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.  

Passage of drugs through cell membranes (absorption):

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  Drug absorption necessitates passage of the drug through various cell 

membranes, including cellular plasma membranes and intracellular membranes like 

nuclear membrane or endoplasmic reticulum.  

  Passage of drugs through cell membranes takes place through one of the 

following pathways: 

1- Passive diffusion and partitioning:  

  Within  the cytoplasm or in interstitial fluid, most drugs undergo transport by 

simple passive diffusion  according to Fick's Law of diffusion, where the rate of 

passage of the drug through cell membrane is directly proportional to the 

concentration gradient of the drug across cell membrane.  

  Passive drug transport across cell membranes involves successive partitioning 

of a solute between aqueous and lipid phases  and diffusion within the respective 

phase. The rate of drug transport depends on both pH, lipid/water partition coefficient 

and surface area of absorption site.   

2-Paracellular transport: 

  This is diffusion and transport of the drug molecules and accompanying water 

across narrow junctions between cells or trans-endothelial channels.  

3- Carrier-mediated transport: 

  This includes active transport and facilitated diffusion. In both types, the drug 

is carried by a carrier selective for the drug which is either an endogenous substance 

or similar to an endogenous agent. The carrier system becomes saturated at high drug 

concentration. The process is competitive as drugs with similar structure compete for 

the same carrier.  

  The difference between the two types is that active transport takes place 

against the concentration gradient and necessitates energy. Facilitated diffusion, on 

the other hand take place along the concentration gradient and does not require 

energy.  

4- P-glycoprotein-mediated efflux: 

  P-glycoproteins are embedded in the lipid bilayers of cell membranes in α-

helical domains.  These proteins are ATP-dependent pumps which  facilitate drug 

efflux from the cell. These glycoproteins are often associated with metabolizing 

enzymes to degrade the drug.  Examples  of drugs affected much by these 

glycoproteins are digoxin, nifedipine and cyclosporin.  

5- Vesicular transport: 

  This is the process of engulfing particles or dissolved materials by a cell. This 

includes: 

  Pinocytosis, which is the engulfment of small solutes or fluids.  

  Phagocytosis, which is the engulfment of large particles or macromolecules, 

usually by phagocytes.  

  Exocytosis, which is the movement of macromolecules out of the cell.  

Pharmacokinetics of administered drugs

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- Drug physicochemical properties: Drug polarity can be expressed as lipid/water partition coefficient, which is the ratio of the lipid-soluble portion to the water-soluble portion of the drug when distributed between water and an immiscible lipid.  

  The lipophilic characters of drugs are enhanced in non-ionizable hydrocarbon 

chains and ring systems. Drug lipophilicity is required for:  

  Drug absorption from GIT and respiratory tract (through the lipid bilayers).  

  Drug penetration of the blood brain barrier.  

  Drug passage through the placental barrier.  

  Drug renal tubular reabsorption in the kidneys.  

  Enhanced depot effect of intramuscular injections.  

  Enhanced topical absorption through skin penetration. 

  Enhanced plasma protein binding.   

Alternatively, the hydrophilic character of drugs is enhanced by the presence of 

polar groups like nitrogen-  and oxygen-containing functional groups. Drug 

hydrophilicity is required for: 

  Drug dissolution in parenteral and ophthalmic preparations. 

  Drug dissolution in GIT. 

  Adequate urine concentration of the drug (for urinary tract infections for 

example).  

  Most drugs are weak acids, weak bases or salts of either of them. Strong acids 

and bases are nearly completely ionized in aqueous media, whilst the ionization and 

hence dissolution weak acids and bases in aqueous media depends on the pH of the 

medium. According to Le Chatelier's principle, weak acids  like acetylsalicylic acid 

are less ionized in acidic media. As the acidity of the medium increases (pH 

decreases), the ratio of non-ionized portion of the acid increases and vice versa. For 

this reason, weak acids are mostly non-ionized and hence more lipid soluble in acidic 

media. The reverse is true for weak bases like morphine, where basic media enhance 

their lipid solubility  due to the predominance of the non-ionized portion and vice 

versa. 

  This is particularly important for drug absorption and elimination kinetics. For 

example, weakly acidic drugs are mostly unionized in the stomach (acidic medium) 

and hence are lipid solube  so can be absorbed from the stomach since absorption 

requires hydrophobicity (lipophilicity) as absorption takes place through the lipid 

bilayers of the GIT.  Alternatively, basic drugs are ionized (hydrophilic) in the 

stomach so absorption of such drugs is minimal in the stomach and is delayed until 

the drug reaches the basic medium of the intestine. 

  Another example is renal elimination from the kidney. Excretion of weakly 

acidic drugs can be enhanced from the kidney by the administration of urinary 

alkalinizers like sodium bicarbonate. This will make the drug predominantly in the 

polar (hydrophilic) form that dissolves in the urine and is not reabsorbed through the 

renal tubules since this reabsorption requires lipophilicity (unionized forms). 

Similarly,  an intoxicated patient with a weakly basic drug can be administered a 

urinary acidifier to enhance drug elimination. The reverse is true if reabsorption of 

the drug is required to prolong its action.  

2- Drug route of administration: 

    Different routes of drug administration differ in drug bioavailability (rate and 

extent of drug absorption).  This may dramatically modify drug effects, drug onset 

and duration of action. These include routes for local action and routes for systemic 

action (including enteral, inhalation and parenteral routes).  

A) Transdermal and topical administration:  

  Transdermal (percutaneous) drug absorption is the placement of a drug 

formulation (lotion, ointment, cream, paste or patch) on the skin surface for systemic 

absorption.  Small  lipid-soluble drugs  (e.g. nitroglycerin, nicotine, scopolamine, 

clonidine, fentanyl, testosterone and 17-β-estradiol)  are absorbed readily from the 

skin. Alternatively, drugs may be applied topically for local effects (to avoid systemic 

toxicity or to localize drug effect).  Examples are antimicrobials (antibacterials and 

antifungals) and local anaesthetics. Local anaesthetics may be applied together with a 

vasoconstrictor like adrenaline to localize the anaesthetic (to increase action) and 

prevent systemic absorption (to decrease drug toxicity).  

  Other topical routes of administration include: 

  Eye, ear and nose drops. 

  Urethral or vaginal solutions. 

  Mouthwashes and gargles. 

B) Enteral administration: 

  This is represented by drug administration through the alimentary canal (from 

mouth to anus), including:

1- Peroral (oral) administration:  

Drug molecules are absorbed throughout the GIT but most absorption takes 

place at the duodenal region due to the greater surface area (more villi and microvilli 

that are responsible for absorption).  

Although the oral route is the most convenient, most economic and safest route 

of drug administration,  many  limitations of  this  route are present, including the 

following: 

  Irritant drugs that cause excessive vomiting, e.g. tartaremetic. 

  Acid-labile drugs such as peptide hormones (insulin). 

  Drugs that are extensively inactivated in the liver through first-pass effect. 

  Insoluble and non-absorbable drugs, e.g. hexamethonium, except when 

required for local effect in the GIT (e.g. streptomycin).  

  Complexation with some food components retards the absorption (e.g. 

tetracycline and calcium). 

  Unconscious patients (unable to swallow). 

  Convulsions (loss of control on epiglottis may lead to respiratory tract 

aspiration).  

  Emergency cases (due to slow action). 

2- Buccal and sublingual administration:  

  A tablet or lozenge is placed in the mouth in contact with  the buccal mucosa. 

This allows for absorption of small, lipid-soluble molecules through the epithelial 

lining of the mouth. Alternatively, a tablet can be  placed  under the tongue 

(sublingual) and the drug is absorbed from the sublingual veins.  

  Buccal and sublingual drug administration allow for systemic absorption of the 

drugs without passing into the liver (no first-pass effect). 

3- Rectal administration: 

  Drugs are administered in the form of liquids (enemas) or suppositories. 

Absorption takes place through the mucosal surface and rectal veins. The lower two-

thirds of the rectum allow for direct systemic absorption bypassing hepatic first-pass 

effect.  

C) Respiratory tract administration: 

  This includes: 

1- Intra-nasal administration: 

  The drug is administered to the nasal mucosa in the form of drops or spray for 

the purpose of local (e.g. decongestants) or systemic effects.  

2- Pulmonary inhalation: 

  The drug is administered by various devices like metered dose inhalers (MDI), 

spacers, nebulizers or dry powder aerosols. Drug absorption from the bronchial tree is 

very rapid and avoids hepatic first-pass effect.  

D) Parenteral administration: 

  This includes: 

1- Intra-venous injection: 

  The drug is injected directly into venous blood, pooled to the heart during 

diastole through superior and inferior vena cavae and then distributed to the whole 

body by cardiac systole.  

  This route has many advantages: 

  Rapid action, so it is most suitable in emergency cases.  

  This type of administration also ensures 100% bioavailability.  

  Large volumes of drugs, nutrients electrolyte solutions can be given. 

  Irritant, hypertonic, acidic or alkaline solutions can be given by this route 

slowly as the preparation is diluted in a large volume of blood.  

However, this route has many disadvantages: 

  Allergic reactions are more common. 

  Rapid administration may cause toxic effects even at normal dose levels.  

  Overdoses can not be withdrawn nor absorption be retarded.  

2- Intra-arterial injection: 

  The drug is injected into an artery to attain high drug concentration in a tissue 

or an organ before being diluted in the general circulation.  

3- Intra-muscular injection: 

  The drug is injected in the form of solution  or suspension deep in skeletal 

muscles. Drug absorption rate is dependent on lipid solubility of the drug, vehicle 

composition and vascularity of the injected region.  

4- Subcutaneous injection: 

    The drug is injected under the skin. The rate of drug absorption is slower than 

intramuscular route  as subcutaneous regions are less vascular than muscular tissue. 

Some drugs in which slow absorption is necessary are given subcutaneously,  e.g. 

insulin and adrenaline.  

5- Inta-articular injection: 

  This route is important when direct injection of a drug inside a joint is 

required, e.g. corticosteroids in arthritis.  

6- Intra-dermal (intra-cutaneous) injection: 

  The drug is injected in the dermis to minimize systemic absorption and 

toxicity, e.g. allergic skin tests.   

7- Intra-thecal injection: 

  The drug is injected into the spinal fluid.  The specific gravity of the drug 

determines the region of its effect.  

3- Host's physiological, biochemical and nutritional status: 

  This is represented by:  

1- Gastric emptying rate  (GER): The average gastric emptying rate is  about  55 

minutes, but many factors cause delay or increase of this time. Factors that 

increase gastric emptying increase drug absorption rate as most drugs are 

absorbed from the intestine. Gastric emptying is affected by the nature of food 

(bulky or hot meals tend to be retained in the stomach for a longer time), 

emotional status and concurrent medication use (anti-cholinergics and pro-

kinetic agents).  

2-  Intestinal motility (peristalsis):  A sufficient period of contact between the drug 

and epithelial lining of the GIT  (residence time) is required for drug 

absorption.  Increasing peristalsis (diarrhea, infections) may decrease drug 

absorption in slowly-absorbed drugs.  

3- Nature of diet: Protein, vitamin or essential fatty acid deficiency in diet retard 

drug metabolism. Fasting induces liver microsomal enzymes.  

4- Diseases: Diabetes potentiates liver microsomal enzymes increasing drug 

metabolism. Liver disease impairs hepatic clearance of drugs causing 

potentiation of drug effect. Renal disease impairs renal drug clearance. 

Neoplastic diseases retard tissue metabolism.  

5-  Physical factors: Exposure to sublethal doses of radiation impairs hepatic drug 

metabolism. 

6-  Species differences: Metabolizing enzymes may differ between different 

species. The rabbit for example deaminates amphetamine to biologically 

inactive ketone while the rat produces the biologically active vasopressor agent 

4-hydroxyamphetamine.  

7- Genetic differences:  Some persons are rapid acetylators thus increasing the 

hepatotoxic effects of isoniazid while others are slow acetylators  thus

increasing the neurological toxicity of isoniazid. Some persons are deficient in 

the intestinal intrinsic factor required for the absorption of vitamin B12. 

8-  Sex differences: Testosterone (male hormone) usually increases the rate of 

drug metabolism.