Mechanisms of drug action

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1- Interaction with cell surface receptors:
  Cell surface receptors may be proteins or glycoproteins. Drug binding to these
receptors is highly specific and depends on the chemical structure of the drug. Drug
binding to the receptor is attained by several types of interactions including
hydrophobic interactions, van der Waals forces, hydrogen bonds, ionic bonds and
covalent bonds.
  Cell surface receptors are composed of extracellular domains that bind the drug
or the endogenous molecule. The ligand binding may act as a triggering signal  that
can be propagated in the target cell through intracellular regulatory molecules known
as  second messengers  or  effectors.  For example, isoproterenol binds with β
adrenergic receptors which are functionally coupled  to adenylate cyclase via the
stimulatory G protein (GS).  As a result, adenylate cyclase  is activated and cyclic
adenosine monophosphate (cAMP) level increases.  
 
 Pharmacology-I

Dr. Basim Anwar Shehata Messiha, PhD.  19
GTP
G-protein
GDP
Adenyl cyclase
ATP
cAMP
Protein
kinase
+
Cell membrane
Drug
Receptor
Effector
Substrate
Inactive
enzyme
Active
enzyme
Active
site
Allosteric
site









Second messenger coupling to cell surface receptors
2- Interaction with enzymes:
  Enzyme activation by drugs may be caused by allosteric binding in which a
drug is bound to an allosteric site of the enzyme resulting in conformational changes
of the enzyme and increased affinity of the endogenous substrate to the active site of
the enzyme.









Allosteric stimulation of enzymes Pharmacology-I                                                                                           Introduction

Dr. Basim Anwar Shehata Messiha, PhD.  20
  Alternatively, enzyme stimulation may take place by a mechanism known as
enzyme induction where enzyme protein synthesis is increased through increased
mRNA transcription, e.g by barbiturates, phenytoin and rifampicin.
  On the other hand, drugs may cause  enzyme inhibition  by one of  two
mechanisms:
i)  Competitive inhibition, where there is mutually exclusive binding of
the substrate and the inhibitor. This occurs when there is a structural
similarity between the substrate and the drug. The inhibition may be
reversed by increasing the concentration of the substrate.
ii)  Non-competitive inhibition, when a drug binds to an allosteric site of
the enzyme resulting in conformational changes of the enzyme
structure leading to loss of affinity at the binding site.






Allosteric inhibition of enzymes
  Binding of inhibitors to enzymes may be reversible, where the drug is free to
dissociate from the enzyme and an equilibrium is attained between free and bound
drug. Alternatively, the inhibitor may be  irreversibly  bound to the enzyme by a
covalent bond so that the enzyme is inactivated irreversibly and the effect of the drug
is continued even after complete drug elimination from the body. The effect may last
for weeks till the synthesis of a new enzyme.

 Pharmacology-I                                                                                           Introduction

Dr. Basim Anwar Shehata Messiha, PhD.  21
3- Interaction with cell membraces and ion channels:
Digitalis glycosides inhibit cell membrane's Na
+
/K+
 pump thus inhibiting the
influx of K+
 and the outflow of Na
+
.
The anti-arrhythmic quinidine affects the membrane potential of myocardial
cell membranes by prolonging both the polarized and depolarized states.
Local anaesthetics affect the nerve cell membrane permeability to Na
+
 and K+
.
4- Interaction with DNA and RNA:
  Some drugs, known as  antimetabolites, interfere with  nucleotide bases
(purines and pyrimidines) synthesis by inhibition of dihydrofolate reductase, e.g.
methotrexate.
  Other drugs are involved in the synthesis of false bases, e.g. purine analogues
(6-mercaptopurine) and  pyrimidine analogues  (5-fluorouracil). These agents,
therefore, inhibit DNA and RNA synthetic enzymes.
Certain drugs interfere with  DNA replication and function including
intercalating agents  (e.g. dactinomycin) and  alkylating agents  (e.g. nitrogen
mustard).
5- Inhibition of protein synthesis:
  Some drugs like tetracycline act by  inhibition of tRNA  binding to the
ribosomes. Chloramphenicol and erythromycin bind to the ribosome and  inhibit
peptidyl transferase  thus blocking the formation of the peptide bond. Quinupristin
and dalfopristin constrict the exit channel on rRNA  thus preventing the release of
newly synthesized polypeptides.
6- Non-specific action:
  Some drugs act nonspecifically by forming a monomolecular layer over an
entire area of certain cells, e.g. volatile general anaesthetics  (like ether and nitrous
oxide),  some antidepressants (ethanol and chloral hydrate) and many antiseptics Pharmacology-I                                                                                           Introduction

Dr. Basim Anwar Shehata Messiha, PhD.  22
A B
C
Emax A or B
Emax C
½ Emax A or B
ED50 A
½ Emax C
ED50 B ED50 C
(phenol and alcohol).  Cathartics such as magnesium sulfate and sorbitol act by
increasing the osmolarity of intestinal fluids.
Drug efficacy and potency:
Efficacy  is measured by the maximal effect attained by the drug. The drug is
more effective when it can attain a higher maximal effect.  Alternatively,  drug
potency is a comparison between drug doses (molar values) and a certain drug effect.
The more potent the drug, the less the dose (or log dose) required to produce the same
effect.









Comparison between drugs A, B and C regarding efficacy and potency
Drugs A and B have the same maximal effect (same efficacy). Drug C has a
lower efficacy. The dose required for drug B to produce 1/2 Emax  is higher
than that for drug A (B is less potent). Drug C is less potent than A or B.






 Pharmacology-I                                                                                           Introduction

Dr. Basim Anwar Shehata Messiha, PhD.  23
Combined drug action:
  Additive effect occurs when two different drugs with the same
pharmacological effect are given together yielding an effect equal in magnitude
to the sum of the individual drug effects, e.g. trimethoprim and
sulfamethoxazole (1 + 1 = 2).
  Synergistic effect occurs when the two drugs with the same effect are
combined together to yield an effect greater in magnitude than the sum of the
individual effects, e.g. penicillin and gentamicin against pseudomonal
infections (1 + 1 = 3).
   Potentiation occurs when a drug lacking an effect alone is combined to a drug
with a pharmacologic effect resulting in increased effect of the latter, e.g.
combination of carbidopa with levodopa (1 + 0 = 2).
Safety of drug action:
  There are two measures of drug safety:
i)  The therapeutic index of a drug is the ratio of the minimum dose toxic (TD)
for 50% of the population to the minimum dose causing an effect  (ED)  to
50% of the population.
ii)  The margin of safety is more practical and is expressed by the ratio of the
minimum dose toxic for 0.1% of the population to the minimum dose
causing an effect to 99.9% of the population.
  The wider the therapeutic index (or window), the more safe the drug is.
Alternatively, the narrow index requires drug monitoring as the drug moves from
effect to toxicity within a small dose interval.



 Pharmacology-I                                                                                           Introduction

Dr. Basim Anwar Shehata Messiha, PhD.  24

Allosteric inhibition of enzymes

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  Binding of inhibitors to enzymes may be reversible, where the drug is free to

dissociate from the enzyme and an equilibrium is attained between free and bound

drug. Alternatively, the inhibitor may be  irreversibly  bound to the enzyme by a

covalent bond so that the enzyme is inactivated irreversibly and the effect of the drug

is continued even after complete drug elimination from the body. The effect may last

for weeks till the synthesis of a new enzyme. 

3- Interaction with cell membraces and ion channels: 

Digitalis glycosides inhibit cell membrane's Na+/K+ pump thus inhibiting the influx of K+ and the outflow of Na+

The anti-arrhythmic quinidine affects the membrane potential of myocardial

cell membranes by prolonging both the polarized and depolarized states.

Local anaesthetics affect the nerve cell membrane permeability to Na+ and K+

.

4- Interaction with DNA and RNA:

  Some drugs, known as  antimetabolites, interfere with  nucleotide bases

(purines and pyrimidines) synthesis by inhibition of dihydrofolate reductase, e.g.

methotrexate. 

  Other drugs are involved in the synthesis of false bases, e.g. purine analogues

(6-mercaptopurine) and  pyrimidine analogues  (5-fluorouracil). These agents,

therefore, inhibit DNA and RNA synthetic enzymes. 

Certain drugs interfere with  DNA replication and function including

intercalating agents  (e.g. dactinomycin) and  alkylating agents  (e.g. nitrogen

mustard). 

5- Inhibition of protein synthesis:

  Some drugs like tetracycline act by  inhibition of tRNA  binding to the

ribosomes. Chloramphenicol and erythromycin bind to the ribosome and  inhibit

peptidyl transferase  thus blocking the formation of the peptide bond. Quinupristin

and dalfopristin constrict the exit channel on rRNA  thus preventing the release of

newly synthesized polypeptides. 

6- Non-specific action:

  Some drugs act nonspecifically by forming a monomolecular layer over an

entire area of certain cells, e.g. volatile general anaesthetics  (like ether and nitrous

oxide),  some antidepressants (ethanol and chloral hydrate) and many antiseptics

Drug efficacy and potency:

Efficacy  is measured by the maximal effect attained by the drug. The drug is

more effective when it can attain a higher maximal effect.  Alternatively,  drug

potency is a comparison between drug doses (molar values) and a certain drug effect.

The more potent the drug, the less the dose (or log dose) required to produce the same

effect.

Comparison between drugs A, B and C regarding efficacy and potency

Drugs A and B have the same maximal effect (same efficacy). Drug C has a

lower efficacy. The dose required for drug B to produce 1/2 Emax  is higher

than that for drug A (B is less potent). Drug C is less potent than A or B. 

Combined drug action:

  Additive effect occurs when two different drugs with the same

pharmacological effect are given together yielding an effect equal in magnitude

to the sum of the individual drug effects, e.g. trimethoprim and

sulfamethoxazole (1 + 1 = 2). 

  Synergistic effect occurs when the two drugs with the same effect are

combined together to yield an effect greater in magnitude than the sum of the

individual effects, e.g. penicillin and gentamicin against pseudomonal

infections (1 + 1 = 3).

   Potentiation occurs when a drug lacking an effect alone is combined to a drug

with a pharmacologic effect resulting in increased effect of the latter, e.g.

combination of carbidopa with levodopa (1 + 0 = 2). 

Safety of drug action:

  There are two measures of drug safety:

i)  The therapeutic index of a drug is the ratio of the minimum dose toxic (TD)

for 50% of the population to the minimum dose causing an effect  (ED)  to

50% of the population.  

ii)  The margin of safety is more practical and is expressed by the ratio of the

minimum dose toxic for 0.1% of the population to the minimum dose

causing an effect to 99.9% of the population. 

  The wider the therapeutic index (or window), the more safe the drug is.

Alternatively, the narrow index requires drug monitoring as the drug moves from

effect to toxicity within a small dose interval.

 

Mechanisms of drug action

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Mechanisms of drug action:

1- Interaction with cell surface receptors:

  Cell surface receptors may be proteins or glycoproteins. Drug binding to these

receptors is highly specific and depends on the chemical structure of the drug. Drug

binding to the receptor is attained by several types of interactions including

hydrophobic interactions, van der Waals forces, hydrogen bonds, ionic bonds and

covalent bonds. 

  Cell surface receptors are composed of extracellular domains that bind the drug

or the endogenous molecule. The ligand binding may act as a triggering signal  that

can be propagated in the target cell through intracellular regulatory molecules known

as  second messengers  or  effectors.  For example, isoproterenol binds with β

adrenergic receptors which are functionally coupled  to adenylate cyclase via the

stimulatory G protein (GS).  As a result, adenylate cyclase  is activated and cyclic

adenosine monophosphate (cAMP) level increases. 

2- Interaction with enzymes:

  Enzyme activation by drugs may be caused by allosteric binding in which a

drug is bound to an allosteric site of the enzyme resulting in conformational changes

of the enzyme and increased affinity of the endogenous substrate to the active site of

the enzyme.  

 

Pharmacodynamics

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  Pharmacodynamics is a branch of pharmacology concerned with the study of
biochemical and physiological effects of drugs  and the mechanisms by which they
produce such effects.
  Drug actions result from the dynamic interactions between drug molecules and
cellular components resulting in perturbation of the normal physiology. Any cellular
macromolecule may act as a drug  receptor.  This receptor may be a cell surface
receptor or an intracellular receptor  (ion channel,  enzyme, protein, microsome or
nuclear material).
  Certain drug receptors normally act as physiological receptors for endogenous
components, e.g. adrenergic receptors for adrenaline and noradrenaline. Drugs whose
responses mimic the response elicited by the endogenous component are termed
agonists. An agonist therefore is a drug having both affinity and intrinsic activity at
the receptor. For example, bethanechol is a cholinergic receptor agonist as its action
on the cholinergic receptor resembles that of the endogenous component
acetylcholine.
  Drugs that have affinity but lack intrinsic activity at the receptor site are termed
antagonists as they block the action of the endogenous component without having an
action themselves. These may be  competitive  or  noncompetitive.  Competitive
antagonists act by interfering with binding of the endogenous ligand to the receptor in
a reversible manner. For example, propranolol is a competitive blocker of β
adrenergic receptors. Alternatively, a noncompetitive antagonist acts by interacting
with the nonligand binding site of the receptor, e.g. through covalent modification, so
that the normal binding of the endogenous ligand to the receptor is irreversibly
inhibited. For example, the monoamine oxidase (MAO) inhibitor tranylcypromine
forms covalent adducts with MAO enzyme so that the enzyme is irreversibly
inhibited.
  Partial agonists act by binding to the receptor thus inhibiting  the endogenous
ligand from binding  to the receptor but they have some intrinsic activity.  For
example, nalorphine is a partial agonist for opiate receptor.
  Physiological antagonism  occurs when the drug acts independently at
different receptors but yielding opposite actions. For example, adrenaline acts as a
bronchodilator, by acting on adrenergic receptors in the bronchial smooth muscles,
that antagonizes the bronchoconstrictor action of acetylcholine that acts on
muscarinic receptors.
  Neutralizing  or  chemical antagonism  occurs when  a drug binds to another
drug directly thus inactivating each other. For example, digoxin binging antibodies
are used as antidotes for digoxin toxicity by forming inactive complexes with the
drug.  

Drug Excretion

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   Renal excretion is the major route of drug elimination for polar drugs, water-
soluble drugs, low molecular weight drugs (below 500) and drugs with slow
biotransformation rates. Renal excretion of drugs through the kidney nephrons
involves three processes, namely glomerular filtration, active tubular secretion and
tubular reabsorption.
Glomerular filtration:
  This is a passive process in which small molecules and drugs are filtered
through the glomerulus of the nephron. Glomerular filtration rate affects drug
elimination rate and is affected by cardiac output. Glomerular filtration rate is
estimated from the elimination rate of creatinine or inulin which are excreted by
glomerular filtration only (without tubular secretion or reabsorption). Drugs bound to
plasma proteins are too large to be excreted by glomerular filtration.
Active tubular secretion:
  This is a carrier-mediated active transport system requiring energy. The kidney
contains two active tubular secretion systems; one for weak acids and another for
weak bases. The active tubular secretion system is competitive. For example, the
weakly acidic drug probenecid competes with penicillin for the same system and
therefore probenecid decreases renal excretion of penicillin resulting in prolongation
of its half life.
Tubular reabsorption:
  This is a passive process that follows Fick's Law of diffusion where lipid
soluble drugs are reabsorbed from the lumen of the nephron back into systemic
circulation. Weakly acidic drugs are mainly reabsorbed from acidic urine and vice
versa as the drug is more lipophilic in the non-inonized form.
  Diuretics decrease the time of drug contact with renal tubules thus decreasing
tubular reabsorption and increasing drug elimination. 

Drug metabolism

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  Biotransformation of drugs is essential to facilitate their excretion. For
example, lipid-soluble drugs are not easily excreted from the kidney as these are
reabsorbed through renal tubules into the blood stream. Drug metabolism aims to
convert the drug into a water-soluble form easily excreted from the body.
  There are two main types of drug biotransformation reactions, namely phase I
and phase II reactions.
Phase I reactions:
  These are non-synthetic reactions  performed mainly by liver microsomal
enzymes called cytochrome P-450 (CYP-450) enzymes. There are many subfamilies,
each responsible for the metabolism of certain drug classes, including CYP1A2,
CYP2E1, CYP3A4, ..etc. Phase I reactions include oxidation, reduction, hydrolysis,
oxidative deamination, sulfoxidation, O-delakylation, N-dealkylation  and  aromatic
hydroxylation.
  Induction and inhibition of  liver microsomal enzymes affect drug
pharmacokinetics massively. For example, induction of liver microsomal enzymes
reduces the action of potent drugs administered in low doses like anticoagulants and
contraceptives.  Additionally, drugs converted to toxic  forms by liver microsomal
enzymes like paracetamol, isoniazid and D-galactosamine, show increased toxicity by
microsomal enzyme induction.  The reverse is true for liver microsomal enzyme
inhibition.
  Inducers of liver microsomal enzymes include:
  Acute alcohol ingestion.
  Drugs like phenobarbital (increases its own metabolism leading to tolerance)
and phenytoin (increases codeine metabolism).
  Diseases like diabetes mellitus.
  Fasting.
  Hormones like insulin (stimulates barbiturate metabolism).
Alternatively, inhibitors of liver microsomal enzymes include:
  Chronic alcohol ingestion (inhibits phenobarbital metabolim).
  Drugs like cimetidine  (broad-spectrum inhibitor), dicoumarol  (inhibits
phenytoin metabolism) and phenylbutazone (inhibits tolbutamide metabolism).
  Toxic doses of radiation.
  Diseases like hypothyroidism and neoplastic diseases.
  Hormones like estrogens and progestins (inhibit mepiridine metabolism).
Effect of biotransformation reactions on drug activity and toxicity:
1- A drug may be converted from an active form to an equally active form (e.g.
hydrolysis of aspirin to salicylic acid).
2- A drug may be converted from an active form to an inactive form (e.g.
hydrolysis of acetylcholine to choline and acetic acid).
3- A drug may be converted from an active form to a toxic form (e.g. oxidation of
methanol to formaldehyde).
4- A drug may be converted from an active form to metabolites with different
activities (e.g. phenylbutazone is oxidized to two metabolites; one anti-
rheumatic and another uricosuric).
5- A drug may be converted from an inactive form to an active form (e.g.
reduction of chloral hydrate to trichloroethanol).
6- A toxicant may be converted from an inactive form to a toxic form (e.g.
oxidation of parathion to toxic metabolite).
Phase II reactions:
  These are synthetic or conjugation reactions. These always terminate in a safe
product that is water-soluble and easily excreatble. Drugs are subjected to phase II
reactions directly or after phase I reactions (most cases). In few cases, drugs may be
subjected to phase I after phase II reactions.
Phase II reactions involve conjugation with water-soluble endogenous
molecules as shown in the following table:
 

Drug distribution

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  After drug absorption, drugs distribute rapidly to tissues with high blood flow
and slowly to tissues poor in blood flow.  Cardiac output affects peripheral drug
penetration by increasing tissue perfusion.
Tissue accumulation:
Drugs may accumulate in tissues based on their physicochemical
characteristics or special affinity of the tissue for the drug. For example, lipid-soluble
drugs accumulate in adipose tissue because of drug partitioning. Tetracycline may
accumulate in bones because of complex formation with calcium.
Plasma protein binding:
Plasma protein binding affects drug distribution to a great extent. Drugs bound
to plasma proteins become unable to penetrate the tissues because of large size. Also
protein binding prolongs the action of the drug due to the presence of a bound form
of the drug  in equilibrium with the free form. The most important plasma protein is
albumin although other plasma proteins like α1-glycoprotein are important in binding
basic drugs like propranolol.  Potent drugs like phenytoin that are highly bound to
plasma proteins (over 90%) may be displaced by other drugs that are also highly
protein-bound (salicylates)  resulting  in drug displacement and increase of the free
form of the drug resulting in increased drug toxicity.
Penetration of the blood brain barrier (BBB):
  The capillaries of the brain are surrounded by a thick lipid membrane layer of
glial cells that create what is called BBB. Only lipophilic drugs can pass this barrier readily.
Placental transfer of drugs:
  The maternal and fetal blood are separated by what is called blood placental
barrier.  Lipid-soluble drugs pass readily to the fetus while water-soluble drugs,
specially large molecular weight drugs, pass slowly. Even though, all drugs should be
considered to be transported to the fetus for the  purpose of taking precautions to
avoid drug-induced malformation.
Redistribution:
  Termination of drug action is usually produced by drug biotransformation or
excretion. However, drug redistribution may terminate drug effect. For example, the
highly lipid-soluble ultra-short acting barbiturate (thiopental)  rapidly penetrates the
blood brain barrier causing CNS depression. However, the drug rapidly redistributes
from the site of action to adipose tissue resulting in rapid fading of the effect.