Pharmacodynamics is the study of how drugs act on biological systems and their mechanisms of action. Drugs can interact with receptors to mimic or block physiological messengers. Agonists activate receptors while antagonists reduce or prevent agonist effects. Receptors are often proteins that drugs bind to through covalent, ionic, or hydrogen bonds. Signaling mechanisms involve ligand-gated ion channels, G-protein coupled receptors, and second messengers such as cAMP or calcium ions. Understanding these interactions is important for elucidating drug actions at the cellular level.

1. Pharmacodynamics
University of Miami
Advanced Practice Preparation

2. Biotransformation
• Preferable to metabolism – drugs do not normally
provide new materials or energy.
• Physiochemical reactions that are not a component of
usual metabolism.
• Prodrug – biotransformed from inactive to active state.
• Precursor to active compound
• Widely used to overcome problems with absorption,
solubility, duration of action, non-compliance, site specific
drug delivery.

3. Prodrugs
• Azarabine – prodrug of Azauridine
• Intesitinal micr0-organisms block the formation of
toxic components – azauracil.
• Therapeutic effects beneficial.
• Levodopa, prodrug of dopamine
• Rapidly absorbed after PO administration –
distributed to CNS.
• Converted to dopamine in the basal ganglia.
• Dopamine is poorly absorbed when given PO –
biotransformation is necessary.

4. Mechanisms of
Biotransformation
• Phase I Reactions
• Cytochrome P 450 microsomal enzymes.
• Found in the endoplasmic reticulum of the liver cells.
• Human genome encodes 57 enzymes.
• 14 metabolize steroids
• 4 oxidize fat soluble vitamins
• 9 metabolize fatty acids and eicosanoids

5. Biotransformation
Classification
• Phase I biosynthetic reaction
• Introduce or expose a functional group
• Results in loss of pharmacologic activity
• Exception is prodrugs
• Oxidations, reductions, hydroxylations, occur

6. Biotransformation
Classification
• Phase II biosynthetic reaction
• Conjugation reactions
• Covalent linkage with functional group on
parent compound.
• Highly polar conjugates
• Generally inactive
• Exception M-6-G
• Alkylations, acetylations, methylations occur
here.

7. Biotransformation
• Lipophilicity of drugs facilitate passage through biologic
membranes
• This property hinders elimination and biotransformation
• Renal excretion of unchanged drug plays modest role in
elimination
• Lipophilic drugs mostly reabsorbed
• Biotransformation generates polar molecules for excretion

8. Enzyme Induction
• Repeated administration of same or similar drugs can
“induce” cytochrome P450
• Accelerates metabolism
• Reduction in pharmacologic activity
• CYP2B1
• Induced by phenobarbital
• CYP1A1
• Polycyclic aromatics
• CYP3A
• Macrolide antibiotics
• Anticonvulsants

9. Enzyme Induction
• CYP2E1
• Induced by chronic EtOH
• Isoniazid
• Environmental pollutants have been shown to induce P450
enzymes
• Benzopyrene
• Charcoal-broiled meat
• Certain environmental chemicals
• Polychlorinated Biphenyls (PCBs)

10. Enzyme Inhibition
• Inhibition of biotransformation results in elevated
levels of the parent compound
• Prolonged pharmacologic effects
• Inhibition of CYP2D6 by quinidine
• Cimetidine and ketoconazole inhibit oxidative drug
metabolism
• Bind with heme iron

11. Pharmacogenetics
• Genetic polymorphisms
• Autosomal recessive traits
• Differences in abilities to metabolize certain
drugs
• Extensive vs. poor (slow) metabolizers
• Poor metabolizers are at increased risk of
adverse effects

12. Pharmacogenetics
• Genetic polymorphisms
• Affects oxidative drug metabolism
• Autosomal recessive traits
• Differences in abilities to metabolize
certain drugs
• Extensive vs. poor (slow) metabolizers
• Poor metabolizers are at increased risk of
adverse effects

13. Pharmacogenetics
• Genetic polymorphisms
• Poor metabolizers of debrisoquin
• 8% - 10% of Caucasions
• 0% - 2% of Asians
• Faulty expression of cytochrome
P450 isozyme (P4502D6)
• Dextromethorphan is used to monitor
pathway

14. Pharmacogenetics
• Genetic polymorphisms
• N-acetylation
• Slow acetylation of certain arylamines
• Procainamide
• Hydralazine
• Isoniazid
• 50% of US are slow acetylators
• 10% of Japanese and Chinese are slow
acetylators
• Important with drugs that have low therapeutic
index

16. Genetic Polymorphisms
• Debrisoquin oxidation • N-Acetylation
• Alprenolol • p-Aminobenzoic acid
• Amitriptyline • Aminogluthemide
• Desipramine • *Caffiene
• *Dextromethorphan • Clonazepam
• Encainide • Dapsone
• Guanoxan • Hydralazine
• Metoprolol • Isoniazid
• Procainamide
• Phenelzine

17. Elimination Kinetics
First-order Kinetics
• Elimination is proportional to the concentration
• A constant fraction of drug is eliminated per unit time
• e.g., sulfisoxazole (10% /hour)
• Elimination rate varies with the first power of the
concentration
• Most drugs follow this pattern
dC(t) = -kEC(T)
dt

18. Elimination Kinetics
Zero-order Kinetics
• A constant amount of drug is eliminated per unit time
• e.g., phenytoin & ethanol
• Rate is independent of concentration
• Result of overwhelmed enzyme system
• Saturation kinetics
C(t) = e-kEnt 1/2
C0

19. Renal Elimination of Drug
• Glomerular filtration – GRF 125 ml/min
• Drugs enter through capillary plexus
• Free drug flows into Bowman’s space
• 20% of renal plasma flow – RPF 600 ml/min
• Lipid solubility and pH have no influence here

20. Renal Elimination of Drugs
• Proximal Tubular Secretion
• Drug not transferred to glomerular filtrate enters
through afferent arterioles into capillary plexus –
surrounds the nephric lumen.
• Secretion occurs by 2 active transport systems
• Anionic – deprotonated forms of weak acids
• Cationic – protonated forms of weak bases
• Low specificity
• Competitive between multiple drugs

21. Renal Elimination of Drugs
• Distal tubular reabsorption
• Distal convoluted tubule receives drug
• Concentration exceeds capacity of perivascular
space
• If uncharged, drug may diffuse out of nephric lumen
• pH manipulation plays a part here – Ion Trapping

22. Biliary Elimination
• Most drugs eliminated by kidney.
• Some removed via enterohepatic recirculation.
• Lipid soluble drugs present in bile
• Reabsorbed
• Returned to liver
• Re-secreted into bil
• Increase in plasma concentration of drug
• Delay in elimination

23. Half-Life t1/2
• Time necessary for drug concentration in plasma to decrease
by one half
• Often related to duration of action
• If peak plasma concentration and half-life are known, then
plasma concentration at any time can be estimated
t1/2 = 0.693 x Vd
CL

24. Accumulation
Elimination

25. Half-Life t1/2
Time after Peak Plasma Concentration
Concentration (hr) (mg/L)
0 100
2 50
4 25
6 12.5
8 6.25
10 3.125

26. Steady State
• Dosing dependent
• Accumulation vs Elimination
• Repeated dosing
• 4 to 5 half-lives are necessary for plasma drug levels
to reach a steady state
• Steady state can be calculated by multiplying drug
half-life by 5.
• HL x 5 = SS
• Approx. 90% SS value

27. Clearance
• Measure of the removal of drug from plasma
• Expressed as volume/time
• A drug’s clearance and volume of distribution
determine drug half-life
• Drugs can be cleared from plasma by several
mechanisms
• Hepatic transformation, renal, biliary etc.

29. Fig. Model for Organ Clearance of a Drug
Organ of
Cin Elimination Cout
drug drug
Q (Liver or Kidney) Q
drug drug drug
drug drug drug
drug drug
Cin Cout
E
Cin
Extraction ratio (no units) is Drug is eliminated in the
a fraction between 0 and 1. drug drug bile and/or the urine
drug drug
drug drug
CLorgan Q E
Q = blood flow (volume . time-1)
C = concentration (amount . volume-1)

30. Drug Modeling
• Use of modeling
• Compartmental models
• Used to describe drugs’ behavior in the
body
• Do not represent single tissue or fluid
• Groups of similar tissues

31. Compartmental Models
• One-compartment model
• Simplest
• All body tissues and fluids
• Instantaneous distribution is assumed
• Two-compartment model
• Some drugs do not distribute instantaneously to all
body parts
• Distribute rapidly to vessel-rich groups
• More slowly to other tissues
• Peripheral compartment
• Drugs move back and forth between these
compartments

32. One Compartment Model
• Simplest model
• Comprises all body tissues and fluids
• Assumes instantaneous distribution of
the dose of the drug throughout the
body

33. Drug Dose Compartment
Elimination

34. Two Compartment Model
• Central Compartment • Peripheral Compartment
• Highly Perfused Tissues • Less perfused tissues
• Rapid Distribution of Drug • Slower distribution of drug

35. Fig. One and Two Compartment Models
Dose Dose
X0 kin or k0 X0 kin or k0 Peripheral
Compartment
One Central k12 (V2)
Compartment Compartment
(Vd) (Vc or V1)
k21
kout or ke kout or ke or k1O
X0 = dose of drug at time zero; units are amount
kin or k0 = infusion rate constant at time zero; units are amount . time-1
k12 = rate constant for transfer of drug from the 1st (central) to the 2nd (peripheral) compartment
k21 = rate constant for transfer of drug from the 2nd (peripheral) to the 1st (central) compartment
kout or ke = first-order elimination rate constant; units are time-1
k1O = first-order elimination rate constant from the 1st (central) compartment; units are time-1

36. Compartmental Models – Clinical Correlate
• Digoxin
• Two-compartment pharmacokinetics
• Plasma concentrations rise initially
• Decline rapidly as drug redistributes to
muscle
• Plasma concentration is the central
compartment
• Muscle is the peripheral compartment

40. Pharmacodynamics
• Study of biological and
physiological effects of drugs and
their mechanisms of actions.

41. Pharmacodynamics
Properties of Drug Receptors
• Interactions with macromolecular components
• Based on work by Ehrlich and Langley (1900s)
• Receptor was term used to denote part of organism that
reacted with drug
• All drugs do not act at receptors
• Osmotic diuretics - mannitol, urea
• Non-specific membrane interactions
• Antacids
• Chelating agents

42. Properties of Drug Receptors
• Drugs interact with receptors
• Receptors mediate physiologic regulators of cell function
• Hormones, neurotransmitters, autocoids etc.
• Drugs may mimic the actions or block the physiologic
messengers
• Agonists
• Antagonists
• Partial agonists
• Inverse agonists

43. Properties of Drug Receptors
• Agonists
• Drugs that produce a response by activating
a receptor
• Antagonists
• Drugs that reduce or prevent the effects of
agonists
• Partial agonists
• Drugs that may act as either agonist or
antagonist

44. Properties of Drug Receptors
• Drug receptors are often proteins
• Soluble proteins
• Protein in intracellular organelle (bacterial
ribosomal protein)
• Membrane bound protein (Na+-K+ ATPase)

45. Properties of Drug Receptors
• To activate a receptor a ligand
(drug) must bind to that receptor
• Covalent bonds
• Ionic bonds
• Hydrogen bonds

46. Properties of Drug Receptors
• Structure-Activity relationships (drug
shape)
• Intrinsic activity and affinity determined by
chemical structure
• The fit of drug with the receptor
• Stereoisomerisms
• One is a better fit with the receptor
• Some drugs are racemic mixtures or individual
isomers

47. Antagonists
• Agonists and antagonists both
occupy receptors
• Only agonists activate receptors
• k3 is high for agonists
• Antagonists have little or no intrinisic
activity
• k3 is equal to zero or a very low value
• Antagonists may act competitively or
non-competitively

48. Antagonists
• Competitive antagonists bind
reversibly to the same receptor site
as the agonists
• Prevents agonist from binding
• Potency of antagonist is determined by
the rate of dissociation
• Usually slower than the dissociation of the
agonist

49. Competitive Antagonism

50. Antagonists
• Non-competitive antagonists can act
in two ways.
• Irreversibly bind (covalently) with the
receptor site that the agonist binds
• Cannot be competed by high concentrations
of agonist
• An irreversible OR reversible non-
competitive antagonist may bind to a
different site on the receptor
• Can regulate affinity of agonist for that site
• This is an allosteric interaction

51. Partial Agonists
• Some drugs have intermediate activity between
full agonists and antagonists
• Full agonists have high efficacy
• Partial agonists only activate a fraction of the
receptors that they bind to
• Effects will depend upon other agonists or
antagonists that are in equilibrium with the
receptor

52. Partial Agonists
• Partial agonist may produce an effect of lessor
magnitude than that of a full agonist
• Partial agonist may produce a maximum response in
the presence of spare receptors
• Partial agonists can prevent full agonists from inducing
a maximum effect
• By competing with full agonist for receptors

54. Signaling Mechanisms and Drug Action
• Receptors regulate the activity of cells
• By activating or inhibiting transduction systems
• Receptors located in plasma membrane
• Ligand-gated ion channels
• Ligand-regulated membrane enzymes
• G-protein-regulated membrane enzymes and ion channels
• Cytoplasmic receptors
• Second messenger systems

55. Ligand-
Gated Ion
Channel

56. Ligand-Regulated Membrane
Enzymes

57. G- Protein-Regulated membrane
Enzymes
• Guanine nucleotide binding protein
• Heterotrimers ( , , subunits)
• Regulated by agonist-activated receptors
• Most receptors are monomeric
• 7 transmembrane regions
• Receptor interacts with G-protein
• Converts it to a form that can activate or inhibit membrane
bound enzymes
• e.g., adenylyl cyclase, phospholipase C,
• Can activate or inhibit ion channels

58. G Protein-Regulated Membrane
Enzymes

59. Second Messengers
• Extracellular ligands can act by increasing concentrations
of second messengers
• e.g., cyclic adenosine-3’5’ -monophosphate (cAMP), calcium
ions, or phosphoinositides

60. Points to Consider
• Drug action occurs at the cellular level.
• Drug effects influence total body functioning.
• Receptors are specialized proteins, cell
membranes, or enzymes – The stronger the
affinity for a receptor, the longer the drug action.
• The intensity of response elicited by a drug is a
function of the dose administered.
• Dosage increases, most persons response to drug is
increased

61. Points to Consider
• Drugs are agonists when they interact with a
receptor to produce an effect of their own.
• Drugs are antagonists when they interact with a
receptor to produce no response of their own, but
impair the receptors ability to combine with
effector molecule.
• Irreversible antagonists remain tightly bound to
receptors. The binding cannot be overcome by
reducing dosage.