Only 1% of the new drugs introduced to the market in the last
25 years were developed to treat tropical diseases, despite the enormous
unmet need for such compounds. Only 10% of current global health research
is directed to address the medical needs of 90% of the human population.
pharmacotherapy / drug therapy or treatment : the treatment of disease
chemotherapy : the treatment of disease by chemical agents; originally
applied to use of chemicals that affect the causative organism unfavorably
but do not harm the patient
patent medicine : a drug or remedy protected by a trademark, available
proprietary medicine : a drug or remedy to which the manufacturing
pharmaceutical house has exclusive (proprietary) rights, and which is marketed
usually under a name that is registered as a trademark.
panacea : 1. a universal remedy. 2. an ancient name for a
healing herb or its juice.
decoction : 1. the act or process of boiling. 2. a medicine
or other substance prepared by boiling.
lanolin : the purified waxlike substance from the wool of sheep,
cleaned, deodorized, and decolorized; mixed with 25 to 30% water, it is
used as a water-in-oil ointment base.
modified lanolin : lanolin that has been processed to reduce the
amount of free lanolin alcohols and detergent and pesticide residues.
menstruum [it was long believed that the menstrual fluid had a peculiar
solvent quality] : a solvent medium
drug market : while historically 14% of drugs that entered Phase
1 trials eventually won approval, in 2004 8% of these drugs make it to
the marketplace, and that 50% of products fail in the late stage of Phase
3 trials, compared to 20% in the past, which has dramatically pushed up
the cost of drug development. Filings of standard new molecular entities
had fallen from 34 in 1995 to 12 last year, while original biological license
applications dropped from 33 in 1997 to 14 in 2003. Some estimates suggest
this has pushed the cost of developing a single drug from $1.1 billion
in 1995 to $1.7 billion in 2002ref.
A 2001 report by Joseph A. Dimasi, director of economic analysis for the
Tufts Center for the Study of Drug Development, found that while failure
rates during Phase 1 and Phase 2 trials increased between 1981–1986 and
1987–1992, failure rates during Phase 3 trials declinedref.
The failure rate of new clinical entities (NCEs) remained relatively
steady through the 1980s and early 1990s. Among NCEs for which an investigational
new drug application was filed in 1981–1983, approval success rates were
23.2%; 1984–1986, 20.5%; 1987–1989, 22.2%; and 1990–1992, 17.2%. This includes
both self-originated and acquired NCEsref.
In 2003 pharmaceutical companies spent 33 billion dollars in R&D and
11 billion dollars on marketing, not including "medical education" of doctors.
They received 22 billion dollars from drug sales. 20 new drugs were approved
in 2004 by the US FDA. 8 books were published in 2004 on the "evils" of
pharma. Americans spent 48.6 millions of dollars out of their own pockets
on prescription drugs in 2003 : they spent 414 millions of dollars on prescription
drugs in Canada in 2002 and 695 billions of dollars in 2003!
active substance : a chemical which
has been shown to have pharmacological activity.
distribution, metabolism, excretion (ADME) and toxicity data (together
called ADMET data)
dose (D) (posology)
dosing rate = dose / t
drug absorption from administration routes of the formulation
(first-pass effect = presystemic elimination)
oral ingestion / peroral (per os
(p.o., PO), i.e. by mouth) :
pill : a small globular or oval medicated mass
to be swallowed. Pills contain, in addition to the active drug, a diluent
(or filler) and an excipient to give the mass adhesiveness, firmness, and
plasticity, so that the pill can be worked by hand or machine to the desired
enteric pill : one coated with a substance, such as salol, which
will not dissolve in the stomach.
dragée [Fr. “sugar-plum”] : a sugar-coated pill, or medicated
capsule : a structure in which something is
enclosed, such as a hard or a soft, soluble container of a suitable substance,
for enclosing a dose of medicine
cachet : a disk-shaped wafer or capsule for
enclosing a dose of medicine.
tablet : a solid dosage form, of varying weight,
size, and shape, which may be molded or compressed, and which contains
a medicinal substance in pure or diluted form
buccal tablet : a small, flat, oval tablet to be held between the
cheek and gum, permitting direct absorption through the oral mucosa of
the medicinal substance contained therein.
dispensing tablet : a compressed or molded tablet containing a large
quantity of a drug, used by dispensing pharmacists in compounding prescriptions.
enteric-coated tablet : one coated with material that delays release
of the medication until after it leaves the stomach.
hypodermic tablet : one containing a medicinal substance to be dissolved
in water for hypodermic injection.
sublingual tablet : a small, flat, oval tablet to be held beneath
the tongue, permitting direct absorption of the medicinal substance contained
tablet triturate : a small, usually cylindrical, molded disk containing
a medicinal substance diluted with a mixture of lactose and powdered sucrose,
in varying proportions, with a moistening agent.
troche / lozenge / morsulus / rotula
/ trochiscus : a small circular or oblong tablet usually for solution
in the mouth, especially for medication of the throat, consisting of an
active ingredient incorporated in a mass made up of sugar and mucilage
or fruit base, and air dried
pastille / pastil : a troche in which the
active ingredient is incorporated in a mass of sweetened gum, glycerin,
and gelatin base.
confection : a medicated ...
conserve : a confection, electuary, or medicated sweetmeat.
electuary / lincture / linctus : a medicinal preparation consisting
of a powdered drug made into a paste with honey or syrup; a confection.
electuary of senna : a mixture of senna, syrup, and tamarind pulp
elixir : a clear, sweetened, usually hydroalcoholic liquid containing
flavoring substances and sometimes active medicinal agents, used orally
as a vehicle or for the effect of the medicinal agent contained.
aromatic elixir : a preparation containing orange, lemon, coriander,
and anise oils, syrup, talc, and alcohol in purified water; used as a flavored
vehicle for pharmaceutical preparations.
red aromatic elixir : aromatic elixir colored by addition of amaranth
compound benzaldehyde elixir : a preparation of benzaldehyde, vanillin,
orange flower water, alcohol, syrup, and purified water; used as a vehicle
for pharmaceutical preparations.
glycerinated gentian elixir : a preparation of gentian and taraxacum
fluidextracts, compound cardamom tincture, raspberry syrup, sweet orange
peel tincture, phosphoric acid, ethyl acetate, glycerin, sucrose, and alcohol,
in purified water; used as a flavored vehicle for drugs.
iso-alcoholic elixir : a mixture of low-alcoholic elixir and high-alcoholic
elixir to produce a solution whose strength is suitable for the medicament
for which it serves as a vehicle.
low-alcoholic elixir : compound orange spirit 10 mL, alcohol 100
mL, glycerin 200 mL, sucrose 320 gm, and sufficient purified water to make
a total of 1000 mL
high-alcoholic elixir : compound orange spirit 4 mL, saccharin 3
gm, glycerin 200 mL, and sufficient alcohol to make a total of 1000 mL.
lactated pepsin elixir : a water preparation containing a proteolytic
enzyme from the glandular layer of the fresh stomach of the hog, with lactic
acid, glycerin, alcohol, orange oil, and amaranth solution.
terpin hydrate and codeine elixir : 2 gm of codeine dissolved in
a sufficient quantity of terpin hydrate elixir to make 1000 mL; used as
an expectorant and antitussive.
terpin hydrate and dextromethorphan hydrobromide elixir : 2 gm of
dextromethorphan hydrobromide dissolved in a sufficient quantity of terpin
hydrate elixir to make 1000 mL; used as an expectorant and antitussive.
mouthwash : a solution for rinsing the mouth, e.g., the official
[NF] preparation of potassium bicarbonate, sodium borate, thymol, eucalyptol,
methyl salicylate, amaranth solution, alcohol, glycerin, and purified water.
better compliance (except for intravenous drug addicted)
long-lasting solid oral preparations (controlled-release (CR), extended-release
(ER), sustained-release (SR), prolonged-action, retard,
...) reduce frequency of administration (recommended for drugs with t1/2
< 4 hours) and maintain therapeutic effect overnight, elimination of
higher peaks => reduction of side effects. Anyway they have greater interpatient
variability and immediate release may cause dose-dumping.
necessity for co-operation on the part of the patient
useless during vomiting
emesis as a result of irritation to the gastrointestinal mucosa
destruction of some drugs by digestive enzymes or low gastric pH (=> gastroresistant
preparations, but they can sometimes impair enteric absorption, too
keratinoid : a form of keratin-coated tablet not soluble in the
stomach, but readily soluble in the intestine
irregularities in absorption or propulsion in the presence of food or other
absorption rate ~ (rate of dissolution if given in solid form) x (concentration)
x (surface area) x (blood flow to the GI tract) / (electrical charge, since
most absorption occurs via passive processes)
even weak acids are better absorbed from the upper intestine (pH
3-6 but surface area ~ 200 m2 !) : any factor that accelerates
gastric emptying will be likely to increase the rate of drug absorpion
first-pass effect : metabolism by enzymes of the intestinal flora,
or hepatocytes before they gain access to systemic circulation =>
sublingual (s.l., SL)
since venous drainage from the mouth is to the superior vena cava, 100%
bypass hepatic first-pass effect !
very small surface area
nasal drip : a method of giving fluid slowly to dehydrated infants
through a catheter inserted into the nose and pushed down into the esophagus.
suppository : a medicated mass adapted
for introduction into the rectal, vaginal, or urethral orifice of the body;
suppository bases are solid at room temperature but melt or dissolve at
body temperature. Commonly used bases are cocoa butter, glycerinated gelatin,
hydrogenated vegetable oils, polyethylene glycols of various molecular
weights, and fatty acid esters of polyethylene glycol.
glycerin suppository : a suppository made up of a mixture of glycerin
and sodium stearate; used as a rectal evacuant
useful when oral ingestion is precluded
50% bypass liver catabolism
irregular and incomplete absorption
irritation of rectal mucosa
sometimes essential for the drug to be delivered in its active form
usable even if the patient is unconscious, uncooperative or unable to retain
anything by mouth
asepsis must be maintained
pain may accompain the injection
it is sometimes difficult for patients to perform the injection themselves
if self-medication is necessary
expensive (syringes, disinfectants, ...)
intravascular injections : infusion : the therapeutic introduction
of a fluid other than blood, as saline solution, solution, into a vein
parenteral infusion : the administration of liquid medication, nutrient,
or other fluid through some other route than the alimentary canal, usually
over minutes or hours, either by gravity flow or often by infusion pumping
constant infusion pump : an electrically driven device for delivery
from a reservoir of a constant, often very small, volume of solution over
a prolonged period of time.
implantable infusion pump : implanted fluid propulsion systems with
self-contained power source for providing long-term controlled-rate delivery
of drugs such as chemotherapeutic agents or analgesics. Delivery rate may
be externally controlled or osmotically or peristaltically controlled with
the aid of transcutaneous monitoring.
home infusion therapy : use of any infusion therapy on an ambulatory,
outpatient, or other non-institutionalised basis
infusion aspiration drainage : a type of drainage in which antibiotics
are continuously infused into a cavity at the same time fluid is being
drained (aspirated) from the cavity
intravenous drip : continuous intravenous instillation, drop by
drop, of saline or other solution.
external jugular vein is used in emergencies but works according to head
central veins :
more difficult and more time required, more complications, interrupt CPR
very short (bolus injection)
very long (intravenous infusion) : the long-term (minutes to hours)
administration of a fluid into the vein through venipuncture, either by
letting the fluid flow by gravity or by pumping it. Steady state can't
be reached if administration time is < 7 t1/2.
intra-arterial infusion : regional infusion of drugs via an arterial
catheter. Often a pump is used to impel the drug through the catheter.
Used in therapy of cancer, upper gastrointestinal haemorrhage, infection,
and peripheral vascular disease.
intraosseous infusion : the
second-line administration of drug (epinephrine, bicarbonate, calcium,
lidocaine, and volume expanders), fluid or blood (and marrow aspirate drawn
for laboratory analysis) through a butterfly needle (18 G)ref
directly into the bone marrow (a "noncollapsible vein") to a hemodynamically
shocked child (mainly due to diarrhea or burns) in whom attempts to access
the systemic vascular system have been unsuccessful. It is indicated in
a child in shock or cardiac arrest when two attempts to access peripheral
vasculature have failed or when more than 2 minutes have elapsed in the
attempt to gain access.
injury to the epiphyseal growth plate during the performance of this technique
remains a serious problem. An insertion site of at least 10 mm distal to
the tibial tuberosity is recommended to avoid epiphyseal growth plate injury
and ensure ease of insertionref
faster, but high risk of bone fracture, lodge syndrome (acute limb ischemia
requiring amputation), osteomyelitis
suitable for moderate volumes, oily vehicles, and some irritating substances
prompt (for aqueous solution) or slow and sustained (from repository preparations)
rate of blood flow (deltoid or vastus lateralis > gluteux maximus)
to the injection sites may be modulated at some extent by local heating,
massage, or exercise, but depends on poor vascularization of subcutaneous
precluded during anticoagulant therapies
may interfere with interpretation of muscle enzymes concentration
subcutaneous injection (s.c., SC)
suitable for some insoluble suspensions and for implantation of solid pellets
prompt (for aqueous solution) or slow and sustained (from repository preparations,
sometimes including a vasoconstrictor agents) absorption
not suitable for large volumes
possible pain or necrosis from irritating substances
hypodermoclysis : introduction into
the subcutaneous tissues of fluids, especially physiologic sodium chloride
solution, to replace inadequate intake or loss of water and salt during
illness or operation.
aerosol therapy : inhalation therapy using an aerosol
humidification therapy : inhalation therapy using air supersaturated
with moisture in treatment of congestive conditions of the upper and lower
large surface areas
avoiding hepatic first-pass effect
larger delivery to organs proximal to heart (e.g. CNS for drugs
90% is entrapped in saliva and swallowed
10% escapes and ...
if Ø > 10 mm => deposits on oropharynx
if 1 < Ø <5 mm => bronchi and alveoli (keep breath for 5-10")
if Ø < 0.5 mm => expulsed with expiration
non-enteral mucous membranes
conjunctiva and cornea (eyewashes) : usually used for their
local effects. Systemic absorption that results from drainage through the
nasolacrimal canal to the superior cava vein is not subject to hepatic
first-pass effect => unwanted side effects !
transdermic (analgesics, estrogens, nitrovasodilatators, or clonidine)
: absorption ~ (lipid solubility of the drug mixture) x (skin hydration)
x (skin integrity) x (blood flow)
aurinarium : a medicated suppository for insertion into the external
cataplasm / cataplasma : a poultice or soft external application,
kaolin cataplasm : a poultice prepared with kaolin, boric acid,
and glycerin; called also cataplasma kaolini.
cataplasma fermenti : a poultice containing yeast
pomatum / pomade : a medicated ointment for the hair.
poudrage : the application of powder to a surface, as between the
visceral and parietal layers of the pericardium or pleura to promote their
fusion in pleurodesis.
poultice : a soft, moist mass about the consistency of cooked cereal,
spread between layers of muslin, linen, gauze, or towels and applied hot
to a given area in order to create moist local heat or counterirritation.
illinition : the application of an ointment or liniment with rubbing
liniment : an oily liquid preparation to be used on the skin.
camphor liniment / linimentum camphorae : a preparation of camphor
and cottonseed oil used as a local irritant to the skin
ointment / unguent / unction / salve : a semisolid preparation for
external application to the body, and usually containing a medicinal substance
belladonna ointment : a preparation of pilular belladonna extract
and diluted alcohol in yellow ointment; used locally as an analgesic.
benzoic and salicylic acids ointment / Whitfield's ointment : a
preparation of benzoic acid and salicylic acid in a ratio of about 2:1
in a water-soluble base, used topically as an antifungal and keratolytic
agent in the treatment of tinea pedis
bland lubricating ophthalmic ointment : an ointment composed of
white petrolatum and mineral oil; it may also contain lanolin, modified
lanolin, or lanolin alcohols.
calamine ointment : a preparation containing calamine, yellow wax,
anhydrous lanolin, and petrolatum; used as an astringent protective application.
coal tar ointment : a preparation of coal tar, polysorbate 80, and
zinc oxide paste, used as a topical antieczematic and antipsoriatic.
erythromycin ophthalmic ointment : a preparation of erythromycin
in a suitable ointment base; used as a topical antibacterial in the treatment
of superficial infections of the conjunctiva and cornea by susceptible
hydrophilic ointment : a water-in-oil emulsion consisting of methylparaben,
propylparaben, sodium lauryl sulfate, propylene glycol, stearyl alcohol,
white petrolatum, and purified water; used as an ointment base.
iodochlorhydroxyquin and hydrocortisone ointment : an ointment containing
90 to 110% of the labeled amounts of iodochlorhydroxyquin and of hydrocortisone;
used for its local anti-infective effect and the anti-inflammatory and
antipruritic activity of glucocorticoids in a wide range of dermatoses,
penicillin ointment : a preparation of calcium penicillin, crystalline
penicillin, or procaine penicillin in a suitable ointment base, with or
without incorporation of a suitable anesthetic.
carbolic acid or phenol ointment : a preparation of phenol, glycerin,
and white ointment, containing 1.8–2.2 per cent of phenol; used as an antipruritic
pine tar ointment : a preparation of pine tar, yellow wax, and yellow
ointment, used as a local antieczematic and rubefacient.
polyethylene glycol ointment : a mixture of polyethylene glycol
4000 and polyethylene glycol 400, used as a water-soluble ointment base.
compound resorcinol ointment : preparation of resorcinol, zinc oxide,
bismuth subnitrate, juniper tar, yellow wax, petrolatum, anhydrous lanolin,
and glycerin, used as a topical antifungal and keratolytic; applied topically.
rose water ointment : a preparation of spermaceti, white wax, almond
oil, sodium borate, stronger rose water, purified water, and rose oil,
used as an emollient and ointment base.
petrolatum rose water ointment : an ointment prepared with spermaceti,
white wax, mineral oil, sodium borate, rose water, purified water, and
scarlet red ointment : a preparation of scarlet red, olive oil,
anhydrous lanolin, and petrolatum, applied locally as a protective agent.
compound tar ointment : a preparation of rectified tar oil, benzoin
tincture, zinc oxide, yellow wax, lard, and cottonseed oil, used locally
as an antibacterial and irritant.
simple or white ointment : an oleaginous ointment base prepared
from white wax and white petrolatum.
yellow ointment : a mixture of yellow wax and petrolatum, used as
an ointment base for drugs.
electrochemotherapy : by using
short, intense electric pulses that surpass the capacitance of the cell
membrane, permeabilization can occur (electroporation).
Thus, molecules that are otherwise non-permeant can gain direct access
to the cytosol of cells in the treated area. A highly toxic molecule that
does not usually pass the membrane barrier is the hydrophilic drug bleomycin
drug distribution (structure-property correlations (SPC))
in systemic circulation
blood or plasma concentration (C)
plasma peak concentrations at peak time (=> peak effect)
depends on rate of absorption
when the effects are difficult to monitor, the desired steady state
concentration (Css) has to fall within a therapeutic
window defined by the minimum effective concentration (MEC)
for adverse response (ARD5-10) and the MEC for desired response.
of effect is the difference between drug effect at the onset and at
for nonelectrolytes the concentration of the unbound drug is the
same on both sides of the membrane
for electrolytes the steady-state concentrations will be dependent
on differences in pH across the membrane (which may influence the state
of ionization of the molecule on each side of the membrane) and on the
electrochemical gradient for the ion. Most drugs are weak acids
For drugs administered ...
at dosing intervals = T, Css= F
. dose / (CL. T) = F . dosing
rate / CL = (dosing rate .KM) / (vmax
- dosing rate).
if C < KM => linear kinetics. This is true
as for most concentrations encountered clinically the transporters are
not saturated and thus elimination follows a first-order kinetics.
if C > KM => nonlinear kinetics => decreased first-pass
effect => higher F. If all transporters become saturated at Css
= C, the elimination follows a zero-order kinetics and CL
= vmax / (KM + C).
maximal Css for a dosing interval = T, Css,
max = (F. dose ) / [Vss.
(1 - e-kt)]
minimal Css for a dosing interval = T, Css,
min = Css, max.e-kt
when T < t1/2, Css, min > Css,
max / 2
measured Css well after the administration of the previous
dose can be used to refine the estimate of CL / F and to
calculate the maintenance dosing rate = desired Css.
(CL / F).
at dosing intervals = t1/2, clinical Css is
attained after approximately 4-5 t1/2, while the pharmacological
plateau occurs after 7 t1/2. In order to reach Css
more rapidly (e.g. in "digitalization"), you can use priming / loading
dose(s) D* = desired Css. (Vss
binding for hydrophobic drugs (usually reversible : covalent binding
of reactive drugs such as alkylating
As for most drugs the therapeutic range of plasma concentrations is limited,
the extent of binding and unbound fraction is relatively constant. Many
drugs can compete with each other and with endogenous substances (e.g.
FFAs mobilized during physical exercise and Trp after meals) with binding
sites on plasma proteins : for narrow-therapeutic-index
drugs, a transient change in unbound concentrations could be of concern
for drug response and also impair measurement of drug concentrations in
plasma, since most assays do not distinguish free drug from bound drug.
low plasma protein binding : high activity, short plasma half-life => need
for repeated administration
high plasma protein binding : low activity, long plasma half-life
Allosteric interactions are often observed during the binding of drugs
to blood proteins such as human serum albumin (HSA) and can be studied
by biointeraction chromatography
volume of distribution (V) = (amount of drug in the body)
/ fictive extrapolated C0 ~ (extravascular tissues binding
/ plasma protein binding) ~ btissue/plasma
at a given pH. It is the apparent space in the body available to
contain all of the drug in the body at the same concentration as in the
plasma. Total body water (~ 42 L) < V < + oo. In a one-compartment
model, all drug administration occurs directly into the central compartment
and distribution of drug is istantaneous throughout the volume of distribution
volume of distribution at steady state (Vss) =
(amount of drug in the body at steady state) / Css.
C = C0 .e-kt
= (dose / V) .e-kt
logC0 - logC = log(C0 / C)
= kt / ln2
when t = t1/2, C0 / C = 2
=> k = elimination rate = 0.693 / t1/2
7 t1/2 are required to completely eliminate a drug (5 from a
clinical point of view).
in a multicompartment model, Varea =
/ k = (dose / AUC) / k ~ Vss
Since the pH difference (7.0 versus 7.4) is small, the more important
determinant of blood:tissue partitioning is the relative binding of drug
to plasma proteins and tissue macromolecules.
amount in the body (Ab)
accumulation ratio (R) = 1 / (1 - F) = amount in the body
(Ab) / amount that reached plasma = Ab / (F . dose).
As Ab .k = (F . dose) / t, and k
= 0.693 / t1/2, Ab/dose = (F . t1/2) /
(0.693 . t) => R = 1.44 . (t1/2) / t.
extraction ratio for a drug in a given organ (EH)
= (Cart - Cvein) / Cart
lectin-directed enzyme-activated prodrug therapy (LEAPT) : a bipartite
drug-delivery system that exploits (I) endogenous carbohydrate-to-lectin
binding to localize glycosylated enzyme conjugates to specific, predetermined
cell types followed by (II) administration of a prodrug activated by that
predelivered enzyme at the desired siteref.
blood flow to an organ (Q)
clearance (CL) from a biological fluid is the rate of theoretically
complete removal from biological fluid to account for the actual incomplete
CLorgan = Q .EH
fractional bioavailability (Fmax) (%) = (dose
that reaches the plasma) / (dose administered) = Cx at t when
a dose is administered via a given route / Cx at t when
the same dose is administered IV = 1- EH = 1 -
(CLfrom organs encountered before reaching the site of action,
i.e. the systemic circulation / Qprior mentioned organs).
Generally dose = 106 [ ]pl.
F. dose = CL. § C.
dt = CL . area under the curve (AUC)
... and drug excretion (phase III reactions) from ...
... surfactant : elimination of volatile lipophilic compounds =>
... hepatocytes => excretion by ...
... canalicular membrane ATPase transporters into bile (usually
for drugs with Mr > 360 kDa) => stools. Enterohepatic
recycling, involving enzymatic hydrolysis of conjugated catabolytes
like glucuronides, may prolong significantly the presence of a drug and
its effects within the body prior to elimination by other slower pathways.
... basolateral membrane ATPase transporters back into plasma (usually
for drugs with Mr < 360 kDa) => excretion by ATPase
transporters in ...
... renal tubular membranes => urine (%). Reabsortion of
drug from the tubular lumen back into the systemic circulation occurs by
nonionic diffusion or active transport.
... mammary gland => colostrum
CLsystemic = CLrenal + CLhepatic
+ ... = rate of elimination / Css[
mL / min / kg ]
blood clearance (CLb) = rate of elimination from
blood / Css, blood
plasma clearance (CLp) = rate of elimination from
plasma / Css, plasma
receptors for endogenous ligands : many G-protein-coupled receptors (GPCRs)
exist in active and inactive conformations, and may spontaneously switch
between the different formsref.
Many receptors spontaneously activate internal machinery. In these cases,
the receptor is more akin to an accelerator.
full agonist : affinity for the active
conformation is far greater than for the inactive one and promote a change
from inactive to active forms
partial agonist : agonist with iintermediate
intrinsic efficacy, whose affinity for the active conformation is moderatly
greater than for the inactive one : they are useful to buffer a response
by inhibiting untoward stimulation without totally abolishing the stimulus
from the receptor. Continued stimulation of cells with agonists generally
results in a state of desensitization
(a.k.a. refractoriness or down-regulation)
homologous desensitization : negative feedback (endocytosis, ...)
directed to the receptor molecule itself (phosphorylation, proteolysis,
dcreased synthessi, etc.), hence limited to output only from the stimulated
heterologous desensitization : negative feedback directed to one
or more downstream proteins common to multiple receptor signal transduction
antagonist binds with equal affinity to
either conformation (competitive antagonism)
competitive antagonism (affinity similar to endogenous ligand)
pseudo-irreversible antagonism (affinity far higher than endogenous
inverse agonist / negative antagonism
have preferential affinity for the inactive conformation and selectively
enrich a less active conformation : they are useful against constitutively
active receptors. But in tissues with low levels of activity, inverse agonists
can act as antagonists, blocking the endogenous transmitter. Some 85% of
drugs traditionally regarded as antagonists seem to be inverse agonistsref
sensitization / supersensitivity / reverse tolerance to agonists
also frequently follows chronic reduction of receptor stimulation. It rusually
equires an interval between doses longer than a day.
protean agonists act as either inverse
agonists or agonists depending on the GPCR's constitutive activity, either
promoting a switch to a less active conformation or enriching the activeref.
osmotic molecules act according to colligative effects without a requirement
for highly specific chemical structure.
quantitation of drug-receptor interactions and elicited effect
Kd = AR / ([A] . [R])
receptor occupancy = [A] / ([A] + Kd)
receptor occupancy.efficacy (e).receptor
number [R] = total receptor-mediated stimulus ===amplification
properties of the cell (stimulus-response capability)==> response.
What drugs do depends on the receptor and its associated signaling proteins;
classification by magnitude of physiological effect can be seriously misleading
when drugs are tested in one cellular format for therapeutic use in another.
The alternative is to classify drugs according to the magnitude of their
2 molecular properties, when the identity of the receptor is known : Kd
individual effective concentration is that concentration that produces
a specified effect in a single patient. This is a quantal response, since
the defined effect is either present or absent.
"quantal concentration-number of responding" curve : a cumulative
frequency distribution of individual effective concentrations
"dose-percent of responding" curve
median effective dose (ED50)
median lethal dose (LD50)
chemotherapeutic or therapeutic
index = originally, the ratio of
the maximum tolerated dose to the minimum curative dose; now defined, so
as to account for variability of individual response, as median lethal
dose (LD50) / median effective
dose (ED50). It is used in assessing the safety of a drug. No
drug produces a single effect, and, depending on the effect being measured,
ED50 (and hence the therapeutic index for a drug) varies
standardized safety margin = (LD1 - ED99)
1 probability unit (probit) / deviation from the mean = 1 standard
"dose-duration of drug effect" curve
ceiling : the maximum biological effect that can be induced in a
tissue by a given drug, regardless of how large a dose is administered.
CT index : (concentration (C) of an agent applied to a biological
system to produce a specific effect) . (duration (T) of application
required to produce the effect)
USP unit : one used in the USP in expressing the potency of antibiotic,
pharmacodynamic, and endocrine preparations, as well as most of the sera,
toxins, vaccines, and related products, corresponding to units established
internationally, by the Food and Drug Administration, or by the National
Institutes of Health.
National Formulary (NF) : a book of standards for certain pharmaceuticals
and preparations that are not included in the USP. It is revised every
five years, and recognized as a book of official standards by the Pure
Food and Drugs Act of 1906
antidotes : antidote control is the safest
way to regulate drug activity, because unlike rapidly clearing drugs, control
of the drug activity is independent of underlying patient physiology and
co-morbidities. Until recently, however, there was no general method to
discover antidote-controlled drugs. The activity and side effects of aptamers
can be controlled by matched antidotes in vivo. The drug, an anticoagulant
aptamer, systemically induces anticoagulation in pigs and inhibits thrombosis
in murine models. The antidote rapidly reverses anticoagulation engendered
by the drug, and prevents drug-induced bleeding in surgically challenged
animals. These results demonstrate that rationally designed drug-antidote
pairs can be generated to provide control over drug activities in animalsref.
reduction or lack of sensitivity to a drug
innate (spontaneous) tolerance : genetically determined, observed
the first time that the drug is administered
acquired (nonspontaneous) drug tolerance
heterologous (cross-tolerance) : tolerance not only to the drug
being used but also to other drugs in the same structural and mechanistic
category. E.g. ethanol
(synergy while the alcoholic is drinking !)
Tolerance may be :
acute tolerance / tachyphylaxis (minutes
or hours) due to depletion of available endogenous mediator caused by massive
exocytosis, developed with repeated use on a single occasion such as in
"classical" or chronic tolerance (days or
/ dispositional / pharmacometabolic tolerance (e.g. barbiturates and
endogenous substances (steroid hormones, cholesterol, bile salts, and vitamins
K and D)
learned tolerance : reduction in the effects of a drug due to compensatory
mechanisms that are learned (expecially for drugs
behavioral tolerance : learned awareness of one's deficit to mask
it in spite of impairment produced by intoxication
conditioned tolerance / situation-specific tolerance is a classical
(Pavlovian) learning mechanism that develops when environmental cues such
as sights, smells, or situations consistently are paired with the administration
of a drug. The reflexive counteractions or adaptations begin to occur even
before the drug reaches its site of action, preventing the full manifestation
of the drug's effects.
Tolerance develops to some drug effects much more rapidly than to other
effects of the same drug.
manufacturing practice (GMP) : set of regulations and guidelines
controlling the quality of manufacturing operations aimed at ensuring consistency
of product quality in order to ensure patient safety
(OTC) drugs are products that intend to treat or prevent disease,
or otherwise affect the structure or functions of the human body, are considered
drugs. They are drugs that can be purchased without a doctor's prescription.
Examples of products that are over-the-counter drugs are fluoride toothpastes,
hormone creams, sunscreen preparations, antiperspirants.
generic drug is
identical, or bioequivalent to a brand name drug in dosage form, safety,
strength, route of administration, quality, performance characteristics
and intended use. Although generic drugs are chemically identical to their
branded counterparts, they are typically sold at substantial discounts
from the branded price. According to the Congressional Budget Office, generic
drugs save consumers an estimated $8 to $10 billion a year at retail pharmacies.
Even more billions are saved when hospitals use generics
sufficient for (Q.S.F.) : abbreviation indicating, in mL or
grammes, at the end of a formula, the volume or weight of the excipient
necessary to obtain the volume or weight of the whole medicine.
Therapeutic Chemical (ATC) classification system is used for
the classification of drugs. It is controlled by the WHO
Collaborating Centre for Drug Statistics Methodology, and was first
published in 1976. Drugs are divided into different groups according to
the organ or system on which they act and/or their therapeutic and chemical
characteristics. In the system drugs are classified into groups at 5 different
first level of the code is based on a letter for the anatomical group and
consists of one letter; there are 14 main groups:
A : alimentary tract and metabolism
B : blood and blood forming organs
C : cardiovascular system
D : dermatologicals
G : genito-urinary system and sex hormones
H : systemic hormonal preparations, excluding sex hormones and insulins
J : anti-infectives for systemic use
L : antineoplastic and immunomodulating agents
M : musculo-skeletal system
N : nervous system
P : antiparasitic products, insecticides and repellents
Q : veterinary drugs
R : respiratory system
S : sensory organs
V : various
second level of the code is based on the therapeutic main group and consists
of two digits.
third level of the code is based on the therapeutic/pharmacological subgroup
and consists of one letter.
fourth level of the code is based on the chemical/therapeutic/pharmacological
subgroup and consists of one letter.
fifth level of the code is based on the chemical substance subgroup and
consists of two digits.
The actual drug name used is the International Nonproprietary Name (INN)
when available. The ATC/DDD system is the ATC system with the addition
of a measure of the assumed average maintenance dose per day for a drug
used for its main indication in adults (Defined Daily Doses).Other
ATC classifications are ATCvet (for veterinary medicinal products) and
ATC herbal classification (for herbal remedies). The ATC classification
system was based on the Anatomical Classification (AC-system) developed
by the European Pharmaceutical Market Research Association (EPhMRA) and
the Pharmaceutical Business Intelligence and Research Group (PBIRG).
United States Adopted Names (USAN) : a nonproprietary designation
for any compound used as a drug, established by negotiation between the
manufacturer of the compound and a nomenclature committee known as the
USAN Council, which is sponsored jointly by the American Medical Association,
the American Pharmaceutical Association, and The United States Pharmacopeial
Convention. A liaison representative of the United States Food and Drug
Administration sits on the USAN Council. The term is currently limited
to names adopted by the Council since June, 1961. These names will appear
as the monograph titles in the official compendia, USP and NF, when and
if the respective drugs are admitted to either compendium
A man-versus-machine challenge has proven that a computer program can help
crack the problems that pharmaceutical companies must tackle when marketing
new drugs. The computer program that met the challenge is that of theoretical
chemist Sally Price of University College London and her team; it has already
attracted the attention of drug companies keen to put the program to work.
The problem such companies face involves the fact that useful drugs often
take several shapes or conformations, known as 'polymorphs'. And
although chemically the same, a drug with a different crystal shape can
have different properties, for example, it can take longer to dissolve
in the bloodstream. This means drug developers can only patent and
market-approved polymorphs, and they must ensure that their production
process carefully produces only the correctly shaped drug. This can have
serious consequences. In 1998, the appearance of an unexpected polymorph
during the production of an anti-HIV drug called ritonavir
forced Abbott Laboratories to withdraw the capsule form of this drug from
the market. Pharmaceutical companies would like nothing more than
to be able to predict all of the obtainable polymorphs of a compound so
they could patent them. They had trouble working out what had gone wrong
and getting their original polymorph back. In the end, they had to gain
approval for the new polymorph, which was less soluble in the bloodstream
and, as a gel capsule, had to be refrigerated. This is estimated to have
cost them hundreds of millions of dollars. To anticipate such potential
problems, researchers attempt to find out about the polymorphs of drugs
using lab techniques such as crystallography. But this takes an enormous
amount of time and leaves a considerable amount to chance. Price's software
aims to cut short this process and predict the shapes a drug might take.
The test for Price's team came when Colin Pulham, a chemist at the University
of Edinburgh, UK, challenged it to predict a new polymorph of piracetam,
a drug used to treat Alzheimer's disease. Pulham had just discovered a
new conformation of this drug in his lab, and wanted to see if Price's
team could guess its shape. Price's team, which was already looking at
piracetam as a test case for their software, fed all the information about
the bonds between atoms of piracetam into their program. Using the processing
power of 30 computers, the program considered some 50,000 possible crystal
structures of the compound, with each structure taking 1-2 hours to generate
and analyse. After a few months, Price handed Pulham a list of possible
polymorphs, ranked in descending order of probability. The conformation
at the top of the list exactly matched the shape that he and his colleagues
had found. The team members, who present their work this week at the e-Science
All Hands Meeting in Nottingham, UK, says the test proves the efficacy
of their computerized method. Being able to meet this blind challenge adds
a lot of credibility. It will be a while yet before companies can put their
faith into Price's program. It's not going to be superseding the experimental
approaches any time soon. But after further testing, it could cut down
the work needed to isolate the best conformation for market, or to anticipate
potential problems in production. Pharmaceutical companies would like nothing
more than to be able to predict all the obtainable polymorphs of a compound
so they could patent them
an analysis of the crucial ADME processes for
which predictive models are available or are being developed
for drug attrition
pharmacovigilance : all physicians
check adverse drug reactions (ADR), patterns of drug utilization,
and additional indications discovered on patients given drug for therapy,
often in comparison with other treatments. 50% of the drug withdrawal that
have occurred since 1998 in the USA when drugs have come on the market
have been attributable to cardiac side effects, often in the form of effects
on the ECG and consequent arrhythmias. ADRs kill 100,000 Americans each
year, registering as the fourth leading cause of death, more lethal than
AIDS or automobile accidentsref.
To explore the epidemiology of adverse events (AEs), which were defined
as injuries due to medical treatment, and that subset of AEs caused
by negligence, interhospital variation in these outcomes were studied in
a sample of 31,000 medical records drawn from a random selection of 51
hospitals in New York in 1984. A substantial variation was found in both
AE rates (0.2% to 7.9%; mean, 3.2%) and the percentage of AEs due to negligence
(1% to 60%; mean, 24.9%) among hospitals. Univariate analyses of AEs revealed
that primary teaching institutions had significantly higher rates (4.1%)
and rural hospitals had significantly lower ones (1.0%). The percentage
of AEs due to negligence was lower in primary teaching (10.7%) and for-profit
(9.5%) hospitals and was significantly higher in hospitals with predominantly
(greater than 80%) minority patients who had been discharged (37%). These
findings were corroborated by multivariate analysis. Our results suggest
that AEs and negligence are not randomly distributed and that certain types
of hospitals have significantly higher rates of injuries due to substandard
care. These observations may represent an important improvement on existing
measures of quality because they take into account the fact that some hospitals'
populations may be at risk of suffering a poor outcomeref.
In paired regression analyses adjusting for multiple factors, including
severity, comorbidity, and case mix, the additional length of stay associated
with an ADE was 2.2 days (P=.04), and the increase in cost associated with
an ADE was $3244 (P=.04). For preventable ADEs, the increases were 4.6
days in length of stay (P=.03) and $5857 in total cost (P=.07). After adjusting
for our sampling strategy, the estimated postevent costs attributable to
an ADE were $2595 for all ADEs and $4685 for preventable ADEs. Based on
these costs and data about the incidence of ADEs, we estimate that the
annual costs attributable to all ADEs and preventable ADEs for a 700-bed
teaching hospital are $5.6 million and $2.8 million, respectively. The
substantial costs of ADEs to hospitals justify investment in efforts to
prevent these events. Moreover, these estimates are conservative because
they do not include the costs of injuries to patients or malpractice costsref.
Physician computer order entry (POE) decreased the rate of nonintercepted
serious medication errors (defined as those that either resulted in or
had potential to result in an ADE and were not intercepted before reaching
the patient) by more than half, although this decrease was larger for potential
ADEs than for errors that actually resulted in an ADEref.
Pharmacist review of medication orders in the intensive care unit (ICU)
has been shown to prevent errors, and pharmacist consultation has reduced
drug costs. The presence of a pharmacist on rounds as a full member of
the patient care team in a medical ICU was associated with a substantially
lower rate of ADEs caused by prescribing errors. Nearly all the changes
were readily accepted by physiciansref.
A study released by the Institute of Medicine's (IOM) of the National Academies
in November 1999 states 'preventable adverse events are a leading cause
of death' and 'at least 44,000 and perhaps as many as 98,000 Americans
die in hospitals each year as a result of medical errors. Anyway the IOM
report is faulty because it does not include a control group and all the
patients studied were 'very sick' : what the figures suggest is that people
don't die without an adverse eventref E.g. :
McBride WG letter in Lancet 16/12/1961 on thalidomide-using
pregnants having 20% malformated newborns vs. 1.5% controls, and expecially
Comparison of the incidence rates of selected gastrointestinal events reported
for patients prescribed rofecoxib
in general practice in England using prescription-event monitoring dataref.
Prolongation of the QT interval and cardiac
associated with cisapride:
limitations of the pharmacoepidemiological studies conducted and proposals
for the futureref
Drug Safety Research Unit (DRSU), Southampton,
UK is an independent registered charity associated with the University
of Portsmouth, an academic and independent unit which operates outside
of the government’s Medicines and Healthcare products Regualtory Agency
(MHRA) or any other government office
a "Dear Doctor" letter is the most commonly used way of communication
from producer to physicians
pharmacogenetics / pharmacogenomics
: there is some lack of appreciation that pharmacogenomic concepts date
back to mid-20th century. In the late 1950s, for example, scientists discovered
that some people inherit a genetic mutation for cholinesterase that causes
the slow breakdown of succinylcholine, a muscle relaxantref:
nowadays a similar case occurs for gefitinib.
Pharmacogenomics explains idiosyncratic
reactions on the basis of genetic polymorphisms. Geographic patterns
of genetic variation, including variation at drug metabolizing enzyme (DME)
loci and drug targets, indicate that geographic structuring of inter-individual
variation in drug response may occur frequently. This raises 2 questions:
how to represent human population genetic structure in the evaluation of
drug safety and efficacy
how to relate this structure to drug response
Inferring the genetic structure present in a heterogeneous sample and comparing
the distribution of DME variants across the inferred genetic clusters of
individuals showed that commonly used ethnic labels are both insufficient
and inaccurate representations of the inferred genetic clusters, and that
drug-metabolizing profiles, defined by the distribution of DME variants,
differ significantly among the clusters. The complexity of human demographic
history means that there is no obvious natural clustering scheme, nor an
obvious appropriate degree of resolution. The comparison of drug-metabolizing
profiles across the inferred clusters establishes a framework for assessing
the appropriate level of resolution in relating genetic structure to drug
The first ethnic drug is likely to be hydralazine
and isosorbide dinitrate combination (H+ISDN)
WHO estimates that 10% of all drugs sold globally are counterfeits and
that the figure is as high as 25% in developing countries. Of particular
concern in Asia is the increasing appearance of counterfeit malaria medications
in countries of the delta of the Greater Mekong River, namely China, Thailand,
Indonesia, Vietnam, Cambodia, and Laos. Studies indicate that up to 40%
of artesunate based malaria medications are fake, especially in the Greater
Mekong region. Lack of any active ingredient is a typical problem, but
there are also fakes with the correct ingredients in insufficient dose
or in fake packaging or drugs containing different active ingredientsref
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MedivoxRx produces Rex, the talking
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