Fate of the Drug

Joanne Katherine T. Manlusoc, MSc.

Overview
The students are oriented with the biological fate of the drug, the
drug’s mechanisms of action and effects on the body. Included in the
discussion are the different possible drug targets, the drug activity on a
given drug-targets.
Objectives
1. Outline the fate of the drug from administration to excretion
2. Identify the different cellular component which interacts with drugs
3. Predict possible interaction of drug with cellular components for
pharmacologic activity
DRUG and its fate
Drug is a chemical molecule that is organic in nature. Following
introduction into the body, a drug must pass through many barriers,
survive alternate sites of attachment and storage, and avoid significant
metabolic destruction before it reaches the site of action, usually a
receptor on or in a cell.
The major exceptions include the alkylating agents used in cancer
chemotherapy and a few inhibitors of the enzyme,
acetylcholinesterase. The fate comprises of absorption, distribution,
metabolism and excretion or the pharmacokinetics.
Pharmacokinetic Phase
• Absorption
• Regardless of the route of administration, is dependent upon drug solubility.
Drugs given as aqueous solutions are more rapidly absorbed than oils,
suspensions or solid form because they mix more readily. Drugs given in a
solid form (pills) are dependent upon the rate of dissolution, which may be a
limiting factor.
• The concentration of a drug influences its rate of absorption. Drugs injected
(or administered) in high concentration are absorbed more quickly than those
at lesser concentrations.
Pharmacokinetic Phase
• The route of administration markedly affects drug uptake. Some
routes of administration are summarized below:

ROUTE ABSORPTION PATTERN LIMITATIONS/PRECAUTIONs

Enteral (oral) variable Absorption potentially erratic.
Absorption potentially incomplete.
Parenteral (non-oral) - 3 major types
Intravenous (i.v.) Absorption circumvented Immediate Effects. Increased risk of
adverse effects.
Subcutaneous (sub Prompt from aqueous soln. Slow and Not suitable for large volume. Possible
cut or s.c.) sustained (suspension) pain, edema.
Intramuscular (i.m.) Prompt from aqueous soln. Slow and Overweight or emaciated patients
sustained (suspension) exhibit unusual patterns of absorption.
Pharmacokinetic Phase
• Distribution
• After a drug is absorbed into the bloodstream it is distributed into /interstitial
and cellular fluids. In the first few minutes, the drug is usually distributed to
high blood flow organs (heart, liver, kidney, brain, etc.). Delivery to muscle,
skin and fat is slower but less reversible (outflow/min).

• Lipid insoluble drugs are restricted in their distribution and hence, their sites
of action. Drugs may accumulate in tissues in high concentration as a result of
pH gradients, binding to intracellular constituents, or partitioning into lipid.
Pharmacokinetic Phase
• Distribution
• The distribution of drugs to the CNS from the bloodstream is unique.
Endothelial cells of the brain capillaries differ from their counterparts in most
tissues by the absence of intercellular pores; thereby restricting bulk aqueous
flow. Thus, organic acids and bases only slowly diffuse into the brain.

• Strongly ionized agents such as quaternary amines or the penicillins are

normally unable to enter the CNS from circulation.

• Many drugs accumulate in muscle and other tissues: cellular reservoirs.

Example of proteins embedded within the cell membrane

Example of lipid structure as drug-target

Example of carbohydrate structure as drug-target
Pharmacokinetic Phase
• Biotransformation
• Many drugs are lipid soluble weak organic acids and bases that are not readily
eliminated from the body. Drug metabolites are usually more polar and less
lipid soluble than the parent material and this enhances their excretion, and
lowering their volume of distribution.

• There are several chemical reactions causing the biotransformation of drugs

classified as Phase-I and Phase-II reactions.
Pharmacokinetic Phase
• Biotransformation
• Phase - I: reactions convert the parent material to a more polar metabolite by
oxidation, reduction or hydrolysis.

• Phase - II: usually synthetic or conjugation reactions and, involve coupling

between the drug or its metabolite and an endogenous substrate (e.g.,
glucuronic acid, sulfuric acid, acetic acid or an amino acid.
Pharmacokinetic Phase
• Biotransformation
• One of the most important systems for biotransformation is the hepatic
microsomal drug-metabolizing system. The endoplasmic reticulum of the liver
has a network of enzymes called microsomes. The microsomes catalyze the
oxidation of drugs (via mixed function oxidases or monooxygenases) as well
as glucuronide conjugation. Drug metabolism, owing to its strong relationship
with organic chemistry shall be the emphasis of this class although classical
medicinal chemistry would provide a more equal distribution of the
aforementioned areas.
• The intention of metabolism or biotransformation is to aid the excretion of a
drug, it is not always consistent that the drug is changed to an "innocuous
form."
Pharmacokinetic Phase
• Excretion
• The kidney is the most important organ for elimination of drugs. Substances
excreted in the feces are mainly unabsorbed orally ingested compounds or
metabolites excreted in the bile and not reabsorbed from the intestine.
• Excretory organs, eliminate polar compounds more efficiently than
substances with high lipid solubility.
Mechanism of Drug Action
• Drug actions  dynamic interactions between drug molecules and cellular
components (receptors)

• Theories describing the pharmacologic activity of the drug (receptor site

theory)
• Lock and Key theory – completely complementary relationship between the drug
molecule and a specific area on the surface of the receptor molecule
• Induced fit theory – complementary relationship between the drug molecule and its
active site
• Occupational theory of response – the intensity of pharmacologic activity of a
structurally specific drug is directly proportional to the number of receptors occupied
by the drug
Pharmacodynamic Phase
• Effects of drugs on the body

• Types of molecules that a drug may act upon:

• lipid – Amphotericin B
• carbohydrate – used as molecular tag
• protein - receptors
• nucleic acids – DNA and RNA acting as drug target
Pharmacodynamic Phase
• RECEPTOR - cell or group of cells specialized to detect changes in the
environment and trigger impulses in the sensory nervous system;
protein in nature and embedded in the cell membrane

• ION channels
• protein complex made up of polar amino acids to give a hydrophilic pore
• controlled by a receptor protein sensitive to the external chemical messenger
• chemical messenger binds to the external binding site of the receptor protein it
subsequently causes a change in shape which in turn results to opening of the channel
(Induced fit theory)
Pharmacodynamic Phase
• MEMBRANE bound enzyme activator
• a protein molecule both acting as a receptor and as an enzyme
• one part expose in the outer surface the other is on the inner side of the cell
• chemical messenger binds with the receptor binding site opening directly the
enzymes active site or
• indirectly using a protein messenger called the G protein.
Drug- receptor interaction
Pharmacodynamic Phase
ENZYME – protein catalysts produced by living cells by acting as a
surface or focus for the reaction, bringing the substrate(s) together and
holding them in the best position for the reaction.

• TARGET specificity and selectivity between species

• a factor for less chance of side effects
Drug-enzyme interaction
Pharmacodynamic Phase
TARGET specificity and selectivity within the body
• enzyme inhibitor should inhibit only the target enzyme
• receptor agonist/antagonist should only interact with a particular receptor
• receptor agonist
• drugs whose response resemble the effects of the endogenous molecule
• required that the drug must have the correct binding groups, that the binding groups be
in the proper position and of the right size for the binding site
• receptor antagonist
• drugs that lack intrinsic activity and produce effects by competitively or non-
competitively inhibiting the action of endogenous molecules by:
• binding with the receptor causing alteration in the shape
• binding to areas close to the neurotransmitter binding site, preventing the
neurotransmitter from binding
Classification of Drug based on affinity for
receptor
1. Agonist – affinity for the receptor and has intrinsic effect
2. Antagonist – lack the intrinsic activity but with affinity for the
receptor
• Competitive – competes with the endogenous molecule from binding at the
receptor; reversible
Ex. propranolol for adrenergic receptor (β)
• Noncompetitive – noncompetitive inhibition of the action of endogenous
molecule from binding at the receptor; irreversible
Ex. MAO inhibitor in MAO
Classification of Drug based on affinity for
receptor
3. Partial Antagonist – inhibit the endogenous ligand from binding the receptor but
possess some intrinsic activity
Ex. Nalorphine in opiate receptor

4. Physiologic antagonism – different receptors, opposing activity.

Ex. SNS – epinephrine
PNS – acetylcholine (Ach)

5. Neutralizing antagonism – binding with each other forms an inactive compound

Ex. Protamine SO4 and Warfarin Na
Digoxin-binding Ab in digoxin overdose
Design of a receptor agonist
Antagonist - competitive
Antagonist – non-competitive
Partial Agonist