principle, essential medicines selected for any country are those which meet the health care needs of the majority of the population.
They are supposed to be available at all times, in sufficient amounts and in the required dosage forms.
The world health organization (WHO) has laid down criteria to guide selection of an essential medicine:
The choice depends on:

Pattern of prevalent diseases in the country

Availability of treatment facilities

Availability of trained personnel

Available financial resources

Demographic and environmental factors

Adequate data on its efficacy and safety

should be available from clinical studies

The medicine being available in a form in

which quality, including bioavailability and stability on storage can be assured.

In the case of two or more similar medicines, choice should be made on the basis of their relative efficacy, safety, quality, price and availability.

Comparative pharmacokinetic properties and local facilities for manufacture and storage.

Most essential medicines should be single compounds.
Fixed ratio combination products should be included only when dosage of each ingredient meets the requirements of a defined population group, and when the combination has a proven advantage in the therapeutic effect, safety, patient compliance, or in reducing the emergence of drug resistance.
Selection of essential medicines should be a continuous process which should take into account the changing priorities for public health action, epidemiological conditions as well as availability of better drugs/ formulations and advancement in pharmacological knowledge.
Selection of essential medicines is also based on rationally developed treatment guidelines.

16 Rational use of drugs

The rational use of drugs requires that an appropriate drug be prescribed, that it be available at the right time at a price which is affordable, that it be dispensed correctly, that it be taken in the right dose at the prescribed intervals and for the correct length of time.
The appropriate drug must be safe, effective and of acceptable quality.
 Rational drug use is an essential component in the implementation of national drug policies.
Education and training are essential components of the rational use of drugs
Appropriate training is given so as to ensure that drugs are prescribed, dispensed and used rationally.
Education and training should be provided for:

Doctors

Dentists

Clinical Officers

Pharmacists / Pharmaceutical technologists

Nurses and others who offer healthcare services Emphasis should be made on the importance of rational drug use.
Objective and unbiased information about the correct handling and use of drugs should be provided to health workers at all levels and to the public.
Guidance for rational prescribing and dispensing of drugs should be made available to health workers in all units.
Patients should be appropriately advised on correct drug use, how to recognize and report adverse drug reactions.
Patients should be made to understand the purpose as well as the effects of the drugs they are taking.
Supply of drugs without medical judgment, over-prescription and polypharmacy should be evaluated periodically to reduce unnecessary consumption.

Advertising and promotion

Ethical drug promotion and advertisement can support improvement of health care through rational drug use
Advertisement of drugs must be based on proven scientific evidence and must be objective and in line with pharmaceutical legislation
Where the advertisement is directed to the public for over the counter (OTC) products it must be educational in purpose
Drug promotions must always comply with national regulations which reflect the national health policy.
Promotional activities are responsible for influencing both the purchasing of OTC drugs by the public and prescribing drugs by clinicians.
As a result, drugs are commonly overused, misused or even abused.

First-line treatment / therapy

  A first-line treatment or first-line therapy is a medical therapy recommended for the initial treatment of a disease, sign or symptom, usually on the basis of empirical evidence for its efficacy.
This evidence typically suggests the recommended therapy is most likely to have an effect for the given condition.
First-line treatment usually consists of drugs in the essential drugs list.
Second-line drugs are alternative drugs for use in case the first line drug is ineffective / contraindicated in the treatment of a disease.
THE END! Thanks

DISTRIBUTION OF A DRUG
Pharmacokinetics Distribution
Distribution of a drug is the transfer of a drug from one location to another within the body.
Once a drug enters the systemic circulation by absorption or direct administration, it must be distributed into various body fluid compartments and tissues.
The rate of entry of a drug into a tissue depends on the rate of blood flow to the tissue, tissue mass, and partition characteristics between blood and tissue.

Body fluid compartments through which a drug is distributed

After absorption, a drug enters or passes through the various body fluid compartments such as:

Plasma

Interstitial fluid compartment

Cellular (intracellular) fluid compartment

Transcellular fluid compartment, e.g. fluids in the gut, bronchi and cerebrospinal fluid.

Some drugs pass into the cell, some remain in the cell membrane, and some remain extracellular.
However, a drug can penetrate into and exist in more than one compartment.
The rate of passage of a drug through a membrane is dependent upon the pH of the drug’s environment and the dissociation constant (pKa) of the drug, the pH at which the non-ionized and ionized drug concentrations are equal.
Non-ionized lipid-soluble drugs that readily cross membranes are distributed throughout all fluid compartments.
Drugs that do not readily cross membranes are restricted in their distribution.
The extent of distribution of a drug depends on its lipid solubility, ionization at physiological pH, extent of binding to plasma and tissue proteins and differences in regional blood flow.
5
Plasma concentration of a drug

Depends upon the rate of absorption, distribution, metabolism and excretion of the drug.
After absorption, the drug circulates in the blood in two forms:

In the free form

Bound to plasma proteins

6
Significance of plasma protein and tissue binding

Binding of drugs to plasma proteins assists in absorption.
Diffusion across the intestinal wall continues as long as the concentration within the gut exceeds that of the unbound portion in the portal capillaries.
The free portion of drug is pharmacologically active.
The protein-bound component is a reservoir of drug that is inactive because of this binding.
Significance of plasma protein and tissue binding…
Protein binding reduces diffusion of the drug into the cell and thereby delays its metabolism (breakdown)
Protein binding also reduces the amount of drug available for filtration at the glomeruli and hence delays its excretion.
Free and bound fractions are in equilibrium and free drug removed from the plasma by metabolism is replaced by drug released from the bound fraction.
Since it is the diffusible portion of the drug that determines its activity, highly protein-bound drugs may have too low concentrations in interstitial fluid, CSF and tissue cells to combat dangerous infections.
Some drugs are extensively tissue-bound. This delays elimination from the body and accounts for the long half-life.

Apparent volume of distribution

Presuming that the body behaves as a single homogenous compartment with volume V into which drug gets immediately and uniformly distributed:
V = dose administered I.V. divide by Plasma concentration
This is only an apparent volume of distribution which can be defined as: “the volume that would accommodate all the drug in the body, if the concentration throughout was the same as in plasma”.
Thus, it describes the amount of drug present in the body as a multiple of that contained in a unit volume of plasma.

Volume of distribution…

The apparent volume of distribution is the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma.
For a drug that is highly tissue-bound, very little drug remains in the circulation; thus, plasma concentration is low and volume of distribution is high.
Drugs that remain in the circulation tend to have a low volume of distribution.

Thank you. 12 The end

METABOLISM (BIOTRANSFORMATION) OF DRUGS

Pharmacokinetics Learning objectives

Define metabolism of drugs

State the three possible fates of drugs after absorption

State the two major ways in which metabolism changes drugs

Discuss how metabolism reduces lipid solubility

Discuss how metabolism alters biological activity of a drug

State the reactions that bring about metabolic changes

Describe the two phases of metabolism

Definition

Metabolism is the process of chemical alteration of drugs in the body.
i.e. the chemical alterations that occur to the drug within the body

Fate of drugs after absorption

The three possible fates of drugs after absorption are:
They could be metabolized by enzymes
They could change spontaneously into other substances without the intervention of enzymes
They could be excreted unchanged

Ways in which metabolism changes drugs

The processes of metabolism change drugs in two major ways:
1.By reducing lipid solubility
2.By altering biological activit

Reducing lipid solubility

Metabolic reactions tend to make a drug molecule more water-soluble and so favour its elimination in the urine.
Drug metabolism often converts lipophilic chemical compounds into more readily excreted hydrophilic products.
Products of lipid soluble drugs are thus more water soluble and more readily excreted by the kidneys

Altered biological activity

Drugs are metabolized by enzymes with resultant:
Activation
Inactivation
Modification
The end result of metabolism is the abolition of biological activity

Steps in drug metabolism:
Conversion of a pharmacologically active to an inactive substance. This applies to most drugs.
Conversion of a pharmacologically active to another active substance. This has the effect of prolonging drug action. Conversion of a pharmacologically inactive to an active substance, i.e. prodrugs

Organs of metabolism

The liver is the most important organ for drug metabolism.
Other tissues also contribute:

Kidneys

Gut mucosa

Lungs

Skin

Plasma

The liver has special drug metabolizing enzyme system. Therefore:
In liver disease drugs may be poorly metabolized, hence drug excretion is reduced.
In a diseased liver, use of drugs may aggravate the illness.
In neonates the liver microsomal enzyme system that metabolizes drugs is poorly developed and thus drug metabolism is slow, hence excretion is slower than in adults

Reactions that bring about metabolic changes (biotransformation reactions) NON-SYNTHETIC REACTIONS
Oxidation
Reduction
Hydrolysis
Cyclization
Decyclization

SYNTHETIC REACTIONS
Glucuronide conjugation
Acetylation
Methylation
Sulphate conjugation
Glycine conjugation
Glutathione conjugation
Ribonucleoside/ nucleotide synthesis

Non-synthetic or phase I reactions

Phase I reactions may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization.
If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point.
However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which
an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate

A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically active on
Non-synthetic reactions

Oxidation:

Involves addition of oxygen/ negatively charged radical or removal of hydrogen / positively charged radical.
Oxidations are the most important drug metabolizing reactions Oxidation results in loss of electrons from the drug.
Oxidation reactions include: Hydroxylation Oxygenation at C, N or S atoms N- or O-dealkylation Oxidative deamina
Non-synthetic reactions

Reduction:

This is the converse of oxidation (and involves cytochrome P-450 enzymes working in opposite direction)
Cytochrome P450 enzymes are housed in the smooth endoplasmic reticulum of the cell. Hydrolysis:
This is cleavage of drug molecule by taking up a molecule of water.
Hydrolysis occurs in liver, intestines, plasma and other tissues
Non-synthetic reactions

Cyclization:

This is formation of ring structure from a straight chain compound. E.g. proguanil. Decyclization:
This is opening up of ring structure of the cyclic drug molecule, e.g. barbiturates and phenytoin

Synthetic reactions
These involve conjugation of the drug or its phase I metabolite with an endogenous substrate, to form a polar, highly ionized organic acid, which is easily excreted in urine or bile.
Conjugation reactions have high energy requiremen
Synthetic reactions

Glucuronide conjugation:

This is the most important synthetic reaction.
Occurs in the hepatocyte cytoplasm
The attachment of an ionized group makes the metabolite more water soluble.
Compounds with a hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid which is derived from glucose. E.g. chloramphenicol, aspirin, morphine, metronidaz
Synthetic reactions

Acetylation:

Compounds having amino or hydrazine residues are conjugated with the help of acetyl coenzyme-A. e.g.
Sulphonamides
Isoniazid
Paraaminosalicylic acid
hydralazin
Synthetic reactions

Methylation:

The amines and phenols can be methylated. E.g. adrenaline, histamine. Sulphate conjugation:
The phenolic compounds and steroids are sulfated by sulfokinases. E.g.
chloramphenicol, adrenal and sex steroid Phases of metabolism
There are two phases of metabolism:
1. Phase I metabolism
Nonsynthetic reactions 2. Phase II metabolism
Synthetic/ conjugation reaction Phase I metabolism

This phase brings about a change in the drug molecule by oxidation, reduction or hydrolysis.
Oxidation, reduction and hydrolysis introduce polar groups such as hydroxyl, amino, carboxyl into drugs, which are consequently made water-soluble, and pharmacologically less active
The new metabolite may retain biological activity but have different pharmacokinetic properties, e.g. a shorter half-life.
The most important single group of reactions is oxidation, in particular those undertaken by the so-called mixed-function (microsomal) oxidases. These are capable of metabolizing a variety of compounds
Phase I oxidation of some drugs results in formation of epoxides, which are short-lived and highly reactive metabolites.
Epoxides are important because they can bind irreversibly through covalent bonds to cell constituents; indeed this is one of the principal ways in which drugs are toxic to body tissues.
Glutathione is a tripeptide that combines with epoxides, rendering them inactive. Its presence in the liver is part of an important defense mechanism against hepatic damage by halothane and paracetamol

Phase II metabolism

This involves union of the drug with one of several polar endogenous molecules to form a water-soluble conjugate which is readily eliminated by the kidney or if the molecular weight exceeds 300, in bile.
Morphine, paracetamol and salicylates form conjugates with glucuronic acid.
Oral contraceptive steroids form sulphates Isoniazid, phenelzine and dapsone are acetylated.
Phase II metabolism almost invariably terminates biological activity

Enzyme induction
Enzyme induction is a process by which enzyme activity is enhanced, usually because of increased enzyme synthesis (or, less often, reduced enzyme degradation).
The capacity of the body to metabolize drugs can be altered by certain medicinal drugs themselves or other substances that induce enzyme activity.
These stimulate the microsomal enzyme systems (enzyme induction) accelerating biotransformation of drugs Enzyme induction… 

Relevance of Enzyme induction to drug therapy: Clinically important drug reactions may result , e.g. failure of oral contraceptives or loss of anticoagulant control.
Disease may result ; e.g. antiepilepsy drugs increase the breakdown of dietary and endogenously formed vitamin D, producing an inactive metabolite – in effect vitamin D deficiency state, which can result in osteomalacia.
The accompanying hypocalcemia can increase the tendency to fits and a convulsion may lead to fracture of the demineralized bone

Enzyme induction…
Relevance of enzyme induction…
Tolerance to drug therapy may result in and provide an explanation for sub-optimal treatment, e.g. with an antiepilepsy drug.
Variability in response to drugs : enzyme induction caused by heavy alcohol drinking or heavy smoking may be an unrecognized cause for failure of an individual to achieve the expected response to a normal dose of a drug
Enzyme induction… Relevance of enzyme induction… Drug toxicity may be more likely . A patient who becomes enzyme-induced by taking rifampicin is more likely to develop liver toxicity after paracetamol overdose by increased production of a hepatotoxic metabolite
Substances that cause enzyme induction
Barbiturates
Barbequed
meats
Carbamazepine
Ethanol
Griseofulvin
Phenytoin
Rifampicin
Tobacco smoke
Enzyme inhibition

Some drugs inhibit enzyme activity thereby inhibiting metabolism of other drugs.
Consequences of inhibiting drug metabolism can be more profound than those of enzyme induction.
Enzyme inhibition is more selective and offers more scope for therapy

Examples of enzyme inhibition
Acetazolamide inhibits carbonic anhydrase and is used for the treatment of glaucoma.
Allopurinol inhibits xanthine oxidase and is used for the treatment of gout.
Disulfiram inhibits aldehyde dehydrogenase and is used for treatment of alcoholism.
Enalapril inhibits angiotensin-converting enzyme and is used for treatment of hypertension and cardiac failure
The end. Thanks.

BIOLOGICAL HALF-LIFE OF DRUGS AND ITS SIGNIFICANCE
Learning objectives
Definebiological half-life of a drug
Explain its importance
Explainexponential kinetics (first-order kinetics)
in relation to drug elimination
Describe thesteady state concentration of a drug
Show how the plasma half-life of a drug can be used to know when the steady state concentration of a drug has been reached
Distinguishzero-order kinetics from first-order kinetics
2

Biological half-life of a drug is the time required to reduce its concentration in the body compartments by 50%.
Thebiological half-life of a drug is an estimate of the time it takes for the concentration or amount in thbeody of that drug to be reduced by exactly one half (50%).
It may also be called the elimination half life. The symbol for half-life is T½.

Importance:
It gives a measure of drug elimination It guides drug therapy
It may be used to predict the manner in which plasma concentration alters in response to starting, altering or ceasing drug administration.
Drugs that have a shorter half-life tend to act very quickly, but their effects wear off rapidly, and thus they usually need to be taken several times a day to have the same effect.
Drugs with a longer half-life may take longer to start working, but their effects persist for longer, and they may only need to be dosed once a day, once a week, once a month, or even less frequently.

Plasma half-life Theplasma half-life of a drug is an estimate of the time it takes for the concentration or amount of that drug in theplasma to be reduced by exactly one half (50%).
This can be different from the biological or elimination half-life of a drug because it depends on: -
How well the drug is distributed in the body,
whether it binds to proteins,
Whether it reaches a saturation point

Exponential (First-order) Kinetics

  Drugs taken into the body are subject to processes of absorption, distribution, metabolism and excretion.
In the majority of instances, the rates at which these processes occur are directly proportional to the concentration of the drug.
Transfer of drug across a cell membrane or formation of a metabolite is high at high concentrations and falls in direct proportion to be low at low concentrations.

This is because the processes follow the law of mass action, which states that the rate of reaction is directly proportional to the active masses of reacting substances.
In other words, at high concentrations, there are more opportunities for crowded molecules to interact with each other or to cross cell membranes than at low, uncrowded concentrations.

8 Exponential (First-order) Kinetics... Elimination of most drugs follows exponential kinetics. i.e.: -
A constant fraction of the drug in the body disappears in each equal interval of time - usually reflected in the rate of lowering of the plasma concentration.

The drug is removed from the body not at a constant rate but at a rate proportional to its plasma concentration; so that a constant fraction of the drug is eliminated in unit time.
Processes for which rate is proportional to concentration are said to undergofirstorder (exponential) kinetics.
For example, if 100mg of a drug with a half-life of
60 minutes is taken, the following is estimated:
60 minutes after administration, 50mg remains
120 minutes after administration, 25mg remains
180 minutes after administration, 12.5mg remains
240 minutes after administration, 6.25mg remains
300 minutes after administration, 3.125mg
remains. Observe that after 300 minutes, almost 97% of this drug is expected to have been eliminated. Most single dose drugs are considered to have a negligible effect after four-to-five half-lives.

Exponential (First-order) Kinetics...  
With drugs whose elimination is exponential, the biological half-life is independent of:
The dose
The rate of administration and The plasma concentration
However, the actual quantity of the drug removed per unit time is smaller at lower plasma concentrations and larger at higher plasma concentrations.

How plasma concentration increases after dosing begins

When a drug is given at a constant rate the amount in the body and with it the plasma concentration rise until a state is reached at which the rate of administration of drug to the body is exactly equal to the rate of elimination.
This is called the steady state and when it is attained the amount of drug in the body remains constant; the plasma concentration is on a plateau.

Increase in plasma conc. with dosing…
If a drug is given by intermittent oral or intravenous dose, the plasma concentration will fluctuate between peaks and troughs, but in time all the troughs will be of equal length.
This is also called a steady-state concentration, since the mean concentration is constant.
14 How the plasma half-life of a drug can be used to know when the steady state concentration of a drug has been reached:
 Certain simple and valuable calculations are dependent on knowing the plasma half-life of a drug: -
Estimation of time taken to eliminate a drug
Construction of dosing schedules
Prediction of the time to achieve steady state plasma concentration.
Plasma half-life and steady-state concentration...
 It is important to know when the steady state concentration of a drug has been reached, for maintaining the same dosing schedule will ensure a constant amount of the drug action and the patient will experience neither toxicity nor decline of effect.

16 Prediction of steady state concentration…  The t ½ provides the answer: With the passage of each t ½ period of time, the plasma concentration rises byhalf the difference between the current concentration and the ultimate steady state (100%) concentration.
The significant fact is that when a drug is given at a constant rate the time to reach the steady state depends only on the plasma half-life.
For all practical purposes, after 5 t ½s the amount of drug in the body will be constant and the plasma concentration will be at a plateau.

Rise in plasma concentration of a drug administered by constant I.V. infusion 

In 1 x t ½ the concentration will reach 100/2 = 50%
In 2 x t ½ the concentration will reach 50+50/2 = 75%
In 3 x t ½ the concentration will reach 75+25/2 = 87.5%
In 4 x t ½ the concentration will reach 87.5+12.5/2 = 93.75%
In 5 x t ½ the concentration will reach 93.75+6.25/2 = 96.875% of the ultimate steady state.

Zero-order Kinetics
 
As the amount of drug in the body rises, those processes that have limited capacity become saturated, i.e. the rate of the process reaches a maximum at which it stays constant.
For example, due to limited amount of enzyme, where further increase in rate is impossible despite an increase in the dose of the drug.

19 Zero-order kinetics… 
Clearly, these are circumstances in which the rate of reaction is not proportional to dose and processes that exhibit this type of kinetics are described as:
Rate limited or
Dose dependent or
Zero order or as showing
Saturation kinetics
Zero-order kinetics…   In practice enzyme mediated metabolic reactions are the most likely to show rate-limitation because the amount of enzyme present is finite and can become saturated.

Examples:
Alcohol and Phenytoin initially show firstorder kinetics but as the amount of drug in the body increases their elimination becomes zero-order.
2 Thank you. 22 The end.

EXCRETION OF DRUGS Pharmacokinetics

Learning objectives     

Define excretion of drugs
Name the organs of drug excretion
Describe the processes which contribute
to drug elimination from the kidneys
Explain how ionisation of a drug andpH of urine affects drug elimination
Discuss biliary excretion of drugs
Introduction  

Excretion of drugs is the process through which drugs are removed from the body.
Drugs are removed from the body after being partly or whollyconverted to watersoluble metabolites or, in some cases, without being metabolised.

Organs of drug excretion
The kidney is the major organ of drug excretion.

Others are:
Biliary tract
Intestines e.g. those not absorbed
Saliva
Skin through sweat or hairs falling off (e.g. heavy metals like mercury and arsenal)
Breast milk
Lungs e.g. volatile general anaest

Renal Elimination
Processes which contribute to drug elimination
Passive glomerular filtration
Active tubular secretion
Passive diffusion across the tubules (renal tubular re-absorption)

Passive glomerular filtration
Substances with molecular weight less than 10,000 (includes almost all drugs) pass easily through the pores of the glomerular membrane.
Those that have a molecular weight in excess of 50,000 are excluded from the glomerular filtrate.
Ionised drugs, which are poorly absorbed, are excreted almost entirely by glomerular filtration and are not reabsorbed.
Unionised drugs, which are well absorbed, are filtered at the glomerulus, but they can diffuse back from the lumen of the renal tubule into the cells lining the tubules.
Some drugs are actively secreted into the renal tubules by the system responsible for the transfer of naturally occurring substances like uric acid.
Cells of the proximal renal tubule actively transfer strongly charged molecules from the plasma to the tubular fluid. There are two such systems, one for acids, e.g. penicillin, frusemide, and one for bases, e.g. amiloride, amphetamine.

Active tubular secretion…
Metabolic inhibitors can block this mechanism.
For example, excretion of penicillin can be competitively inhibited by Probenecid. This leads to the prolongation of the halflife of the drug and higher concentration in blood for longer periods.

Passive diffusion
This is a bi-directional process and drugs may diffuse across the tubules in either direction depending upon the drug concentration and the pH.
Ionisation of a drug and pH of tubular fluid Since the tubular epithelium has the properties of a lipid membrane, the extent to which a drug diffuses back into the blood will depend on its lipid solubility, i.e. on its dissociation constant and on the pH of the tubular fluid.

Passive diffusion…
If the fluid becomes more alkaline, an acidic drug ionises, becomes less lipid soluble, and its re-absorption diminishes, but a basic drug becomes un-ionised (and therefore more lipid soluble) and its reabsorption increases.
Therefore, thepH of urine (tubular fluid) exerts an influence on the excretion of certain weak acids and bases.
Weak acids are quickly eliminated in alkaline urine
e.g. barbiturates and salicylates. Weak bases are rapidly excreted in acidic urine
e.g. pethidine, amphetamin

Importance :
May be used to enhance the elimination of drugs in overdose (poisoning) with either weak acids or weak bases e.g. phenobarbitone or aspirin.
1. Sodium bicarbonate is given to treat overdose with aspirin

Biliary excretion of drugs Some drugs areexcreted actively by liver cells into bile.
In the liver there is one active transport system for acids and one for bases, and in addition, there is a system that transports un-ionised molecules e.g. digoxin into the bile.
Small molecules tend to be reabsorbed by the bile canaliculi and in general only compounds that have a molecular weight greater than 300 are excreted in bile.
Impaired liver functions lead to decreased liver secretion.

Examples of drugs excreted through the biliary tract
Erythromycin
Doxycycline
Minocycline
Chlortetracycline
Chloramphenicol
Phenolphthalein

Novobiocin
Oral contraceptives
Ampicillin
Rifampicin
Some of these drugs are reabsorbed in the intestines (enterohepatic cycling) and ultimately excreted in urine.

Salivary excretion
The pH of saliva varies between 5.8 and 8.4 Unionized lipid soluble drugs are excreted passively
The bitter taste in the mouth of a patient is indicative of drug excretion through saliva
Compounds excreted in saliva include caffeine, phenytoin and theophylline.
Thank you The end.

PRESCRIPTION OF DRUGS

Prescription of drugs 
The treatment of a sick person includes many aspects, and administration of drugs is one of them.
In certain patients drugs are of the greatest importance while in others they have only a minor role to play. 2

Before prescribing drugs one should know:

1.Pharmacological actions and toxicity of the drug he uses
2.The natural course of the disease he is treating
3.Reasons for choosing a particular preparation, more so if it is a costly one
4.The possible interactions when several drugs are administered simultaneously
The cost of the therapy
Benefits versus risks of using the drug Availability of the drug

Components of a prescription
A prescription should include the following:
1. Date of prescription
2. Patient information:

Name of the patient

Age of the patient – especially important in children to allow for the pharmacist to check the correctness of the dose

Sex of the patient

Patient’s number (OP or IP) where necessary
3. Superscription: take thou of (Rx symbol)

4 . Inscription:
The name of the drug
The form in which the drug is to be supplied – syrup, tablet, capsule, injection, cream, suppository, pessary, etc.

Subscription: instructions to the pharmacist or dispenser to compound medications. It indicates the quantity of medication (number of capsules, tablets) or the size of bottle to be dispensed (5ml, 10ml, 15ml).

Transcription:
instructions to the pharmacist or dispenser indicating how the patient should use the medication.
The dose (amount of drug)
The frequency
The duration of the therapy
The route of administration
The manner in which the drug is to be taken e.g. chew, swallow whole, take with meals, after meals or on an empty stomach
Signature of the licensed practitioner or prescriber.

ABBREVIATIONS IN PRESCRIPTION WRITING

Abbreviations in prescription writing
Abbreviation From the Latin Meaning
a.c. ante cibum before meals
ad lib. ad libitum use as much as one desires; freely
a.m. ante meridiem morning, before noon amp ampoule
aq aqua water
b.i.d. bis in die twice daily bol. bolus as a large single dose (usually intravenously

Abbreviations in prescription writing
Abbreviation From the Latin Meaning
cap., caps. capsula capsule
c cum with (usually written with a bar on top of the "c")
comp. compound
elix. elixir
emuls. emulsum emulsion g gram
gtt(s) gutta(e) drop(s)

Abbreviations in prescription writing
Abbreviation From the Latin Meaning
h, hr hora hour
h.s. hora somni at bedtime
ID intradermal
IM intramuscular (with
respect to injections) inj. injectio injection
IP intraperitoneal
IV intravenous

Abbreviations in prescription writing
Abbreviation From the Latin Meaning
lin linimentum liniment
mcg microgram
mg milligram
mist. mistura mixture
mL millilitre
nocte nocte at night

11 Abbreviations in prescription writing
Abbreviation From the Latin Meaning
non rep. (non repet.) non repetatur no repeats (not to be repeated)
NS normal saline (0.9%)
per per by or through
p.c. post cibum after meals
p.m. post meridiem evening or afternoon prn pro re nata as needed (as need arises)
p.o. per os by mouth or orally

Abbreviations in prescription writing
Abbreviation From the Latin Meaning
p.r. Per rectum by rectum
q quaque every
q.h. quaque hora every hour
q.h.s. quaque hora somni every night at bedtime
q.1h quaque 1 hora every 1 hour; (can replace "1" with other numbers)
q.d. quaque die every day q.i.d. quater in die four times a day

Abbreviations in prescription writing
Abbreviation From the Latin Meaning
repet. repetatur Repeats (to be repeated)
s sine without (usually written with a bar on top of the "s")
U Units
MU Mega units
IU International units
x for
OD Once a day

Abbreviations in prescription writing
Abbreviation From the Latin Meaning
SC subcutaneous
SL sublingually, under the tongue
sol solutio solution
stat statim immediately
supp suppositorium suppository
susp suspension
syr syrupus syrup

Abbreviations in prescription writing
Abbreviation From the Latin Meaning
tab tabella tablet
t.i.d. ter in die three times a day
t.d.s. ter die sumendum three times a day
t.i.w. three times a week
top. topical

T.P.N. total parenteral nutrition
tinc., tinct. tincture

Prescription writing
Practice prescription writing using correct format and abbreviations:

Septrin tablets, two to be taken twice daily for five days.
Intramuscular injection of chlorpromazine, fifty milligrams immediately, then tablets twenty-five milligrams orally twice daily.
Methyldopa tablets, two hundred and fifty milligrams to be taken three times daily for two weeks.
Frusemide tablets, forty milligrams once daily for one month.
Omeprazole capsules twenty milligrams once daily for four weeks.
Paracetamol tablets one gram three times a day for three days.
Intravenous ceftriaxone four grams immediately, then two grams once daily for ten days.
Piriton tablets four milligrams three times a day for four days.
Cetirizine tablets ten milligrams once daily for five days.
Norfloxacin tablets four hundred milligrams twice daily for five days.
Adrenaline injection 0.5 milliliters subcutaneously, immediately. Repeat same dose after half an hour.
Tetracycline capsules five hundred milligrams every six hours for five days.
Actal tablets, chew two when the need arises. Erythromycin syrup, five milliliters four times a day for one week.
Intravenous fifty per cent dextrose, twenty milliliters immediately as a bolus.
Crystapen injection two mega units intravenously, six hourly for forty-eight hours, then review.

20 Thank you. 21 The end.

PHARMACOKINETICS DRUG MOVEMENT ACROSS CELL MEMBRANES

Introduction
Pharmacokinetics is the process whereby drug concentrations at effecter sites are achieved, maintained and diminished; that is, the study of the absorption, distribution, metabolism and excretion of drugs in the intact animal or human.
The quantitative study of drug movement in, through and out of the body.

Importance 
Pharmacokinetics quantifies the component parts of drug disposition to determine:

Absorption
Distribution
Metabolism
Elimina

Importance
It helps to know the:
Optimum routes
Absorption rates
Timing of drug administration
Regimes of drug administration are determined from pharmacokinetic studies

Importance…  Pharmacokinetics is concerned with the rate at which drug molecules cross cell membranes to enter the body, to distribute within it and to leave the body, as well as with the structural changes (metabolism) to which they are subject within it.

Pharmacokinetics Drug movement across cell membranes Learning objectives
Describe the components of a cell membrane
Explain how passage across cell membranes affects drug use
Describe the processes through which drugs cross cell membranes
Describe the physicochemical classification of drugs and explain its relationship to drug passage across cell membranes
Explain the clinical relevance of drug passage across cell membranes

Structure of cell membrane

Cell membranes are essentially bilayers of lipid molecules with ‘islands’ of protein.
The hydrophilic ends of the lipids orientate themselves at both the inner and outer surfaces, while the hydrophobic portions occupy the center of the membrane.

Cell membrane…
Cell membrane…
Cell membrane structure…

Integral proteins extend the full length of the membrane and show a predominance of either hydrophilic or hydrophobic groups at their surfaces – contiguous to the corresponding lipids according to their depth within the membrane.
Peripheral proteins are attached either to integral proteins at the inner side of the membrane and are predominantly hydrophilic or to the hydrophilic ends of lipids at either surface.

Cell membrane structure…  
Some of the integral proteins, which extend through the full thickness of the membrane, surround fine aqueous pores.
Carbohydrates – glycoproteins or glycolipids are formed on the outer surface of the membrane by the attachment of different polymeric arrangements of monosaccharides.

Relationship with drug use   
The extent to which a drug can cross epithelia is fundamental to its clinical use.
It is the major factor that determines whether a drug can be taken orally for systemic effect and whether within the glomerular filtrate it will be reabsorbed or excreted in the urine.
Lipid-soluble substances diffuse readily into cells and therefore throughout body tissues.

Relationship with drug use
Adjacent epithelial or endothelial cells are joined by tight junctions, some of which contain waterfilled channels through which water-soluble substances of small molecular size may filter.

The jejunum and proximal renal tubules contain many such channels and are called leaky epithelia. The tight junctions in the stomach and urinary bladder do not have these channels and water cannot pass; they are termed tight epithelia.

Special protein molecules within the lipid bilayer allow specific substances to enter or leave the cell preferentially (carrier proteins)

Processes through which drugs pass across membranes 

The passage of drugs across cell membranes is determined by the natural processes of:

Filtration
Carrier-mediated transport
Diffusion
Filtration
   
Aqueous channels in the tight junctions between adjacent epithelial cells (paracellular spaces) allow the passage of some water-soluble substances.
Filtration is mainly important in drug excretion by glomerular filtration.
Capillaries (except those in the brain) have large pores and most drugs filter through these.
Diffusion of drugs through capillaries is dependent on the rate of blood flow through them rather than on lipid solubility or pH.

Filtration…  

Drugs may also pass through aqueous pores in the membrane.
Majority of cells (including intestinal mucosa) have very small pores and drugs with molecular weight of more than 100 or 200 are not able to penetrate.

Carrier-mediated transport    
This comprises active transport and facilitated diffusion
In carrier transport, the drug combines with a carrier present in the membrane and the complex then translocates from one face of the membrane to the other.
The carriers for polar molecules appear to form a hydrophobic coating over the hydrophilic groups and thus facilitate passage through the membrane.
Carrier transport is specific, saturable and is competitively inhibited by analogues which utilize the same carrier.

Active transport   
This is a specialized process requiring energy and enables some drugs to move into or out of cells against a concentration gradient.
They often require a carrier substance, and the movement is independent of the physical properties of the membrane.
It results in selective accumulation of the substance on one side of the membrane.

Facilitated diffusion     This is carrier mediated transport that does not require energy.
This proceeds more rapidly than simple diffusion and translocates even non-diffusible substrates, but along their concentration gradient.
It, therefore, does not require energy. Vitamin B12 absorption is an example. Diffusion

  This is the most important means by which a drug enters the tissues and is distributed through them.
Simple diffusion requires:

A favorable concentration gradient of the drug Sufficient lipid-solubility to pass through the membrane
Diffusion …   In the context of an individual cell, the drug moves passively at a rate proportional to the concentration difference across the cell membrane; that is, it shows first-order kinetics.

Cellular energy is not required, which means that the process does not become saturated and is not inhibited by other substances.

Diffusion…   
Drugs exhibit greater or less degrees of lipid solubility according to environmental pH and the structural properties of the molecule.
Broadly, water solubility favored by the possession of alcoholic (-OH), amide (-CO.NH2) or carboxylic (-COOH) groups, and the formation of glucuronide and sulphate conjugates.
Presence of a benzene ring, a hydrocarbon chain, a steroid nucleus or halogen (-Br, -Cl, -F) groups favours lipid solubility.

Physicochemical classification of drugs    
Drugs can be classified in a physicochemical sense into:
Those that are variably ionized according to environmental pH (electrolytes). These can either be lipid soluble or water-soluble, depending on the environmental pH.
Those that are incapable of becoming ionized whatever the environmental pH (unionized, nonpolar substances). These are lipid soluble.
Those that are permanently ionized whatever the environmental pH (ionized polar substances). These are water-soluble.

Drugs that are variably ionized according to the environmental pH
   Many drugs are weak electrolytes, i.e. their structural groups ionize to a greater or lesser extent, according to environmental pH.
Most such elements are present partly in the ionized and partly in the un-ionized state.
The degree of ionization influences lipid solubility (and hence diffusibility) and so affects absorption, distribution and elimination.

Drugs that are variably ionized…
 Ionizable groups in a drug molecule tend either to lose a hydrogen ion (acidic groups) or to add a hydrogen ion (basic groups)

Drugs that are variably ionized…  
 In an acidic environment, i.e. one already containing many hydrogen ions, an acidic group tends not to lose a hydrogen ion and remains un-ionized.
A relative deficit of hydrogen ions, i.e. a basic environment, favors dissociation of the hydrogen ion from an acidic group which thus becomes ionized.
The opposite is the case for a base.

Drugs that are variably ionized… 

In summary:
Acidic groups become less ionized in acidic environment
Basic drugs become less ionized in a basic (alkaline) environment and vice versa.
This in turn influences diffusibility since:
Un-ionized drugs are lipid-soluble and diffusible, and

Ionized drugs are lipid-insoluble and nondiffus Drugs that are incapable of becoming ionized

  These include digoxin and chloramphenicol.
Having no ionizable groups, they are unaffected by the environmental pH, are lipidsoluble and diffuse readily across tissue boundaries.

Drugs that are predominantly ionized    

These drugs remain ionized at all values of pH. This is because they carry groups which dissociate so strongly.
Such compounds are called polar, as their groups are either negatively charged (acidic, e.g. heparin) or positively charged (basic, e.g. tubocurarine) and all have very limited capacity to cross cell membranes.
Advantage: heparin is a useful anticoagulant in pregnancy because it does not cross the placenta.
Disadvantage: heparin must be given parenterally as the gut does not absorb it.

The clinical relevance of drug passage across membranes

 

Blood-brain barrier:
The capillaries of the cerebral circulation lack the channels between endothelial cells through which substances in the blood normally gain access to the extracellular fluid.
There are tight junctions between adjacent capillary endothelial cells, which together with their basement membrane separate the blood from the brain tissue.

Clinical relevance – blood-brain barrier   

This blood-brain barrier places constraints on the passage of substances from blood to the brain and CSF.
Compounds that are lipid-insoluble do not cross it readily, e.g. atenolol, compared with propranolol (lipid-soluble), and CNS side effects are prominent with the latter.

Therapy with methotrexate (lipid-insoluble) may have no effect on leukaemic cells in the CNS.

Clinical relevance…  Lipid-soluble substances enter brain tissue with ease.
thus diazepam (lipid-soluble) given intravenously is effective in one minute for status epilepticus;
the level of general anaesthesia can be controlled closely by altering the concentration of inhaled anaesthetic gas (lipid-soluble)

The clinical relevance of drug passage across membranes  
Placenta:
Chorionic villi, consisting of a layer of trophoblastic cells that enclose foetal capillaries, are bathed in maternal blood.

The large surface area and blood flow (500ml/ min.) are essential for gas exchange, uptake of nutrients and elimination of waste products.

The clinical relevance of drug passage across membranes  
The fetal and maternal blood streams are therefore separated by a lipid barrier that readily allows the passage of lipid-soluble substances but excludes water-soluble compounds, especially those with molecular weight exceeding 600.

This exclusion is of particular importance with short-term use, e.g. tubocurarine (lipidinsoluble) given as a muscle relaxant during Caesarean section, does not affect the infant.

Thank you. The end

PHARMACODYNAMICS Structure-activity

relationship, Doseresponse relationship: drug potency, efficacy and therapeutic index

Learning objectives … david ouma
2  
Show how the knowledge of the chemical structure of a drug is useful Explain the terms:
Potency
Therapeutic efficacy
Therapeutic in Pharmacodynamics
3 Structure activity relationship Structure activity relationship
  The activity of a drug is intimately related to its chemical structure.
Knowledge about the chemical structure of a drug is useful for:
Synthesis of new compounds with more specific actions and fewer adverse reactions Synthesis of competitive antagonists Understanding the mechanism of drug action
Structure activity relationship …    Synthesis of new compounds, for the following purposes:
To increase or decrease the duration of action of the original drug or to get a more potent compound. E.g. Procaine –When given intravenously reduces the rate and excitability of the myocardium, but is very rapidly hydrolyzed in plasma hence cardiac action is too transient.
Procainamide, is structurally similar to procaine but resistant to hydrolysis, and is a valuable antiarrythmic drug.

Structure activity relationship … 

Synthesis of new compounds :
To restrict drug action to a particular system of the body. E.g.

Chlorpromazine has antihistaminic, anticholinergic, hypotensive and tranquillizing actions.
By structural modification of chlorpromazine molecule, trifluoperazine was produced and has more potent tranquillizing effect but negligible antihistaminic and hypotensive properties.

Structure activity relationship … 

Synthesis of new compounds …
To reduce the adverse reactions, toxicity and other disadvantages associated with the available drugs E.g.

New penicillins have been synthesized which are not inactivated by gastric acid, and hence can be taken by mouth.

Penicillins that destroy staphylococci resistant to benzyl penicillin have been synthesized – cloxacillinM, flucloxacillin

Structure activity relationship … 

Synthesis of competitive antagonists: Para-amino benzoic acid (PABA) is an essential growth factor for several microorganisms

Sulphonamides are structural analogues of PABA. They act by competing with PABA for uptake by bacteria in the synthesis of folic acid. This arrests folic acid formation and bacterial multiplication stops.

Structure activity relationship … 

Understanding the mechanism of drug action:

Understanding the basic chemical groups responsible for drug action gives some idea about their mechanism of action.
E.g. Chlorpromazine is a tranquillizer. Structurally related Imipramine, on the other hand, is an antidepressant due to slight alteration in chemical group in the formula.

Pharmacodynamics Dose-response relationship
1. 2.  When a drug is administered systemically, the dose-response relationship has two components:

1.Dose-plasma concentration relationship and
2.Plasma concentration-response relationship.
Generally, the intensity of response increases with increase in dose.

DOSE-RESPONSE CURVE  
The measured dose (usually in milligrams, micrograms) is generally plotted on the X axis and the response is plotted on the Y axis.

The curve produced is the dose-response curve.
Drug potency and efficacy   

Potency
Drug potency refers to the amount of drug needed to produce a certain response.
A dose-response curve positioned rightward indicates lower potency
If 10mg of morphine = 100mg of pethidine, morphine is 10 times more potent than pethidine. Potency …
  If weight for weight, drug A has a greater effect than drug B, then drug A is more potent than drug B, but the maximum therapeutic effect obtainable may be similar with both drugs.

The diuretic effect of Bumetanide 1mg is equivalent to Frusemide 50mg, thus bumetanide is more potent than Frusemide but both drugs achieve about the same maximum effect.

Efficacy  
Drug efficacy refers to the maximal response that can be elicited by the drug
If drug A can produce a therapeutic effect that cannot be obtained by drug B however much of drug B is given, then drug A has the higher therapeutic efficacy. e.g. morphine produces a degree of analgesia not obtainable by any dose of aspirin. So morphine is more efficacious than aspirin.

Efficacy … 
 Efficacy is a more decisive factor in the choice of a drug.
The slope of the DRC is important in that, a steep slope indicates that a moderate increase in dose will markedly increase the response, while a flat one implies that little increase in response will occur over a wide dose range (standard dose can be given to most patients)

Therapeutic index
 The therapeutic index (TI) (also referred to as therapeutic window or safety window or sometimes as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity
TI  
The concept of therapeutic index refers to the relationship between toxic and therapeutic dose.

This pharmacodynamic parameter is relevant to clinical practice because it determines how safe (or toxic) a drug is.

Therapeutic Index   
TI is therefore an approximate assessment of the safety of the drug.

It is the gap between the therapeutic effect DRC and the adverse effect DRC.

In experimental animals, it is expressed as the ratio of the median lethal dose to the median effective dose.

Therapeutic Index …    For animal studies,
‘the median lethal dose’ or LD50 is the dose (mg/kg) that results in death of 50% of the study population.
‘the median effective dose’ or ED50 is the dose (mg/kg) which produces a desirable response in 50% of the test population.
Therapeutic index (TI) = LD50 ED50

TI in human trials
 Classically, in an established clinical indication setting of an approved drug, Therapeutic Index refers to the ratio of the dose of drug that causes adverse effects (toxic dose) at a severity not compatible with the targeted indication, in 50% of subjects,

T p 5 h 0 D a % 50 rm o to f a s t c h u o e b lo j d e g o c i s c ts e a , l t E h e D a f 5 t e 0 l . c e t a ( d e s ffi t c o a t c h i e ou d s e s d i o re s d e)in TI  

The dose required to cause a therapeutic effect (positive response) in 50% of a population is the ED50
. The dose required to produce a toxic effect in 50% of the studied population is the TD50 .

TI THERAPEUTIC INDEX
Therapeutic Index

    The larger the TI the safer is the drug For safe therapeutic application of a compound, its TI must be more than one.

Penicillin and sulphonamides have high Therapeutic indices.

Digitalis preparations have much smaller Therapeutic indices.
• • • • • • •
Narrow therapeutic index drugs
The list below shows some examples of narrow therapeutic index drugs:
Warfarin
Lithium
Digoxin
Phenytoin
Gentamycin
Amphotericin B
5-fluorouracil
Thanks. The end.

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Pharmacology and Therapeutics

Pharmacology and Therapeutics

Pharmacology

Drug

Therapeutics

Pharmacy

Pharmacognosy

Pharmacokinetics

Pharmacogenomics (pharmacogenetics)

Pharmacology and genetics…

Chemotherapy

Pharmacopoeia

Toxicology

Receptor

Hormones

Xenobiotics

Poisons

Toxins

Metabolism of drugs

Biological lag

Bioavailability of a drug

Biological half-life of a drug

Drug interactions

Sources of Drugs

1.Plant sources 2.Animal sources 3.Mineral sources 4.Microbiological sources (microorganisms) 5. synthetic sources/ Synthetic sources 6.Recombinant DNA technology

Plant Sources

Pharmacologically active principles in plants

Alkaloids

Glycosides

Oils

Volatile oils are used as: Carminatives – for expulsion of gas from the stomach e.g. oil of eucalyptus, ginger. Antiseptics – in mouth wash, pastes. Counter-irritants – e.g. turpentine oil Flavoring agents – e.g. oil of peppermint Pain relieving agents – e.g. oil of clove in toothache

Animal Sources

Metallic and Non metallic sources:

Miscellaneous Sources:

Synthetic/ Semi synthetic Sources

Semi Synthetic Source:

Microbiological Sources

Recombinant DNA technology

Advantages:

Classification and naming of drugs

Therapeutic use

Mode or site of action

Molecular structure

Nomenclature (Names)

Any drug may have names in all three of the following classes/ categories: The full chemical name A nonproprietary (official, approved, generic) name A proprietary (brand) name

The full chemical name describes the compound for chemists. It is obviously unsuitable for prescribin Nonproprietary name

Routes of Administration of Drugs

1.Describe the various routes of drug administration 2.Explain the advantages and disadvantages of each route of drug administration 4.Select a suitable route of drug administration Main routes of drug administration

This is when a drug is administered directly at the site where it is to produce effects, e.g. of dusting powder, paste, lotion, cream, drops, ointment, vaginal pessaries

Advantages of rectal route

Disadvantages

Examples of drugs that can be given rectally

Enemata

Evacuant enema

Retention enema

Enteric coating of pills and tablets

Parenteral routes

Inhalation

Intradermal injection:

Subcutaneous (S/C) injection:

Intramuscular (I.M.) injection:

I.M. injection…

Intravenous (I.V. ) Injection

Intravenous (I.V. ) Injection…

Before injecting ensure that the needle is in the vein The injection should be given slowly in the case of certain drugs such as iron and aminophylline, as sudden high blood concentrations may be dangerous. Only the minimum quantity required to elicit a particular effect should be injected

Intra-arterial injection

Intra-thecal injection:

Intra-peritoneal injection:

Intramedullary injection:

Intra-articular injection:

THE CONCEPT OF ESSENTIAL MEDICINES AND RATIONAL USE OF MEDICINES

learning objectives

Criteria for selection of essential medicines

16 Rational use of drugs

Advertising and promotion

First-line treatment / therapy

DISTRIBUTION OF A DRUG Pharmacokinetics Distribution

Body fluid compartments through which a drug is distributed

Plasma concentration of a drug

Significance of plasma protein and tissue binding

1.Plant sources
2.Animal sources
3.Mineral sources
4.Microbiological sources (microorganisms)
5. synthetic sources/ Synthetic sources
6.Recombinant DNA technology

Volatile oils are used as:
Carminatives – for expulsion of gas from the stomach e.g. oil of eucalyptus, ginger.
Antiseptics – in mouth wash, pastes.
Counter-irritants – e.g. turpentine oil
Flavoring agents – e.g. oil of peppermint
Pain relieving agents – e.g. oil of clove in toothache

Any drug may have names in all three of the following classes/ categories:
The full chemical name
A nonproprietary (official, approved, generic) name
A proprietary (brand) name

1.Describe the various routes of drug administration
2.Explain the advantages and disadvantages of each route of drug administration
4.Select a suitable route of drug administration

Main routes of drug administration

Before injecting ensure that the needle is in the vein
The injection should be given slowly in the case of certain drugs such as iron and aminophylline, as sudden high blood concentrations may be dangerous.
Only the minimum quantity required to elicit a particular effect should be injected

DISTRIBUTION OF A DRUG
Pharmacokinetics Distribution