1. Introduction

2.  the body of knowledge concerned with the
action of chemicals (drugs) on biologic
systems
 Medical Pharmacology – use of drugs in the
prevention, diagnosis, and treatment of
disease, especially in humans
 Toxicology – undesirable effects of drugs on
biologic systems

3.  Commonly include:
 inorganic ions
 nonpeptide organic molecules
 small peptides and proteins
 nucleic acids
 lipids
 Carbohydrates
 Often found in plants and animals
 Many partially or completely synthetic

4.  Vary from MW 7 (Li) to over MW 50,000
(thrombolytic enzymes)
 Majority have MW 100-1000

5.  Very strong covalent bonds
 Weaker electrostatic bonds
 Much weaker interactions (H-bonds, van der
Waals, hydrophobic bonds)

6.  1. AQUEOUS DIFFUSION – passive movement
through the extracellular and intracellular
spaces (usually through water-filled pores)
 2. LIPID DIFFUSION – passive movement
through membranes

7.  3. FACILITATED DIFFUSION – transport by
special carriers across barriers
- capacity-limited
- may be inhibited
 4. ENDOCYTOSIS, PINOCYTOSIS – permit
transport of very large (peptides) or very
lipid-insoluble molecules or complexes
(small, polar molecules combined to
special proteins)

8.  Predicts the rate of movement of molecules
across a barrier
Rate = (C1 – C2) x Permeability coefficient x Area
Thickness

9.  Weak bases – ionize when protonated; more
water-soluble
 RNH3+ ⇋ RNH2 + H+
Water-sol. Lipid-sol.
 Weak acids – do not ionize when protonated;
more lipid-soluble
 RCOOH ⇋ RCOO- + H+
Lipid-sol. Water-sol.

10.  can predict the fraction of molecules in the
ionized state (water-soluble) if the pKa of the
drug and the pH of the medium are known
 pKa - pH = log Protonated form
Unprotonated form
 Clinically important when it is necessary to
estimate or alter the partition of drugs
between compartments of differing pH

11.  “Trapping” is a method for accelerating
excretion of drugs.
 Nonionized form diffuses readily across the
lipid barriers of the nephron
 Protonation will occur within the blood and
urine
 Example: Pyrimethamine – pKa 7.0 >

12. Blood Membranes of Urine
pH 7.4 the nephron pH 6.0
Lipid diffusion
NH3 NH3
H+ H+
NH4+ NH4+

13.  Rate and efficiency of absorption differ
depending on a (1) drug’s route of
administration, (2) blood flow, (3)
concentration of drug at site of administration
 Bioavailability = The amount absorbed into
systemic circulation divided by the amount of
drug administered

14. Oral (swallowed)
 maximum convenience
 slower absorption and less complete
 drugs are subject to first-pass effect (a
significant amount is metabolized in the gut
wall, portal circulation, and liver before
reaching systemic circulation)

15. Intravenous
 Instantaneous and complete absorption
 Potentially more dangerous if administration
is too rapid (high blood levels is reached)

16. Intramuscular
 Often faster and more complete than oral
 Large volumes may be given if drug is not too
irritating
 First-pass metabolism is avoided
 NOT applicable to anticoagulants (heparin) as
this may cause bleeding

17. Subcutaneous
 Slower absorption than intramuscular
 First-pass metabolism is avoided
 Large-volume bolus doses are less feasible
 Applicable to heparin

18. Buccal and sublingual
 Permits direct absorption into systemic
venous circulation
 Bypasses hepatic portal circulation and first-
pass metabolism
 Fast or slow depending on physical
formulation of drug

19. Rectal (suppository)
 Partial avoidance of first-pass effect
(absorption from this location is partially into
portal circulation)
 May cause significant irritation
 Drugs with unpleasant tastes may be
administered rectally

20. Inhalation
 Offers delivery closest to the target tissue
(respiratory diseases)
 Rapid absorption
 Convenient for drugs that are gases at room
temperature (NO, N2O) or easily volatilized
(anesthetics)

21. Topical
 Application to skin or mucous membrane of
the eye, nose, throat, airway, or vagina for
local effect
 Rate of absorption varies with area of
application and drug’s formulation
 Usually slower than any of the previous
routes listed

22. Transdermal
 Involves application to the skin for systemic
effect
 Absorption usually occurs very slowly
 First-pass effect is avoided

23.  SIZE OF THE ORGAN – determines the
concentration gradient between blood and
the organ
- larger organs can take
up more (eg. muscles)

24.  BLOOD FLOW – determines the rate of uptake,
although it may not affect the steady-state
amount of drug in the tissue
- well-perfused tissues (eg.
brain, heart, kidneys, splanchnic organs) will
often achieve high tissue concentrations
sooner than poorly-perfused tissues (eg. fat,
bone)

25.  SOLUBILITY – influences the concentration of
the drug in the extracellular fluid surrounding
the blood
- example: some organs (like
brain) have a high-lipid content; thus, very
lipid-soluble anesthetic will diffuse into the
brain tissue more rapidly and to a greater
extent than a drug with low lipid-solubility

26.  BINDING – binding of a drug to
macromolecules in blood or tissue
compartment will tend to increase its
concentration in that compartment

27.  Occurs primarily in the liver
 Conversion to a metabolite terminates drug
action (a form of elimination)
 Prodrugs ( eg. Levodopa, minoxidil) are
metabolized to become active
 Some drugs are not metabolized and
continue to act until they are excreted

28.  Not the same as drug excretion
 Excretion is primarily by way of the kidneys,
except anesthetic gases (lungs)
 Some drugs (diazepam) have active
metabolites
 For drugs that are not metabolized, excretion
is the mode of elimination
 A few drugs combine irreversibly with
receptors, so disappearance from the
bloodstream is not equivalent to termination
of action

29.  FIRST-ORDER ELIMINATION
 Rate of elimination is proportionate to
concentration
 Plasma concentration decreases exponentially
with time
 Drugs have a characteristic half-life

30. FIRST-ORDER ELIMINATION

31.  ZERO-ORDER ELIMINATION
 Rate is constant regardless of concentration
 Plasma concentration decreases linearly
 Typical of ethanol and aspirin at toxic levels

32. ZER0-ORDER ELIMINATION

33.  Deals with effects of drugs on biologic
systems
 RECEPTOR – specific molecules in the biologic
system to which a drug binds to bring about
change in function of the system
 AGONIST – drug that activates its receptor
upon binding

34.  EFFECTOR – channel or enzyme that
accomplishes the effect after activation by the
receptor
 INERT BINDING SITE – component to which a
drug binds without changing any function
 ANTAGONIST – drug that binds to receptor
without activating it

35. 1. Competitive – can be overcome by increasing
the dose of the agonist
2. Irreversible – cannot be overcome by increasing
the dose of the agonist
3. Physiologic – counters the effects of another by
binding to a different receptor and causing
opposing effects
4. Chemical - counters the effects of another by
binding the drug and preventing its action
5. Partial – binds to its receptor but produces a
smaller effect at full dosage than a full agonist

36.  Maximal efficacy (Emax)
 The maximum effect an agonist can bring
about regardless of dose
 Determined mainly by the nature of the
receptor and its associated effector system

37.  Dose or concentration required to bring about
50% of a drug’s maximal effect (EC50) – in
graded-dose response
 Determined mainly by affinity of the receptor for
the drug
 Typical variables in *quantal dose-response:
ED50 – median effective
TD50 – median toxic
LD50 – median lethal
*minimum dose required to produce a specific
response in each member of the population

39.  index of safety
 Dosage range between the minimum effective
therapeutic concentration or dose, and the
minimum toxic concentration or dose.
 Eg. Theophylline: 8 – 18 mg/mL

40.  Distribution - the process by which a drug
diffuses or is transferred from intravascular
space to extravascular space (body tissues).
These spaces are described mathematically as
volume(s) of distribution.
 Volume of distribution is that volume of
bodily fluid into which a drug dose is
dissolved

41. The body is usually divided into two spaces, a
central and a tissue compartment.
Central volume (Vc) = blood in vessels and
tissues which are highly perfused by blood.
Vc = Dose / Peak serum level
 Peak = Dose / Vc

42.  Peripheral volume (Vt) = sum of all tissue
spaces outside the central compartment
Vc + Vt = Vd
 Distribution volumes are important for
estimating:
Amount of drug in the body, Peak serum
levels, and Clearance

43.  Volume of distribution (Vd)
Vd = Amount of drug in the body
Plasma drug concentration
 Clearance (CL)
CL = Rate of elimination of drug
Plasma drug concentration

44.  PHASE I REACTIONS
- oxidation, reduction, deamination, and
hydrolysis
 PHASE II REACTIONS
- synthetic reactions that involve addition
(conjugation) of subgroups to –OH, -NH2, and
–SH on the drug molecule;
- subgroups include glucoronate, acetate,
glutathione, glycine, sulfate, and methyl
groups

45.  Liver
 Kidneys
 Other tissues (blood, intestinal wall)