General Pharmacology
Greek:Pharmacon- drugs ; logus-discourse or study
Pharmacology is the scienceof drugs,deals with interaction of exogenouslyadministerd chemical molecules(drugs) with living system.
1. Pharmacodynamics:- ( Greek- Dyanamis- power)
"What the drugs does to the body?" is pharmacodyanamics. this includes physiological and biochemical effects of drugs and their mechanism of actionj at macromolecular/subcelluler/organ system levels.
2. Pharmacokinetics:- (Greek-kinesis- movement)
"what the body does to the drugs?" is pharmacokinetics. This means movement of the drugs in and alteration of the drugs by the body. This includes absorption,distribution,binding/localization,storage,biotransformation abd excreation of drugs.
Terminology
1. Drugs : (French-Drogue--a dry herbs)
Drug is a single active chemical substance or products that is used or is inteded to be used to modify or explore physiological system or pathological states for the benefit of the recipient.
2. Pharmacotherapeutic :
It is the application of pharmacodynamics information together with knowledge of the disease for it's prevention, mitigation or cure.
3. Chemotherapy :
It is the treatment of systemic infection/malignancy with specific drugs that has selective toxicity for infecting organism cell eith no/minimal effects on the host cell.
4. Clinical Pharmacology :
Clinical pharmacology is the scientific study of drugs in man, it includes pharmacodynamics and pharmacokinetics investigation in healthy voluntears and in patients.
The aim of clinical pharmacology is to generate data for optimum use of drugs.
5. Pharmacy :
It is the art and science of compounding and dispencing drugs or preparing suitable dosage form for administration of drugs in man and animals. This includes collection,identification,isolation,purification,synthesis,standardization and quality control of medicinal substances.
The large scale manufacture of drugs is called pharmaceutics. It is primarily a technological science.
6. Toxicology :
Toxicology is the study of poisonous effects of drugs and other chemicals with emphasis on detection, prevention, and treatment of poisonings. It aslo includes the study of adverse effects of drugs.
Drugs Nomenclature
A drug generally has three categoris of names
a. Chemical name :-
It describes the substances chemically. It is not Suitable for use in priscribing.
b. Non-proprietaory name :-
It is the name accepted by a competent scientific body such as the United States Adopted Name( USAN) Council. The non-proprietory name of newer drugs are uniform all over the world by an internatural agreement through World Health Organization (WHO). This name commonly called Generic Name.
c. Proprietory(Brand) Name :
It is the name assigned by the manufacturer and is his property or trade mark. this name is also called Brand or Trade Name. One drug may have multiple proprietory names.
Essential Drug Concept
The WHO has defined essential Drugs as " those that satisfy the healthcare needs of majority of the population; they should therefore be available at all times in adequate amounts and in apprppriate dosages forms.
The WHO has laid down criteria to guide selection of an essential drugs. these are:
- Adequate data on it's efficacy and safety should be available from clinical studies.
- It should be available in a form in which quality,including bioavialability, and stabilityon
storage can be assured.
- It's choice should depend upon pattern of prevalent disease.
- In case of two or more similar drugs choice should be made on the basis of their relative
efficacy.
- Most essential drugs should be simple compounds.
Routes of drug administration
* Factors governing choice of route :
> Physical and chemical properties of drugs (solid,liquid,& gas ; soulubility,stability,
pH,irritances).
> Ste of desired action.
> Rate and extant of absorption of drugs from different route.
> Effects of digestive juice and first pass metabolism on drugs.
> Condition of the patients (Uncounsious, vomiting).
Routes can be divided in to two:
1. Local routes
2. Systemic routes
1. Local routes :
These routes can only be used for localization lesion at accessible site , systemic absorption of drugs from these route is minimal or absent., thus high concentration are attained at disired site without exposing the rest of the body. local routes are :
a. Topical route:
Externally use of drugs to the surface for localized action . It is often more convenient
as well as encouraging to the patients.
- Skin:- Drug is applied as ointments, crean,lotion,paste, powder, dressing etc.
- Mucous membrane:- The dosage form deoends onthe site;
* Mouth & pharynx- as paints, lozenges,mouth wash,gargles etc.
* Eye, Ear, & Nose- as Drops, ointments, nasal spray ets.
* Bromchi & lungs- as inhalation, aerosols, nebulizer.
* Urethra- as Jellys
* Vagina - as pesseries, vaginal tablets,cream, inserts, powder,douches etc.
* Anal canal- as ointments, supposaitories etc.
b. Deeper tissue :
Certain deep area can be approached by using a syringe and needle, but the drugs should be such that systemic absorption is slow. eg. intrathecal injection
( lidocaine, amphotericin B).
c. Arterial supply :
Close intra-arterial injection is used for contrast media in angiography, anticancer drugs can be infused in femoral or brachial artery for limb malignancies.
2. Systemic routes :
The drug administered through systemic route is intended to be absorbed into blood and distributed all over, including the site of action, through circulatiom.
1. Oral :
Oral ingestion is the oldest and commonest mode of drug administration. It is safer, more convenient, does not need assistance, noninvasive,often painless, the medicaments need not be sterile and is cheaper. both solid dosage forms( powders,tablets,capsulesetc.)and liquid dosage formd( elixirs,syrups,emulsion,mixtures) can be given orally.
*Limitation
- Action is slower and thus not suitable for emergencies.
- Unpalatable drugs are difficult to administer, drug may be filled in capsules to
circumvent this
- May cause neausea and vomiting (emetine).
- Can not be used for uncooperative/unconsious/vomiting patients.
- Certain drugs are not absorbed (streptomycin).
- Other are destroyed by digestive juice (eg. penicillin-G, insulin) or in liver( nitro-glycerine), lidocaine.
2. Sublingual(S.I.) or Buccal :
The tablet or pellet containing the drug is placed under the tongue or crussed in the mouth and spread over the buccal mucosa. Absorption is relatively rapid -action can be produced in minutes. Only lipid soluble and non-irritating drugs can be so administered.
The chief advantage is that liver is bypassed and drugs with high first pass metabolism can be absorbed directly into systemic circulation. Drug given sublingually are - nitroglycerine, isoprenaline, methyl testosterone, clonidine.
The main disadvantage of this route of administration is that most drugs do not taste
nice.
Rectal administration
Rectal administration avoids drug inactivation by stomach acid and digestive enzymes
and about 50% of that absorbed bypasses the liver and goes directly into the systemic
circulation. In some circumstances, it may be advantageous to administer a drug rectally,
for example if a patient is unconscious or vomiting, or uncooperative in some way, but
generally, it is considered an unpleasant method.
Many of the general factors considered above that affect absorption from the gastrointestinal
tract apply equally to this route of administration.
Nasal administration
Nasal administration is often intended to have a local effect, as in the use of nasal
decongestants, although certain drugs are given this way to have a systemic effect. For
example, antidiuretic hormone used to treat diabetes insipidus and hormones used for
infertility treatment can be given by this route. This route can be another way of avoiding
destruction of a drug by liver enzymes or stomach acid and digestive enzymes. Factors
affecting absorption across mucosal membranes, similar to those considered under oral
administration.
Administration by injection
Drugs can also be given by injection. Methods of injection include subcutaneous, intramuscular,
intravenous, intra-arterial, intra-articular, intraspinal and epidural.
Drugs injected subcutaneously or intramuscularly have to diffuse between loose connective
tissue or muscle fibres. The rate of absorption depends on the usual parameters for
passage across cell membranes but also on the blood or lymphatic supply to a particular
region. Increasing the blood supply by applying heat or massage will increase the rate of
absorption. Conversely, for a local effect, addition of a vasoconstrictor to the injection
decreases the rate of removal of the drug from the site of injection. Depot preparations
are designed to give a slow sustained release of drug.
Drugs injected intravenously go directly into the blood stream and are rapidly distributed
around the body. An advantage of intravenous injection is that it is possible to
get high concentrations of a drug very quickly to its site of action, although this may
also lead to toxic effects in other tissues. Disadvantages of intravenous injection are that
it requires trained personnel using sterile techniques and once the drug has been given,
mistakes cannot be rectified. Drugs can be given by continuous intravenous infusion, for
example in cancer chemotherapy.
Intra-arterial injections are rarely used. Radio-opaque substances and cytotoxic drugs
are sometimes injected into arteries in the diagnosis and treatment of cancer.
Intra-articular injections are sometimes used to administer a drug directly into a joint,
for example with a corticosteroid in the treatment of arthritis or a contrast agent for
imaging.
Intraspinal and epidural injections are given under certain circumstances to have a
local effect, either as anaesthesia or to treat infection of the central nervous system. For
details of injection techniques.
Absorption of drugs
Whatever the route of administration, a drug must reach its site of action. In order to do
this, the drug will have to cross several cell membranes to reach the blood (unless it is
injected intravenously).
The three ways by which substances, including drugs, can cross cell membranes are
simple diffusion, facilitated diffusion and active transport.
Diffusion
Diffusion is the mechanism by which the vast majority of drugs pass across cell membranes.
Both simple diffusion and facilitated diffusion are passive processes in that no
energy is required other than the kinetic energy of the molecules themselves.
Several factors are known to influence the diffusion of substances across the cell
membrane:
• the membrane must be permeable to the substance in question;
• there must be a concentration gradient;
• the molecular size/weight of the substance must be small enough;
• a large surface area is necessary for efficient diffusion;
• a short distance is necessary for efficient diffusion.
In practice, there is a concentration gradient because the drug is given in sufficient dose,
most drug molecules are small enough to be absorbed (otherwise, they would be of no
use) and the surface area and distance of the absorbing membrane are favourable.
Simple diffusion
Simple diffusion of drug molecules depends mostly on lipid solubility.
The structure of the cell membrane can be a barrier to diffusion of drugs because it is
essentially a lipid bilayer with proteins embedded in the inner and outer surfaces.
Lipid-soluble substances diffuse easily through the lipid bilayer and include oxygen,
carbon dioxide, fatty acids, steroids and fat-soluble vitamins. The lipid solubility of a drug
depends on its state of ionization. Certain small ions, for example sodium, potassium,
calcium and chloride can pass through ion channels in the cell membrane. Such channels
are highly specific and do not allow the passage of relatively large ionized drug molecules.
Drugs in the unionized form are generally lipid soluble whereas ionized drugs are not.
The extent to which a drug is ionized depends on the pH of the local environment and the pKa of the drug. pH is a measure of hydrogen ion concentration – the lower the pH,
the higher the hydrogen ion concentration and the greater the acidity of a solution. The
pKa of a drug molecule is the pH at which the drug is 50% ionized and is different for
different drugs. Chemically, most drugs are either weak acids or weak bases. In an acidic
environment, as in the stomach, acidic drugs are unionized according to the following
simple equation:
HA = H+ + A−
where A− is an acidic drug and the excess hydrogen ions (H+) drive the equation to the
left.( = , this indicates irriversible reaction in the equation)
In an alkaline environment, as in the small intestine and the majority of body fluids,
basic drugs are unionized according to the following simple equation:
BH+ = B + H+
where B is a basic drug and the deficit of hydrogen ions drives the equation to the right.
Thus, acidic drugs are preferentially absorbed in the stomach and basic drugs are
preferentially absorbed in the intestine. In practice however, because of the large surface
area of the small intestine, the majority of drug absorption takes place there. Nevertheless,
alteration of stomach pH can alter the absorption characteristics of acidic drugs.
A few drug molecules are small enough to diffuse through aqueous pores in the cell
membrane with water, for example alcohol. However, the majority of drugs are too large
to diffuse in this way.
ABSORPTION OF DRUGS
Many nutrients and a few drugs can pass across the cell membrane by facilitated
diffusion. In this case, in addition to the concentration gradient, a membrane protein acts
as a carrier to transport a substance from one side of the membrane to the other. Carrier
proteins are specific and only transport molecules that they ‘recognize’. Glucose enters
many body cells by facilitated diffusion and the process appears to be more efficient than
simple diffusion.
Carrier systems exist for the transport of some amino acids and vitamins and the same
carrier can transport drugs that are structurally similar to them.
Active transport
Active transport involves a carrier protein but differs from diffusion in two important
ways. Cellular energy in the form of ATP (adenosine triphosphate) is required to drive
the process and transport goes against the concentration gradient. By such a mechanism,
substances can be concentrated in certain parts of the body. Active transport mechanisms
are particularly important in the transport of ions, nutrients and neurotransmitters and
may be involved in the transport of some drugs. Many drugs have been developed that
interfere with the active transport of neurotransmitters
Absorption from the gastrointestinal tract
Since the vast majority of drugs are administered by mouth, it is important to consider
factors that affect absorption of drugs from the gastrointestinal tract. See Figure 2.3 for
a diagram of the digestive system.
The function of the digestive system is to provide nutrients for the body through the
processes of mechanical degradation and liquefaction and the action of enzymes on the
food we eat. Drugs taken orally are also subjected to these processes.
The digestive system consists of the mouth, oesophagus, stomach, small intestine, large
intestine, rectum and anus together with the liver and pancreas.
The mouth is where food is chewed and mixed with saliva before being swallowed.
The oesophagus conveys food to the stomach.
In the stomach food is stored while further digestion takes place. The stomach produces
acid and enzymes to begin protein digestion. It can take 2–4 hours before food is passed
onto the small intestine.
Stomach acid and enzymes can destroy some drugs and they have to be protected by
an enteric coat so they pass unharmed into the small intestine.
Semi-digested and liquidized food passes gradually from the stomach into the duodenum,
the first part of the small intestine.
The small intestine is the most important part of the digestive system for digestion
because it produces many enzymes and is highly adapted for absorption of nutrients. It
has a large overall surface area because of its length and because its inner lining is folded
into villi.
As food enters the small intestine secretions are added from the gall bladder and
pancreas. Pancreatic secretions contain many digestive enzymes and sodium bicarbonate,
which neutralizes stomach acid. Bile contains bile acids, which are essential for the
emulsification of fats prior to their digestion.
The pH in the small intestine is slightly alkaline. While this favours the absorption
of basic drugs because they will be unionized, most drug absorption takes place in the
small intestine anyway because of the large surface area.
Nutrients (and drugs) absorbed pass directly to the liver in the hepatic portal system
before going to other parts of the body.
The liver excretes some drugs into the intestine via bile. Once back in the small
intestine the original drug can be reabsorbed.
The large intestine is where water is reabsorbed from the remains of digested food.
Here some drug metabolites that have been excreted in bile can be regenerated by the
action of bacteria in the large intestine.
The absorbing membrane for nutrients and drugs is the mucous membrane of the
epithelial cells lining the gastrointestinal tract. General factors affecting diffusion across
cell membranes, considered above, apply in addition to the pH of gastrointestinal contents:
surface area of the gastrointestinal tract; gastric emptying and intestinal transit time; blood
flow from the gastrointestinal tract; plasma protein binding; active transport mechanisms
and drug formulation. Table 2.1 gives some of the effects these factors have on drug
absorption.
Once absorbed from the gastrointestinal tract a drug passes directly to the liver in the
portal circulation and may be subjected to metabolism before further distribution round the body. This is known as first pass metabolism, which can result in considerable loss
of activity for some drugs on first pass through the liver.
Some drugs are recycled by enterohepatic shunting (or cycling). Enterohepatic shunting
describes the process whereby a drug is first metabolized and then excreted into the
intestine via bile. Once in the intestine gut bacteria or intestinal enzymes convert the
drug back to its original form, which is then reabsorbed. This effect, which can be
repeated many times, prolongs the duration of action of the drug until it is eventually
excreted by the kidneys.
Factors affecting absorption from the gastrointestinal tract
Factor Effect
pH of gastrointestinal contents Acidic drugs are unionized in acidic conditions and
preferentially absorbed in the stomach; basic drugs
are unionized in alkaline conditions and
preferentially absorbed in the small intestine
Surface area The gastrointestinal tract and the small intestine in
particular has a huge surface area, adapted for
absorption; because of this and despite the effects of
pH most drugs are predominantly absorbed in the
small intestine
Gastric emptying and intestinal
transit time Drugs given with a meal take longer to be absorbed;
this may be necessary for drugs principally absorbed
in the stomach or for those that irritate the stomach
lining; some very lipid-soluble drugs are better
absorbed with a fatty meal; other drugs can delay
gastric emptying or increase/decrease intestinal
transit time
Blood flow The intestine has a good blood flow that creates a
concentration gradient as the drug is constantly
being removed from its site of absorption
Plasma protein binding Many drugs are bound to plasma proteins and this
helps maintain the concentration gradient because
the bound drug is effectively removed
Active transport mechanisms Of minor importance but drugs related to nutrients can
be absorbed more rapidly by transport mechanisms
Formulation Some drugs can be made to be rapidly dissolving for
quick effect; others may have an enteric coat to
protect the stomach lining/protect the drug from
stomach acid
Drug distribution
Only a free drug at its site of action can have a pharmacological effect, therefore it is
important that a drug is distributed around the body effectively.
