General Pharmacology AND FULL HISTORY
Lecture
Nr.1 General Pharmacology
History of Pharmacology. Since time immemorial, medicaments have been
used for treating disease in humans and animals. The herbals of antiquity
describe the therapeutic powers of certain plants and minerals. Belief in the
curative powers of plants and certain substances rested exclusively upon
traditional knowledge, that is, empirical information not subjected to critical
examination.
Claudius Galen (129–200 A.D.) first attempted to consider the
theoretical background of pharmacology. Both theory and practical experience
were to contribute equally to the rational use of medicines through
interpretation of observed and experienced results. “The empiricists say
that all is found by experience. We, however, maintain that it is found in part
by experience, in part by theory. Neither experience nor theory alone is apt to
discover all.”
The Impetus
Theophrastus von Hohenheim (1493– 1541 A.D.), called Paracelsus, began to
quesiton doctrines handed down from antiquity, demanding knowledge of the
active ingredient(s) in prescribed remedies, while rejecting the irrational
concoctions and mixtures of medieval medicine. He prescribed chemically defined
substances with such success that professional enemies had him prosecuted as a
poisoner. Against such accusations, he defended himself with the thesis that
has become an axiom of pharmacology: “If you want to explain any poison
properly, what then isn‘t a poison? All things are poison, nothing is without
poison; the dose alone causes a thing not to be poison.”
Early Beginnings
Johann Jakob Wepfer (1620–1695) was the first to verify by animal
experimentation assertions about pharmacological or toxicological actions. “I
pondered at length. Finally I resolved to clarify the matter by experiments
Foundation
Rudolf Buchheim (1820–1879) founded the first institute of
pharmacology at the University
of Dorpat Tartu , Estonia
“The science of medicines is a theoretical, i.e., explanatory, one. It
is to provide us with knowledge by which our judgement about the utility of
medicines can be validated at the bedside.” Consolidation – General
Recognition
Oswald Schmiedeberg (1838–1921), together with his many disciples (12 of
whom were appointed to chairs of pharmacology), helped to establish the high
reputation of pharmacology. Fundamental concepts such as structure-activity
relationship, drug receptor, and selective toxicity emerged from the work of,
respectively, T. Frazer (1841– 1921) in Scotland Langley England Germany England
laboratory and was founder of the Journal of Pharmacology and
Experimental Therapeutics (published from 1909 until the present).
Status Quo
After 1920, pharmacological laboratories sprang up in the pharmaceutical
industry, outside established university institutes. After 1960, departments of
clinical pharmacology were set up at many universities and in industry.
Drug Sources
Drug and Active Principle
Until the end of the 19th century, medicines were natural organic or inorganic
products, mostly dried, but also fresh, plants or plant parts. These might
contain substances possessing healing
(therapeutic) properties or substances exerting a toxic effect. In order
to secure a supply of medically useful products not merely at the time of
harvest but year-round, plants were preserved by drying or soaking them in
vegetable oils or alcohol. Drying the plant or a vegetable or animal product
yielded a drug (from French “drogue” – dried herb). Colloquially, this
term nowadays often refers to chemical substances with high potential for
physical dependence and abuse. Used scientifically, this term implies nothing
about the quality of action, if any. In its original, wider sense, drug could
refer equally well to the dried leaves of peppermint, dried lime blossoms,
dried flowers and leaves of the female cannabis plant (hashish, marijuana), or
the dried milky exudate obtained by slashing the unripe seed capsules of Papaver
somniferum (raw opium). Nowadays, the term is applied quite
generally to a chemical substance that is used for pharmacotherapy.
Soaking plants parts in alcohol (ethanol) creates a tincture. In
this process, pharmacologically active constituents of the plant are extracted
by the alcohol. Tinctures do not contain the complete
spectrum of substances that exist in the plant or crude drug, only those
that are soluble in alcohol. In the case of opium tincture, these ingredients
are alkaloids (i.e., basic substances of plant origin) including:
morphine, codeine, narcotine = noscapine, papaverine, narceine, and others.
Using a natural product or extract to treat a disease thus usually entails the
administration of a number of substances possibly possessing very different
activities. Moreover, the dose of an individual
constituent contained
within a given amount of the natural product is subject to large variations,
depending upon the product‘s geographical origin (biotope), time of harvesting,
or conditions and length of storage. For the same reasons, the relative
proportion of individual constituents may vary considerably. Starting with the
extraction of morphine from opium in 1804 by F. W. Sertürner (1783–1841), the
active principles of many other natural products were subsequently isolated in
chemically pure form by pharmaceutical laboratories.
The aims of isolating active principles are:
1. Identification of the active ingredient(s).
2. Analysis of the biological effects
(pharmacodynamics) of individual ingredients and of their fate in the
body (pharmacokinetics).
3. Ensuring a precise and constant dosage in the therapeutic use of
chemically pure constituents.
4. The possibility of chemical synthesis, which would afford
independence from limited natural supplies and create conditions for the
analysis of structure-activity relationships.
Finally, derivatives of the original constituent may be synthesized in
an effort to optimize pharmacological properties. Thus, derivatives of the
original constituent with improved therapeutic usefulness may be developed.
Drug Development
This process starts with the synthesis of novel chemical
compounds. Substances with complex structures may be obtained from various
sources, e.g., plants (cardiac glycosides), animal tissues
(heparin), microbial cultures (penicillin G), or human cells
(urokinase), or by means of gene technology (human insulin). As more insight is
gained into structure-activity relationships, the search for new agents becomes
more clearly focused.
Preclinical testing yields information on the biological effects of new
substances. Initial screening may employ biochemical-pharmacological
investigations (e.g., receptor-binding assays or experiments on cell cultures, isolated
cells, and isolated organs. Since these models invariably fall short of
replicating complex biological processes in the intact organism, any potential
drug must be tested in the whole animal.Only animal experiments can reveal
whether the desired effects will actually occur at dosages that produce little
or no toxicity. Toxicological investigations serve to evaluate the
potential for: (1) toxicity associated with acute or chronic administration;
(2) genetic
damage (genotoxicity, mutagenicity); (3) production of tumors (onco- or
carcinogenicity); and (4) causation of birth defects (teratogenicity). In
animals, compounds under investigation also have to be studied with respect to
their absorption, distribution, metabolism, and elimination (pharmacokinetics). Even at the level
of preclinical testing, only a very small fraction of new compounds will prove
potentially fit for use in humans. Pharmaceutical technology provides
the methods for drug formulation.
Clinical testing starts with
Phase I studies on healthy subjects and seeks to determine whether effects
observed in animal experiments also occur in humans. Dose-response
relationships are
determined.
In Phase II, potential drugs are first tested on selected
patients for therapeutic efficacy in those disease states for which they are
intended. Should a beneficial action be evident and the incidence of adverse
effects be acceptably small,
Phase III is entered, involving a larger group of patients in whom the new drug
will be compared with standard treatments in terms of therapeutic outcome. As a
form of human experimentation, these clinical trials are subject to review and
approval by institutional ethics committees according to international codes of
conduct (Declarations of Helsinki, Tokyo Venice
substances.
The decision to approve a new drug is made by a national
regulatory body (Food & Drug Administration in the U.S.A. Canada UK Europe ,
Australia
and thus become available for prescription by physicians and dispensing
by pharmacists. As the drug gains more widespread use, regulatory surveillance
continues in the form of postlicensing
studies (Phase IV of clinical trials). Only on the basis of
long-term experience will the risk: benefit ratio be properly assessed and,
thus, the therapeutic value of the new drug be determined.
Compartments
and branches of pharmacology.
Pharmacology
can be defined as the study of
substances that interact with living systems through chemical processes,
especially by binding to regulatory molecules and activating or inhibiting
normal body processes. These substances may be chemicals administered to
achieve a beneficial therapeutic effect on some process within the patient or
for their toxic effects on regulatory processes in parasites infecting the
patient. Such deliberate therapeutic applications may be considered the proper
role of medical pharmacology, which is often defined as the science of
substances used to
prevent, diagnose, and treat disease.
Pharmacokinetic is the actions of the body on the drug
Pharmacodynamic is the actions of the drug on the body
Pharmacogenomics (or pharmacogenetics) is the study of the
genetic variations that cause individual differences in drug response. Future
clinicians may screen every patient for a variety of such differences before
prescribing a drug.
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1.general 2.special
- Pharmacokinetics a.
The remedies with action in
- Absorption the central nervous system
- Distribution (transport) b. Autonomic drugs
- Metabolism
c. Anti-inflammatory and
- Elimination
immunosuppresant drugs
- Pharmacodynamics d. Antimicrobial drugs
-Drug’s effects
e. Drugs affecting
-Mechanism of
action
internal system
-Place
of action
-Indications
-Contraindications
-Toxicity
-Unwanted effects
- Pharmacogenetics
-Interaction between drugs
and genetic system
Main indexes of
pharmacokinetics:
1.Volume of distribution (apparent)- the ratio of the amount of a drug
in the body to its concentration in the plasma or blood.
2. Clearance- the ratio of the rate of elimination of a drug to its
concentration in plasma or blood.
3. Half- life- the time it takes for the amount or concentration of a drug
to fall to 50 % of an earlier measurement
4. Biovailability- the fraction of the
administrated dose of a drug that reaches the systemic circulation.
5. Plasmatic concentration- the
ratio of a drug that reaches the
systemic circulation and make an effect.
Characteristics of ways of administration.
Ways
of administration
I. The main routs of administration are:
A. With skin’s lesion B. Without skin’s
lesion
1.intravasculars 1.through digestive
system
- intravenous oral,
sublingual, rectal
- intracardiac 2. local
administration
- intraarterial (application
to the skin, cornea)
2.extravascular 3.
intracavy
subcutaneous
-inhalation
intramuscular
-intravaginal
3. intracavity
-intranasal
intrathecal
intraventricular
intraatrial
intraperitonial
intrapleural
intraarticular
II. An alternate method of classifying these routes
of administration is ENTERAL
and PARENTERAL.
Enteral means to do with the GI tract and includes oral, buccal, and rectal.
Parenteral means not through the alimentary canal and commonly refers to injections
such as IV, IM, and SC; but could
also include topical and inhalation. We can also
distinguish IV from the rest, as with all others at least one membrane must be
crossed, thus an absorption process is involved in the administration and the
pharmacokinetics.
Particularities of enteral ways of administration:
Buccal/Sublingual
Some drugs are taken as smaller tablets which are held in the mouth or
under the tongue. These are buccal or sublingual dosage forms. Buccal tablets
are often harder tablets [4 hour disintegration time], designed to dissolve
slowly. Nitroglycerin, as a softer sublingual tablet [2 min disintegration
time], may be used for the rapid relief of angina. This ROA is also used for
some steroids such as testosterone and oxytocin. Nicotine containing chewing
gum may be used for cigarette smoking
replacement.
Advantages
First pass - The liver is by-passed thus there is no loss of drug
by first pass effect for buccal administration. Bioavailability is higher.
Rapid absorption - Because of the good blood supply to the area
absorption is usually quite rapid.
Drug stability - pH in mouth relatively neutral (cf. stomach -acidic).
Thus a drug may be more stable.
Disadvantages
Holding the dose in the mouth is inconvenient. If any is swallowed that
portion must be treated as an oral dose and subject to first pass metabolism.
Small doses only can be accommodated easily.
Oral
Only some advantages and disadvantages of oral administration will be
presented in this Chapter. Oral administration will be covered in more detail
in subsequent Chapters.
Advantages
Convenient - portable, no pain, easy to take. Cheap - no
need to sterilize (but must be hygienic of course),compact, multi-dose bottles,
automated machines produce tablets in large quantities.
Variety - fast release tablets, capsules, enteric coated, layered tablets, slow
release, suspensions, mixtures
Disadvantages
Sometimes inefficient - high dose or low solubility drugs may suffer poor
availability, only part of the dose may be absorbed. Griseofulvin was
reformulated about 1970 to include the drug as a micronized powder. The
recommended dose at that time was decreased by a factor of two because of the
improved bioavailability.
First-pass effect - drugs absorbed orally are transported to the general
circulation via the liver. Thus drugs which are extensively metabolized will be
metabolized in the liver during absorption.
e.g. the propranolol oral dose is somewhat higher than the IV, the same
is true for morphine. Both these drugs and many others are extensively
metabolized in the liver.
Food - Food and G-I motility can effect drug absorption. Often patient
instructions include a direction to take with food or take on an empty stomach.
Absorption is slower with food for
tetracyclines and penicillins, etc. However, for propranolol
bioavailability is higher after food, and for griseofulvin absorption is higher
after a fatty meal.
Local effect - Antibiotics may kill normal gut flora and allow
overgrowth of fungal varieties. Thus, antifungal agent may be included with an
antibiotic.
Unconscious patient - Patient must be able to swallow solid dosage forms.
Liquids may be given by tube.
Rectal
Most commonly by suppository or enema. Some drugs given
by this route include aspirin, theophylline, chlorpromazine and some
barbiturates
Advantages
By-pass liver - Some of the veins draining the rectum lead directly to
the general circulation, thus by-passing the liver. Reduced first-pass effect. Useful
- This route may be most useful for patients unable to take drugs orally or
with younger children.
Disadvantages
Erratic absorption - Absorption is often incomplete and erratic. However
for some drugs it is quite useful. There is research being conducted to look at
methods of improving the extent and variability of rectal administration. Not
well accepted.
Particularities of injectable and non-injectable
parenteral ways of administration
Subcutaneous
This involves administration of the drug dose just under the skin.
Advantages
Can be given by patient, e.g. in the case of insulin Absorption slow but
usually complete. Improved by massage or heat. Vasoconstrictor may be added to
reduce the absorption of a local anesthetic agent, thereby prolonging its
effect at the site of interest.
Disadvantages
Can be painful. Irritant drugs can cause local tissue damage. Maximum of
2 ml injection thus often small doses limit use.
Intramuscular
Advantages
Larger volume, than
sc, can be given by IM A depot or sustained release effect is possible with IM
injections, e.g. procaine penicillin
Disadvantages
Trained personnel
required for injections. The site of injection will influence the absorption,
generally the deltoid muscle is the best site Absorption is sometimes erratic,
especially for poorly soluble drugs, e.g. diazepam, phenytoin. The solvent
maybe absorbed faster than the drug causing precipitation of the drug at the
site of injection.
Intravenous
Drugs may be given into a peripheral vein over 1 to 2 minutes or longer
by infusion. Rapid injections are used to treat epileptic seizures, acute
asthma, or cardiac arrhythmias.
Advantages
Rapid - A quick response is possible
Total dose - The whole dose is delivered to the blood stream. Large
doses can be given by extending the time of infusion.
Veins relatively insensitive - to irritation by irritant drugs at higher
concentration in dosage forms.
Disadvantages
Suitable vein - It may be difficult to find a suitable vein.
Maybe toxic - Because of the rapid response, toxicity can be a
problem with rapid drug administrations, could then give as an infusion,
monitoring for toxicity.
Requires trained personnel - Trained personnel are required to give
intravenous injections.
Expensive - Sterility, pyrogen testing and larger volume of
solvent means greater cost for preparation, transport and storage
Inhalation
Local Effect - bronchodilators
Systemic Effect - general anesthesia Rapid absorption, by-passing the
liver Absorption of gases is relatively efficient, however solids and liquids
are excluded if larger than 20 micron and even then only 10 % of the dose may
be absorbed. Cromolyn is taken as a powder with 50 % of the particles within
the range of 2 to 6 micron. Larger than 20 micron and the particles impact in
the mouth and throat. Smaller than 0.5 micron and they aren’t retained.
Topical
Local effect - eye drops, antiseptic, sunscreen, callous removal,
etc.
Systemic effect - e.g., nitroglycerin ointment. Absorption through the
skin, especially via cuts and abrasions but also intact, can be quite marked. This
can be a real problem in handling toxic materials in the laboratory or
pharmacy.
Other ROA’s
Other routes of administration include: intra-nasal, some
systemic absorption has been demonstrated for propranolol and some low dose
hormones; intra-arterial for cancer chemotherapy to maximize drug
concentrations at the tumor site; and intrathecal directly into the
cerebrospinal fluid.
Notion of transdermal therapeutic systems.
A transdermal therapeutic system for the release
of active substances to a substrate is characterized by the structure of the
system comprising a substrate (1) provided with a separating layer (2), a film
layer (3) comprising the active substance, and a protective layer (4) provided
with a nonstick finish, the separating layer (2) consisting of a material whose
bond to the film layer (3) may be abolished. By means of printing methods, such
systems having small application thickness and high flexibility can be
manufactured, it being possible to provide a substrate that has been rendered adhesive
as an alternative to the substrate/separating layer-complex. A printing method
limiting the active substance-containing region to the application site reduces
disposal problems. Adhesive patches containing drugs for delivery through
the skin. Packaged in a membrane, the drug is released at a controlled rate.
Not all drugs can be administered in this way, but a number of preparations are
available, including: glyceryl trinitrate to treat angina; hyoscine for travel
sickness; oestrogen replacement for menopausal problems; and the nicotine patch
as an aid to giving up smoking.
The main components to a
transdermal patch are: 
- Liner - Protects the patch during storage.
The liner is removed prior to use.
- Drug - Drug solution in direct contact with
release liner
- Adhesive - Serves to adhere the components of
the patch together along with adhering the patch to the skin
- Membrane - Controls the release of the drug
from the reservoir and multi-layer patches
- Backing - Protects the patch from the outer
environment
Penetration of drug through biological
membranes. Factors that influence the permeability of membranes for drugs. Characteristics of biological barriers.
External Barriers of the Body
Prior to its uptake into the blood (i.e.,during absorption), a drug has
to overcome barriers that demarcate the body from its surroundings, i.e.,
separate the internal milieu from the external milieu.
These boundaries are formed by the skin and mucous membranes. When
absorption takes place in the gut (enteral absorption), the intestinal
epithelium is the barrier. This singlelayered epithelium is made up of
enterocytes and mucus-producing goblet cells. On their luminal side, these
cells are joined together by zonulae occludentes (indicated by black
dots in the inset, bottom left). A zonula occludens or tight junction is
a region in which the phospholipid membranes of two cells establish close
contact and become joined via integral membrane proteins (semicircular inset,
left center). The region of fusion surrounds each cell like a ring, so that
neighboring cells are welded together in a continuous belt. In this manner, an
unbroken phospholipid layer is formed (yellow area in the schematic drawing,
bottom left) and acts as a continuous barrier between the two spaces separated
by the cell layer – in the case of the gut, the intestinal lumen (dark blue)
and the interstitial space
(light blue). The
efficiency with which such a barrier restricts exchange of substances can be
increased by arranging these occluding junctions in multiple arrays, as for
instance in the endothelium of cerebral blood vessels. The connecting proteins
(connexins) furthermore serve to restrict mixing of other functional membrane
proteins (ion pumps, ion channels) that occupy specific areas of the cell
membrane. This phospholipid bilayer represents the intestinal mucosa-blood
barrier that a drug must cross during its enteral absorption. Eligible drugs
are those whose physicochemical properties allow permeation through the
lipophilic membrane interior (yellow) or that are subject to a special carrier
transport mechanism. Absorption of such drugs proceeds rapidly, because the
absorbing surface is greatly enlarged due to the formation of the epithelial
brush border
(submicroscopic foldings of the plasmalemma). The absorbability of a
drug is characterized by the absorption quotient, that is, the amount
absorbed divided by the amount in the gut available for absorption. In the respiratory
tract, cilia-bearing epithelial cells are also joined on the luminal side
by zonulae occludentes, so that the bronchial space and the interstitium
are separated by a continuous phospholipid barrier. With sublingual or buccal
application, a drug encounters the non-keratinized, multilayered squamous
epithelium of the oral mucosa. Here, the cells establish punctate
contacts with each other in the form of desmosomes (not shown); however, these
do not seal the intercellular clefts. Instead, the cells have the property of
sequestering phospholipid- containing membrane fragments that assemble into
layers within the extracellular space (semicircular inset, center right). In
this manner, a continuous phospholipid barrier arises also inside squamous
epithelia, although at an extracellular location, unlike that of intestinal
epithelia. A similar barrier principle operates in the multilayered keratinized
squamous epithelium of the outer skin. The presence of a continuous
phospholipid layer means that squamous epithelia will permit passage
of lipophilic drugs only, i.e., agents capable of diffusing through
phospholipid membranes, with the epithelial thickness determining the extent
and speed of absorption. In addition, cutaneous absorption is impeded by the
keratin layer, the stratum corneum, which is very unevenly developed in various
areas of the skin.
Blood-Tissue
Barriers
Drugs are transported in the blood to different tissues of the body. In
order to reach their sites of action, they must leave the bloodstream. Drug
permeation occurs largely in the capillary bed, where both surface area and
time available for exchange are maximal (extensive vascular branching, low
velocity of flow). The capillary wall forms the blood-tissue barrier.
Basically, this consists of an endothelial cell layer and a basement membrane
enveloping the latter (solid black line in the schematic drawings). The
endothelial cells are “riveted” to each other by tight junctions or occluding
zonulae (labelled Z in the electron micrograph, top left) such that no clefts,
gaps, or pores remain that would permit drugs to pass unimpeded from the blood
into the interstitial fluid.
The blood-tissue barrier is developed differently in the various
capillary beds. Permeability to drugs of the capillary wall is determined by
the structural and functional characteristics of the endothelial
cells. In many capillary beds, e.g., those of cardiac muscle,
endothelial cells are characterized by pronounced endo- and transcytotic
activity, as evidenced by numerous invaginations and vesicles (arrows in
the EM micrograph, top right). Transcytotic activity entails transport of fluid
or macromolecules from the blood into the interstitium and vice versa. Any
solutes trapped in the fluid, including drugs, may traverse the blood-tissue
barrier. In this form of transport, the physicochemical
properties of drugs are of little importance. In some capillary beds
(e.g., in the pancreas), endothelial cells exhibit fenestrations.
Although the cells are tightly connected by continuous junctions, they possess pores
(arrows in EM micrograph, bottom right) that are closed only by diaphragms.
Both the diaphragm and basement membrane can be readily penetrated by
substances of low molecular weight — the majority of drugs — but less so by
macromolecules, e.g., proteins such as insulin (G: insulin storage granules.
Penetrability of macromolecules is determined by molecular size and electrical
charge. Fenestrated endothelia are found in the capillaries of the gut and
endocrine glands. In the central nervous system (brain and spinal
cord), capillary endothelia
lack pores and there is little transcytotic activity. In order to cross
the blood-brain barrier, drugs must diffuse transcellularly, i.e.,
penetrate the luminal and basal membrane of endothelial cells. Drug movement
along this path requires specific physicochemical properties or the presence of
a transport mechanism Thus, the
blood-brain barrier is permeable only to certain types of drugs.
Drugs exchange freely between blood and interstitium in the liver,
where endothelial cells exhibit large fenestrations (100nm in diameter) facing Disse’s
spaces (D) and where neither diaphragms nor basement membranes impede drug
movement. Diffusion barriers are also present beyond the capillary wall: e.g., placental
barrier of fused syncytiotrophoblast cells; blood: testicle barrier —
junctions interconnecting Sertoli cells; brain choroid plexus: blood barrier
— occluding junctions between ependymal cells. (Vertical bars in the EM
micrographs represent 1 µm; E: cross-sectioned
erythrocyte; AM: actomyosin; G: insulin-containing granules.)
Membrane Permeation
An ability to penetrate lipid bilayers is a prerequisite for the
absorption of drugs, heir entry into cells or cellular organelles, and passage
across the bloodbrain barrier. Due to their amphiphilic nature, phospholipids
form bilayers possessing a hydrophilic surface and a hydrophobic
interior.Substances may traverse this membrane in three different ways.
Diffusion . Lipophilic substances (red dots) may enter the membrane from the
extracellular space (area shown in ochre), accumulate in the membrane, and exit
into the cytosol (blue area). Direction and speed of permeation depend on the
relative concentrations in the fluid phases and the
membrane. The steeper the gradient (concentration difference), the more
drug will be diffusing per unit of time (Fick’s Law). The lipid membrane
represents an almost insurmountable obstacle
for hydrophilic substances (blue triangles).
Transport . Some drugs may penetrate membrane barriers with the help of transport
systems (carriers), irrespective of their physicochemical properties,
especially lipophilicity. As a prerequisite, the drug must have affinity for
the carrier (blue triangle matching recess on “transport system”) and, when
bound to the latter, be capable of being ferried across the membrane. Membrane
passage via transport mechanisms is subject to competitive inhibition by
another substance possessing similar affinity for the carrier. Substances
lacking in affinity (blue circles) are not transported. Drugs utilize carriers
for physiological substances, e.g., L-dopa uptake by L-amino acid carrier
across the blood-intestine and blood-brain barriers , and uptake of
aminoglycosides by the carrier transporting basic polypeptides through the
luminal membrane of kidney tubular cells . Only drugs bearing sufficient resemblance
to the physiological substrate of a carrier will exhibit affinity for it.
Finally, membrane penetration may occur in the form of small membrane- covered
vesicles. Two different systems are considered.
Transcytosis (vesicular transport). When new vesicles are pinched off, substances
dissolved in the extracellular fluid are engulfed, and then ferried through the
cytoplasm, vesicles (phagosomes) undergo fusion with lysosomes to form
phagolysosomes, and the transported substance is metabolized. Alternatively,
the vesicle may fuse with the opposite cell membrane (cytopempsis).
Receptor-mediated endocytosis The drug first binds
to membrane surface receptors (1, 2) whose cytosolic domains contact special
proteins (adaptins, 3). Drug-receptor complexes migrate laterally in the
membrane and aggregate with other complexes by a clathrin-dependent process
(4). The affected membrane region invaginates and eventually pinches off to
form a detached vesicle (5). The clathrin coat is shed immediately (6),
followed by the adaptins (7). The remaining vesicle then fuses with an “early”
endosome (8), whereupon proton concentration rises inside the vesicle. The
drug-receptor complex dissociates and the receptor returns into the cell
membrane. The “early” endosome delivers its contents to predetermined
destinations, e.g., the Golgi complex, the cell nucleus, lysosomes, or the
opposite cell membrane (transcytosis). Unlike simple endocytosis,
receptor-mediated endocytosis is contingent on affinity for specific receptors
and operates independently of concentration gradients.
The
rules drugs transfer through membranes
Easy transfer
for :
Difficult transfer for:
1. small size 1 big size
2 free
molecular in the blood 2 fixed with protein
3 undissociated
3 dissociated (ionization)
4 with high lipid-soluble
Drug distribution in organism (transport,
distribution and deposition).
Following its uptake into the body, the drug is distributed in the blood
(1) and through it to the various tissues of the body. Distribution may
be restricted to the extracellular space (plasma volume plus interstitial
space) or may also extend into the intracellular space. Certain drugs may bind
strongly to tissue structures, so that plasma concentrations fall significantly
even before elimination has begun . After being distributed in blood,
macromolecular substances remain largely confined to the vascular space,
because their permeation through the blood-tissue barrier, or endothelium, is
impeded, even where capillaries are fenestrated. This property is exploited
therapeutically when loss of blood necessitates refilling of the vascular bed,
e.g., by infusion of dextran solutions. The vascular space is, moreover,
predominantly occupied by substances bound with high affinity to plasma
proteins ; determination of the plasma volume with protein-bound dyes).
Unbound, free drug may leave the bloodstream, albeit with varying ease, because
the blood-tissue barrier is differently developed in different segments of the
vascular tree. Distribution in the body is determined by the ability to
penetrate membranous barriers . Hydrophilic substances (e.g., inulin) are
neither taken up into cells nor bound to cell surface structures and can, thus,
be used to determine the extracellular fluid volume. Some lipophilic substances
diffuse through the cell membrane and, as a result, achieve a uniform
distribution. The volume ratio interstitial: intracellular water varies with
age and body weight. On a percentage basis, interstitial fluid volume is large
in premature or normal neonates (up to 50% of body water), and smaller in the
obese and the aged. The concentration (c) of a solution corresponds to the
amount (D) of substance dissolved in a volume (V); thus, c = D/V. If the dose
of drug (D) and its plasma concentration (c) are known, a volume of distribution
(V) can be calculated from V = D/c. However, this represents an apparent volume
of distribution (Vapp),
because an even distribution in the body is assumed in its calculation.
Homogeneous distribution will not occur if drugs are bound to cell membranes or
to membranes of intracellular organelles or are stored within
the latter. In these cases, Vapp can exceed the actual size of the available fluid
volume.
The types of transport
(drugs transport in the body)
I Passive II Specialized
-filtration
active
-simple diffusion
exchange diffusion
facility diffusion
pinocytosis
1.Filtration-is aqueous diffusion of
molecules into and within the watery extracellular and intracellular spaces.
The membranes of most capillaries have small water-filled pores that permit the
filtration of the molecules up to the size of small proteins between the blood
and the extravascular space. This filtration takes place according to the
concentration gradient without the energy consume.
2. Simple diffusion-is the movement of
molecules trough membranes and other lipid structures. This is a passive
process after the concentration gradient. These molecules with high
lipid-soluble and undissociated are moving after concentration gradient and
without the consume of energy. If the pKa of the drug and pH of the medium are
known the fraction of molecules in the ionized state can be predicted by means
of the Henderson-Hasselbach equation:
Log Protonated form = pKa-pH
Unprotonated form
“Protonated” means associated with a proton (a
hydrogen ion): this form of the equation is applied to both acids and bases.
3.Active transport: The system of
transport, energy is necessary in this case. Dissociated molecules of bigger
size can move against concentration gradient.
4. Facilitated diffusion is effectuated with transport’s system,
without energy and after concentration gradient.
5. Changing diffusion is the transport
of two substances with the same system of transport.
Binding to Plasma
Proteins
Having entered the blood, drugs may bind to the protein molecules that
are present in abundance, resulting in the formation of drug-protein complexes.
Protein binding involves primarily albumin and, to a lesser extent,
!-globulins and acidic glycoproteins. Other plasma proteins (e.g., transcortin,
transferrin, thyroxin-binding globulin) serve
specialized functions in connection with specific substances. The degree
of binding is governed by the concentration of the reactants and the affinity
of a drug for a given protein. As a rule, drugs exhibit much lower affinity for
plasma proteins than for their specific binding sites (receptors).
In the range of therapeutically relevant concentrations, protein binding
of most drugs increases linearly with concentration (exceptions: salicylate and
certain sulfonamides). The albumin molecule has different binding sites for
anionic and cationic ligands, but van der Waals’ forces also contribute.
The extent of binding correlates with drug hydrophobicity (repulsion of drug by
water).
Binding to plasma proteins is instantaneous and reversible, i.e., any
change in the concentration of unbound drug is immediately followed by a
corresponding change in the concentration of bound drug. Protein binding is of
great importance, because it is the concentration of free drug that determines
the intensity of the effect. At an identical total plasma concentration (say,
100
ng/mL) the effective concentration will be 90 ng/mL for a drug
10% bound to protein, but 1 ng/mL for a drug 99 % bound to protein. The
reduction in concentration of free drug resulting from
protein binding affects not only the intensity of the effect but also
biotransformation (e.g., in the liver) and elimination in the kidney, because
only free drug will enter hepatic sites of metabolism
or undergo glomerular filtration. When concentrations of free drug fall,
drug is resupplied from binding sites on plasma proteins. Binding to plasma
protein is equivalent to a depot in prolonging
the duration of the effect by retarding elimination, whereas the
intensity of the effect is reduced. If two substances have affinity for the
same binding site on the albumin molecule, they may compete for that site. One
drug may displace another from its binding site and thereby elevate the free
(effective) concentration of the displaced drug (a form of drug interaction).
Elevation of the free concentration of the displaced drug means increased
effectiveness and accelerated elimination.
A decrease in the concentration of albumin (liver disease, nephrotic
syndrome, poor general condition) leads to altered pharmacokinetics of drugs
that are highly bound to albumin. Plasma protein-bound drugs that are
substrates for transport carriers can be cleared from blood at great velocity,
e.g., p-aminohippurate by the renal tubule and sulfobromophthalein by
the liver. Clearance rates of these substances can be used to determine renal
or hepatic blood flow.
Biotransformation
of Drugs
Many drugs undergo chemical modification in the body (biotransformation).
Most frequently, this process entails a loss of biological activity and an
increase in hydrophilicity (water solubility), thereby promoting elimination
via the renal route. Since rapid drug elimination improves accuracy in
titrating the therapeutic concentration, drugs are often designed with built-in
weak links. Ester bonds are such links, being subject to hydrolysis by the
ubiquitous esterases. Hydrolytic cleavages, along with oxidations,
reductions, alkylations, and dealkylations, constitute Phase I
reactions of drug metabolism. These reactions subsume all metabolic
processes apt to alter drug molecules chemically and take place chiefly in the
liver. In Phase II (synthetic) reactions, conjugation products of either
the drug itself or its Phase I metabolites are formed, for instance, with
glucuronic or sulfuric acid.
Enterohepatic Cycle
After
an orally ingested drug has been absorbed from the gut, it is transported via
the portal blood to the liver, where it can be conjugated to glucuronic or
sulfuric acid or to other organic acids. At the pH of body fluids, these acids
are predominantly ionized; the negative charge confers high polarity upon the
conjugated drug molecule and, hence, low membrane penetrability. The conjugated
products may pass from hepatocyte into biliary fluid and from there back into
the intestine. O-glucuronides can be cleaved by bacterial !-glucuronidases in
the colon, enabling the liberated drug molecule to be reabsorbed. The enterohepatic
cycle acts to trap drugs in the body. However, conjugated products enter
not only the bile but also the blood. Glucuronides with a molecular weight (MW)
> 300 preferentially pass into the blood, while those with MW > 300 enter
the bile to a larger extent. Glucuronides circulating in the blood undergo
glomerular filtration in the kidney and are excreted in urine because their
decreased lipophilicity prevents tubular reabsorption.
Drugs that are subject to enterohepatic cycling are, therefore, excreted
slowly. Pertinent examples include digitoxin and acidic nonsteroidal
anti-inflammatory agents.
Conjugations
The most important of phase II conjugation reactions is glucuronidation.
This reaction does not proceed spontaneously, but requires the activated
form of glucuronic acid, namely glucuronic acid uridine diphosphate. Microsomal
glucuronyl transferases link the activated glucuronic acid with an acceptor
molecule. When the latter is a phenol or alcohol, an ether glucuronide will be
formed. In the case of carboxyl-bearing molecules, an ester glucuronide is the
result. All of these are O-glucuronides. Amines may form N-glucuronides that,
unlike O-glucuronides, are resistant to bacterial !-glucuronidases. Soluble
cytoplasmic sulfotransferases conjugate activated sulfate (3’-
phosphoadenine-5’-phosphosulfate) with alcohols and phenols. The
conjugates are acids, as in the case of glucuronides. In this respect, they
differ from conjugates formed by acetyltransferases
from activated acetate (acetylcoenzyme A) and an alcohol or a
phenol. Acyltransferases are involved in the conjugation of the amino acids glycine
or glutamine with carboxylic acids. In these cases, an amide bond is
formed between the carboxyl groups of the acceptor and the amino group of the
donor molecule (e.g., formation of salicyluric acid from salicylic acid and
glycine). The acidic group of glycine or glutamine remains free.
Enzymopathy is an inborn error
of metabolism consisting of defective or absent enzymes, as in the glycogenoses
or the mucopolysaccharidoses.
Glucose-6-phosphate dehydrogenase (G6PD)
deficiency is an inherited condition in which the body doesn't have enough of the
enzyme glucose-6-phosphate dehydrogenase, or G6PD, which helps red blood cells
(RBCs) function normally. This deficiency can cause hemolytic anemia,
usually after exposure to certain medications, foods, or even infections.Most
people with G6PD deficiency don't have any symptoms, while others develop
symptoms of anemia only after RBCs have been destroyed, a condition called hemolysis.
In these cases, the symptoms disappear once the cause, or trigger, is removed.
In rare cases, G6PD deficiency leads to chronic anemia
Main drugs
which produce enzymatic induction and inhibition.
Enzymes are biomolecules
that catalyze
. Almost all enzymes are proteins. Enzyme activity can be affected by other molecules.
Inhibitors
are molecules that decrease enzyme activity; activators
are molecules that increase activity. Many drugs and poisons are enzyme
inhibitors. Activity is also affected by temperature,
chemical environment (e.g. pH),
and the concentration of substrate. Some enzymes are used
commercially, for example, in the synthesis of antibiotics.
In addition, some household products use enzymes to speed up biochemical
reactions (e.g., enzymes in biological washing
powders break down protein or fat stains on clothes; enzymes in meat
tenderizers break down proteins, making the meat easier to chew).
Drugs enzymatic induction: cyclophosphamide,
phenobarbitale, rifabutin, izoniazide, rifampicin
Drugs enzymatic supresors: anticoagulants,
ketoconazole, cimetidine etc.
Notion about drug removal and excretion.
The ways of drugs
elimination from the body
1 Through urine (urinary excretion) 4 Through
sweat
2 Through lungs
5 Through intestine
3 Through milk
Most drugs are eliminated in urine either
chemically unchanged or as metabolites. The kidney permits elimination because
the vascular wall structure in the region of the glomerular capillaries allows
unimpeded passage of blood solutes having molecular weights (MW) < 5000.
Filtration diminishes progressively as MW increases from 5000 to 70000 and
ceases at MW > 70000. With few exceptions, therapeutically used drugs and
their metabolites have much smaller molecular weights and can, therefore,
undergo glomerular filtration, i.e., pass from blood into primary urine.
Separating the capillary endothelium from the tubular epithelium,
the basal membrane consists of charged glycoproteins and acts as a
filtration barrier for high-molecular-weight substances. The relative density
of this barrier depends on the electrical charge of molecules that attempt to
permeate it. Apart from glomerular filtration, drugs present in blood
may pass into urine by active secretion. Certain cations and anions are
secreted by the epithelium of the proximal tubules into the tubular fluid via
special, energyconsuming transport systems. These transport systems have a
limited capacity. When several substrates are present simultaneously,
competition for the carrier may occur. During passage down the renal tubule,
urinary volume shrinks more than 100-fold; accordingly, there is a
corresponding concentration of filtered drug or drug metabolites. The resulting
concentration gradient between urine and interstitial fluid is preserved in the
case of drugs incapable of permeating the tubular epithelium. However, with
lipophilic drugs the concentration gradient will favor reabsorption of
the filtered molecules. In this case, reabsorption is not based on an active process
but results instead from passive diffusion. Accordingly, for protonated
substances, the extent of reabsorption is dependent upon urinary pH or the
degree of dissociation. The degree of dissociation varies as a function of the
urinary pH and the pKa, which
represents the pH value at which half of the substance exists in protonated (or
unprotonated) form. This relationship is graphically illustrated with the
example of a protonated amine having a pKa of 7.0.
In this case, at urinary pH 7.0, 50% of the amine will be present in the
protonated, hydrophilic, membrane-impermeant form (blue dots), whereas the
other half, representing the uncharged amine (orange dots), can leave the
tubular lumen in accordance with the resulting concentration gradient. If the pKa of an amine is higher (pKa = 7.5) or lower (pKa = 6.5), a correspondingly smaller or larger proportion
of the amine will be present in the uncharged, reabsorbable form. Lowering or
raising urinary pH by half a pH unit would result in analogous changes for an
amine having a pKa of 7.0. The
same considerations hold for acidic molecules, with the important difference
that alkalinization of the urine (increased pH) will promote the
deprotonization of -COOH groups and thus impede reabsorption. Intentional alteration
in urinary pH can be used in intoxications with proton-acceptor substances in
order to hasten elimination of the toxin (alkalinization ! phenobarbital; acidification !amphetamine).
Elimination of Lipophilic and Hydrophilic Substances
The terms lipophilic and hydrophilic
(or hydro- and lipophobic) refer to the solubility of substances in media
of low and high polarity, respectively. Blood plasma, interstitial fluid, and
cytosol are highly polar aqueous media, whereas lipids — at least in the
interior of the lipid bilayer membrane — and fat constitute apolar media. Most
polar substances are readily dissolved in aqueous media (i.e., are hydrophilic)
and lipophilic ones in apolar media. A hydrophilic drug, on reaching the
bloodstream, probably after a partial, slow absorption (not illustrated),
passes through the liver unchanged, because it either cannot, or will only
slowly, permeate the lipid barrier of the hepatocyte membrane and thus will
fail to gain access to hepatic biotransforming enzymes. The unchanged drug
reaches the arterial blood and the kidneys, where it is filtered. With
hydrophilic drugs, there is little binding to plasma proteins (protein binding
increases as a function of lipophilicity), hence the entire amount present in
plasma is available for glomerular filtration. A hydrophilic drug is not
subject to tubular reabsorption and appears in the urine. Hydrophilic drugs
undergo rapid elimination. If a lipophilic drug, because of its
chemical nature, cannot be converted into a polar product, despite having
access to all cells, including metabolically active liver cells, it is likely
to be retained in the organism. The portion filtered during glomerular passage
will be reabsorbed from the tubules. Reabsorption will be nearly complete,
because the free concentration of a lipophilic drug in plasma is low
(lipophilic substances are usually largely proteinbound). The situation portrayed for a lipophilic
non-metabolizable drug would seem undesirable because pharmacotherapeutic
measures once initiated would be virtually irreversible (poor control over
blood concentration).
Lipophilic drugs that are converted in the liver to hydrophilic
metabolites permit better control, because the lipophilic agent can be
eliminated in this manner. The speed of formation of hydrophilic metabolite
determines the drug’s length of stay in the body. If hepatic conversion to a
polar metabolite is rapid, only a portion of the absorbed drug enters the
systemic circulation in unchanged form, the remainder having undergone presystemic
(first-pass) elimination. When biotransformation is rapid, oral
administration of the drug is impossible. Parenteral or, alternatively,
sublingual, intranasal, or transdermal administration is then required in order
to bypass the liver. Irrespective of the route of administration, a portion of
administered drug may be taken up into and transiently stored in lung tissue
before entering the general circulation. This also constitutes presystemic
elimination. Presystemic elimination refers to the fraction of drug absorbed
that is excluded from the general circulation by biotransformation or by
first-pass binding. Presystemic elimination diminishes the bioavailability of
a drug after its oral administration. Absolute bioavailability =
systemically available amount/ dose administered; relative bioavailability
= availability of a drug contained in a test preparation with reference
to a standard preparation.
Drug Concentration in the Body as a Function of Time. First-Order
(Exponential) Rate Processes
Processes such as drug absorption and elimination display exponential
characteristics. As regards the former, this follows from the simple fact that
the amount of drug being moved per unit of time depends on the concentration
difference (gradient) between two body compartments (Fick’s Law). In drug
absorption from the alimentary tract, the intestinal contents and blood would
represent the compartments containing an initially high and low concentration,
respectively. In drug elimination via the kidney, excretion often depends on
glomerular filtration, i.e., the filtered amount of drug present in primary
urine. As the blood concentration falls, the amount of drug filtered per unit
of time diminishes. The resulting exponential decline is illustrated in (A).
The exponential time course implies constancy of the interval during which the
concentration decreases by one-half. This interval represents the half-life (t1/2) and is related to
the elimination rate constant k by the equation t1/2 = ln 2/k. The two parameters, together with the
initial concentration co,
describe a first-order (exponential) rate process. The constancy of the process
permits calculation of the plasma volume
that would be cleared of drug, if the remaining drug were not to assume
a homogeneous distribution in the total volume (a condition not met in
reality). This notional plasma volume freed of drug per unit of time is
termed the clearance. Depending on whether plasma concentration falls as
a result of urinary excretion or metabolic alteration, clearance is considered
to be renal or hepatic. Renal and hepatic clearances add up to total clearance
(Cltot) in the case of drugs
that are eliminated unchanged via the kidney and biotransformed in the liver.
Cltot represents the sum of
all processes contributing to elimination; it is related to the half-life (t1/2) and the apparent
volume of distribution
Vapp
by the equation:
t1/2
= In 2 x Vapp
Cltot
The smaller the volume of distribution or the larger the total
clearance, the shorter is the half-life.
In the case of drugs renally eliminated in unchanged form, the half-life
of elimination can be calculated from the cumulative excretion in urine; the
final total amount eliminated corresponds to
the amount absorbed.
Hepatic elimination obeys exponential kinetics because metabolizing
enzymes operate in the quasilinear region of their concentration-activity
curve; hence the amount of drug metabolized per unit of time diminishes with
decreasing blood concentration. The best-known exception to exponential
kinetics is the elimination of alcohol (ethanol), which obeys a linear time
course (zero-order kinetics), at least at blood concentrations > 0.02 %. It
does so because the rate-limiting enzyme, alcohol dehydrogenase, achieves
half-saturation at very low substrate concentrations, i.e., at about 80 mg/L
(0.008 %). Thus, reaction velocity reaches a plateau at blood ethanol
concentrations of about 0.02 %, and the amount of drug eliminated per unit of
time remains constant at concentrations above this level.
Time Course of Drug Concentration in Plasma
A. Drugs are taken up into and eliminated from the body by various routes.
The body thus represents an open system wherein the actual drug concentration
reflects the interplay of intake (ingestion) and egress (elimination). When an
orally administered drug is absorbed from the stomach and intestine, speed of
uptake depends on many factors, including the speed of drug dissolution (in the
case of solid dosage forms) and of gastrointestinal transit; the membrane
penetrability of the drug; its concentration gradient across the mucosa-blood
barrier; and mucosal blood flow. Absorption from the intestine causes
the drug concentration in blood to increase. Transport in blood conveys the
drug to different organs (distribution), into which it is taken up to a
degree compatible with its chemical properties and rate of blood flow through
the organ. For instance, well-perfused organs such as the brain receive a
greater proportion than do less well-perfused ones. Uptake into tissue causes
the blood concentration to fall. Absorption from the gut diminishes as the
mucosa-blood gradient decreases. Plasma concentration reaches a peak when the
drug amount leaving the blood per unit of time equals that being absorbed. Drug
entry into hepatic and renal tissue constitutes movement into the organs of
elimination. The characteristic phasic time course of drug concentration in
plasma represents the sum of the constituent processes of absorption,
distribution, and elimination, which overlap in time. When
distribution takes place significantly faster than elimination, there is an
initial rapid and then a greatly retarded fall in the plasma level, the former
being designated the !-phase (distribution phase), the latter the "-phase
(elimination phase). When the drug is distributed faster than it is absorbed,
the time course of the
plasma level can be described in mathematically simplified form by the
BatBateman function (k1 and
k2 represent the rate
constants for absorption and elimination, respectively).
B. The velocity of absorption depends on the route of administration. The
more rapid the administration, the shorter will be the time (tmax) required to reach
the peak plasma level (cmax),
the higher will be the cmax, and the earlier the plasma level will begin to fall
again. The area under the plasma level time curve (AUC) is independent
of the route of administration, provided the doses
and bioavailability are the same (Dost’s law of corresponding areas).
The AUC can thus be used to determine the bioavailability of a drug. The
ratio of AUC values determined after oral or intravenous administration of a
given dose of a particular drug corresponds to the proportion of drug entering
the systemic circulation after oral administration. The determination of plasma
levels affords a comparison of different proprietary preparations containing
the same drug in the same dosage. Identical plasma level time-curves of
different manufacturers’ products with reference to a standard preparation
indicate bioequivalence of the preparation under investigation with the
standard.
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