Pharmacodynamics pdf - غير معروف

Pharmacology

Stage

Dr. Nabeel

Mechanism of Drug Action

Pharmacodynamics

Mechanisms of drug action:

1. Receptor occupation as cholinergic, adrenergic and histamine receptors,

occupied by acetylcholine, adrenaline and histamine respectively

2. Interference with ion channels, some drugs acts directly on ion channels and

alters their function as local anaesthetics act by blocking Na+-channels

3. Inhibition of membrane bound enzymes as Na+/K+ ATP-ase inhibition by

digoxin

4. Through physicochemical properties; like osmotic effect as magnesium

sulphate, a laxatives acts by increasing water in the faecal material and
facilitate their passage through the colon, manitol acts as osmotic diuretic

5. Direct chemical reaction as the use of alklines to neutralize gastric acid in

the stomach and Chelating agents as penicillamine in heavy metals
poisoning

6. Enzyme inhibition as cholinesterase inhibition by nesostigmine and

angiotension converting enzyme inhibition by captopril

7. Antimicrobial cause inhibition of bacterial metabolic processes as

sulphonamide inhibit bacterial dihydrofolate reductase enzyme, this lead to
inhibition of folic acid synthesis by the bacteria, but not affect the human
which does not synthesis folic acid

8. Carrier mechanism: some drugs act by interfering with passage of olecules

across the cell membrane such as the inhibition of neradrenaline uptake by
tircyclic antidepressants, carrier mechanism is important for the transport
of moplecules as glucose, amino acids and organic molecules.

Receptors

are protein macromolecules situated usually but not always situated on the cell
membrane and has the ability to combine with the drug molecule, and transmit
the drug effect to the inside of the cell. The drug molecule has to be similar in size,
shape, chemical structure in order to combine to its specific receptor. So the
receptors are important for the specific and selective action of the drug.

Usually the presence of receptors indicate that there are endogenous substances
of similar shape that can combine to these receptors such as endogenous opiates
that bind to opiates receptors, adrenaline and noradrenaline that combines to
adrenoceptros

Mechanisms of drug binding to receptors:

1. Covalent binding: are strong and usually irreversible bonds and rarely

mediate drug effect as cytotoxic drugs

2. Electrostatic bonds: are more common than covalent binding
3. Hydrophobic bonds: are usually are weak bonds and are important in highly

lipid soluble drugs binding with the lipids cell membranes

Receptors can be divided into three different types:

1. Receptors linked to ion channels: these receptors regulate the flow of ions

across their channels in the cell membrane example; nicotinic cholinergic
receptors and Na+ ion channels, GABA receptors and Cl- ion channels, they
are activated in milliseconds

2. G-protein coupled receptors: these receptors are linked to G protein which

mediate the intracellular action by binding to guanosine triphosphate. This
will  lead  to  the  activation  of  a  second  messenger  mechanism  called
adenylcyclase  which  result  in  the  production  of  cyclic-adenosine
monophosphate(cAMP),  and  this  regulate  protein  phosphorylation,  they
acts in seconds to minutes, as the beta-adrenoceptors

3. Intracellular receptors; these receptors are located inside the cell ad

therefore the drug molecule must diffuse to the inside of the cell to interact
with these receptor as in estrogen receptors which are located in the
nucleus of the cell and they stimulates DNA and proteins synthesis and
usually take hours to act, also corticosteroids has similar receptors

Second messenger:

The second messenger is an intracellur component that can transmit the effect of
the  drug  to  the  inside  of  the  cell  following  receptor  stimulation,  such  as  cyclic
adenosine  monophosphate  (c-AMP)    and  calcium  ions,  changes  in  these  second
messenger  will  produce  the  drug  effects  as  muscle  contraction  or  relaxation  or
gland secretion.

Receptors regulations:

 The response to drug depends on the number of receptors occupied.
 The number of receptors may be affected by the continued presence of the

drug.

 In general the number of receptors tend to decrease with continuous agonist

drug administration and this will lead to decrease in drug response
(receptors down-regulation) This is in order to protect the cell from excessive
stimulation.

 The reduction in receptors occur by the process of endocytosis, which means

that the cell engulf the receptors and degrade it

Tachyphylaxis

rapid reduction in the response to the drug following repeated administration (this
is due to receptors down-regulation)

The continuous administration of the antagonist will increase the number of
receptors (receptors up-regulation), which makes sudden withdrawal of the
antagonist dangerous after prolonged use as beta-blockers

Dose response relation

The effect produce by a drug is generally a function of the amount of the drug
administered "dose-Response Curve". The magnitude of the drug effect depend on
its concentration at the receptor site, which is in term determined by the dose of
the drug administered and affected by factors related to the drug characteristics
and the pharmacokinetics parameters.

Dose-Response Curve:

As the concentration of the drug increase, the magnitude of its pharmacological
effect will also increase( i.e. increasing the drug amount will increase the
response). The curve has S shape with a linear part in the middle.

Quantal-dose response (dose percent effect)

for determination of drug response in the population, it is used for all or none
effect as prevention of convulsion, cardiac arrhythmias and in acute toxicity
studies.

Therapeutic index

  is the ratio of toxic dose to the effective dose
  Therapeutic index = toxic dose/effective dose
  Therapeutic index is a measure of the drug safety, the larger the index, the

safer is the drug .

Lethal dose (LD50)

it is the dose that kills 50% of the experimental animals, it is also useful in finding
the therapeutic dose in the early experimental studies of drug discovery. It can
also be used to measure the therapeutic index a follow:



Therapeutic index = LD50/ ED50



LD 50 is the lethal dose in 50% of animals



ED50 is the effective dose in 50% of the animals

Agonist

any substance which has the affinity to combine with the receptors and causes
receptors stimulation and pharmacological action. Example is acetylcholine which
combine to muscarinic receptors and adrenaline which combine to the adrenergic
receptors.

Partial agonist

is a drug which has affinity and some efficacy to the receptors and it does not
produce maximum effect even when all the receptors are occupied and it may
antagonize the action of other agonist that have a greater efficacy

Antagonists

is the substance which has the affinity for the receptors but when combine with
the receptors does not cause stimulation. The antagonist usually block or
antagonize the effect of the agonist. Example atropine which can combine with
muscarinic receptors and antagonize the effects of acetylcholine, also propranolol
can combine with adrenergic receptors and antagonized the effects of adrenaline

Sensitivity

is the ability of a given dose of a drug to act on one system rather than the other

Affinity

is the ability to combine with receptors , drugs has high affinity will displace
drugs with low affinity from receptors binding

Potency

is a given response for certain receptor occupation, the more potent drug will give
similar response at lower doses than the less potent drug, this usually determine
the dose of the drug

Efficacy

is the maximum response to drug, that is no further increase in response occur
when we increase the dose. Drugs can have high efficacy as frusemide or low
efficacy as spironolactone

Competitive antagonism

when two drugs compete on the same receptor site, it occur between two drugs of
similar chemical structure and usually occur between the agonist and its
antagonist on the same receptor site, example atropine can compete with
acetylcholine on the muscarinic receptors. The antagonist cause parallel shift to
the right of the dose response curve (i.e. you need higher dose to produce the same
effect)

Physiological antagonism

Occur when two drugs antagonize the  effect of each other, but they act on two
different receptors ( the drugs have opposing pharmcological actions). Example is
histamine  which  act  on  histaminic  receptors  and  cause  vasodilatation,  while
adrenaline acts on adrenergic receptors and cause vasoconstriction , so adrenaline
is a physiological antagonist to histamine and it is useful in anaphylactic reactions

Factors modifying drug response:

1. Age: various physiological changes with age that might affect the

pharmacokinetics or pharmacodynamics of drugs include body fat contents,
volume of distribution, hepatic blood flow, glomerular filtration rate and
changes in homeostatic mechanisms

2. Body weight: as this affect the body fluids and fat, which may change the

drug concentration in the body

3. Gender : generally lower doses for females also note hormonal, changes,

menstruation, pregnancy and lactation. This can also modify the adverse
effects of the drugs ِ

4. Racial factors Negros, Asians and Caucasians, may show different response

to the same drug

5. Genetic factors: as variation in cytohcrome P450 enzymes will alter the rate

of drug metabolism, also genetic deficiency of G6PD enzyme will lead to
hemolysis of the red blood cell by some drugs as primaquine

6. Disease states: include hepatic and renal diseases. These can change drug

metabolism rate, drug clearance from the body and the body response to
drugs

7. Drug: dose, route of administration, frequency of administration, drug

interactions, tolerance and tachyphylaxis



No drug produce only a single specific effect



Drug may act on the same receptors at different cells or it may act on different

receptors at the same time



Drug effects can be divided into toxic (adverse or unwanted) and (therapeutic

or useful)