VARIATIONS IN DRUG RESPONSE TACHYPHYLAXIS • frequent or continuous exposure to agonists

often results in short-term diminution of the receptor response. • Many mechanisms may be
responsible: o Blocking access of G protein to activated receptor (ß-arrestin) o Receptor molecules
may be internalized by endocytosis (to prevent exposure to extracellular molecules) o Tolerance:
Depletion of substrates required for downstream effects (EXAMPLE: depletion of thiol cofactors in
nitroglycerin tolerance, reversible with administration of glutathione) • e.g. Theophylline,
Salbutamol. Nitrates, Dobutamine MNEMONIC: Tachyphylaxis What drugs display tachyphylaxis?
MEDical students Love to watch CNN in HD! Metoclopramide Nitroglycerin Ephedrine Nicotine
Dobutamine LSD Calcitonin Hydralazine Desmopressin • Downregulation: Long term reduction in
receptor number due to continuous exposure to agonist • Upregulation: Increase in receptor
number, which occurs when receptor activation is blocked for prolonged periods IDIOSYNCRATIC
DRUG RESPONSE • one that is infrequently observed in most patients. • EXAMPLES: o aplastic
anemia with chloramphenicol o cataracts with allopurinol PHARMACOKINETICS As a guide in this
section, we will be discussing first the properties of drugs (solubility and dissociation principles).
Then followed by the ADME of pharmacokinetics (Absorption, Distribution, Metabolism, Excretion)
Dr. Rodriguez WATER AND LIPID SOLUBILITY OF DRUGS • aqueous solubility is directly proportional to
electrostatic charge (ionization, polarity) o ionized and polar drugs are more water-soluble, hence
increased clearance (less absorption) • lipid solubility is inversely proportional to electrostatic charge
(ionization, polarity) o non-ionized and non-polar drugs are more lipid-soluble, hence increased
absorption (less clearance) In absorption REMEMBER the mnemonic LUNA Lipid soluble , Unionized,
Neutral molecules, are Absorbed. Recall that cell membranes are made up of lipids; and like dissolves
like – therefore, drugs that are lipid soluble, unionized and neutrally charged will pass through the
lipid membrane Dr. Rodriguez PERMEATION This is the movement of drug molecules into and within
biologic environments. It involves the ff. processes: 1. AQUEOUS DIFFUSION • Passive movement of
small drugs through small water-filled pores between the blood and extravascular space (exceptions:
brain, testes, and eye barriers that have no pores) • Affected by drug concentration and charge •
Governed by Fick’s Law of Diffusion; to be discussed below. TOPNOTCH MEDICAL BOARD PREP
PHARMACOLOGY MAIN DIGITAL HANDOUT BY MARIA YNA PEREYRYA-BORLONGAN, MD-MBA For
inquiries visit www.topnotchboardprep.com.ph or
https://www.facebook.com/topnotchmedicalboardprep/ Page 3 of 95 This handout is only valid for
the October 2022 PLE batch. This will be rendered obsolete for the next batch since we update our
handouts regularly. TOPNOTCH MEDICAL BOARD PREP PHARMACOLOGY MAIN HANDOUT BY DR. YNS
PEREYRA-BORLONGAN, MD-MBA For inquiries visit www.topnotchboardprep.com.ph or
https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for October 2022
PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.
2. LIPID DIFFUSION • Movement of drugs through lipid membranes between body compartments,
and from the ECF to the ICF • Most important limiting factor for permeation • Governed by Fick’s law
of diffusion • Very important for the diffusion of weak acids and weak bases 3. TRANSPORT BY
SPECIAL CARRIERS • Drugs that do not readily cross through membranes may be transported across
barriers by mechanisms that carry similar endogenous substances o ions through Na+/K+ pump o
neurotransmitter through reuptake transporters o metabolites such as glucose through GLUT o
carriers for foreign molecules or xenobiotics • NOT governed by Fick’s law of diffusion and is
capacity-limited 4. ENDOCYTOSIS AND PINOCYTOSIS • Endocytosis: large drugs bind to receptors, are
internalized and released after vesicle breakdown (reverse: exocytosis) • Small polar drugs combine
with special proteins to form complexes which undergo endocytosis: o vitamin B12 bound to intrinsic
factor o iron bound to transferrin DISSOCIATION OF WEAK BASES • Protonated (BH+) form is more
water-soluble and undergoes better clearance o Weak base is better excreted in acidic environment
(Amphetamine is better excreted in acidic urine) • Unprotonated (B) form is more lipid-soluble and
more likely to cross biological membranes o Weak base is better absorbed in basic environment
(Allopurinol is better absorbed in the basic environment of the small intestines) To simplify the
concept, the pH characteristic of the drug same to the environment to which it will be absorbed. In
other words, ang weakly acidic na drug ay ma-absorb sa acidic environment (e.g. Aspirin is acidic; it’s
absorbed in relatively acidic parts of the GIT). Weakly basic drug ma-absorb sila sa relatively basic
portions of the GIT. On the opposite, if gusto mo sila tanggalin sa body, expose them in an
environment na opposite sa pH characteristic nila. Example, to excrete a weakly acidic drug,
alkalinize it’s environment with a basic agent. Let’s apply this to the examples below. Dr. Rodriguez
FICK’S LAW OF DIFFUSION • Predicts the rate of movement of molecules across a barrier !"#$ = ('! −
'")×Permeability Coefficient Thickness ×"?@A • Pharmacologic implications: o absorption is faster in
organs with larger SA (intestinal > stomach) o absorption is faster in organs with thinner membranes
(lung > skin) WEAK ACIDS AND BASES • Many drugs are weak acids and weak bases which dissociate
into ionized and non-ionized forms • pH determines the fraction of drug molecules charged (ionized)
versus uncharged (non-ionized) • Predicted by Henderson-Hasselbach equation o relationship
between pH, pKa (dissociation constant) and concentration of charged and uncharged forms
HENDERSON-HASSELBACH EQUATION DISSOCIATION OF WEAK ACIDS • Protonated (HA) form is more
lipid soluble and more likely to cross biological membranes o Weak acid is better absorbed in acidic
environment (Phenobarbital is better absorbed in the acidic environment of the stomach) •
unprotonated (A-) form is more water-soluble and undergoes better clearance o Weak acid is better
excreted in basic environment (Aspirin is better excreted in a basic urine) Again, same principle
“LUNA.” U = uncharged. Uncharged is absorbed. Look at the equations above HA has no charge, so it
is the one absorbed. HA is called protonated dahil meron siyang H; H in basic chemistry is a proton,
hence “protonated” Dr. Rodriguez BASIC PHARMACOKINETIC PROCESSES For you to remember the
pharmacokinetic processes please remember the mnemonic ADME. It stands for absorption,
Distribution, Metabolism and Excretion. Please also remember that Elimination is different from
excretion. Elimination = Metabolism and Excretion. Dr. Rodriguez A. ABSORPTION • Transfer of a drug
from its site of administration to the bloodstream • Affected by 3 major factors 1. Route of
administration 2. 3. Blood flow Concentration Classically, absorption is defined as the process by
which the drug reaches the SYSTEMIC CIRCULATION. Different routes have different sets of barriers
that the drug needs to pass through, thus affecting absorption. More blood flow in a site of
absorption means higher absorption also. For concentration, remember the Fick’s law of diffusion,
where is (C1-C2) found in the equation? _____________ Go back to the previous page. It’s found in
the numerator, hence bigger difference in concentration would have a directly proportional effect to
the rate of movement of molecules through a barrier. Dr. Rodriguez ROUTES OF DRUG
ADMINISTRATION 1. Oral Route • Most common route of drug administration • Absorption is slower
• Subject to first-pass effect (a significant amount of the drug is metabolized in the gut wall, portal
circulation and liver before it reaches the systemic circulation) 2. Buccal and Sublingual • Direct
absorption into the systemic venous circulation (bypasses the first pass effect). o Buccal (pouch
between the gums and cheek) -> Facial vein -> Internal jugular vein o Sublingual (under the tongue) -
> Lingual vein → Internal jugular vein (IJV) → brachiocephalic (innominate) vein → superior vena
cava → right atrium 3. Intravenous • Instantaneous and complete absorption that bypasses first pass
effect (100% bioavailability) • Potentially more dangerous: Inadvertent systemic introduction of
bacteria through the IV line (line sepsis); Difficult to reverse effects 4. Intramuscular • Absorption is
faster and more complete than oral (bypasses first-pass effect, higher bioavailability) • Large volumes
may be delivered if drug is not too irritating (i.e. 5g of MgSO4) • Anticoagulants cannot be given by
this route because they may cause bleeding (hematomas)