PHARMACODYNAMICS

Pharmacology 1
Instructor: Paulleen Apostol, Rph.
Pharmacodynamics • addresses metal poisoning
• what the drug does to the body • ex: BAL (British anti-Lewisite), Dimercaprol, EDTA,
• study of the biochemical and physiologic effects of the drug Penicillamine
in the biological system and the mechanism by which these Iodism
effects are produced
• iodine toxicity
Receptor
• cellular macromolecules, or an assembly of • chelating agents bind to the excess iodine to be
macromolecules that is concerned directly and specifically excreted
in chemical signaling between and within cells • antidote: Deferoxamine or Desferoxamine
• aka biologic site of action, target site of action, target b) Colligative Properties
protein • properties of solutions dependent on number of
• where drug molecules and endogenous substances go or particles in solution
bind to 1. Boiling point 2. Vapor pressure
• examples of endogenous substances: hormones (glands), elevation lowering
neurotransmitters (neurons) 3. Freezing 4. Osmotic
Mechanisms of Drug Action point pressure
1. NON-RECEPTOR-MEDIATED depression
• no receptors involved  solute =  colligative properties
a) Direct Chemical Interaction Osmotic pressure
• directly affects (increases or inhibits) > Osmotic diuretics
• ex: Acid Neutralizers and Chelating Agents > ex: Mannitol
Acid Neutralizers o works on the water permeable regions of the renal
•  acidity tubules
• neutralizes the acid in the stomach o Nephron – basic unit of the kidneys; responsible for
• addresses HYPERACIDITY directly the filtering and reabsorption of ions from the blood
• Antacids o MOA: forms water permeable osmotic regions in the
• ex: Maalox® [Mg (OH)2 + Al (OH)3] proximal renal tubule to the ascending loop of Henle
synergistic

• magnesium hydroxide – causes diarrhea for the water reabsorption in the nephron to facilitate
• aluminum hydroxide – causes constipation urination
Chelating Agents c) Counterfeit Incorporation
• purine-pyrimidine analogues (Uracil)
• bind to heavy metals (in excess or foreign to the body)
 • Uracil – important in protein synthesis; undergoes o from electrical to chemical signal
the central dogma Examples of G-protein Coupled Receptors:
• ex: 5-fluorouracil α1 = Gq protein M1 = Gq protein
o inhibiting the protein synthesis α2 (presynaptic) = Gi protein M2 = Gi protein
2. RECEPTOR-MEDIATED α2 (postsynaptic) = Gq protein M3 = Gq protein
3 Major Receptor Locations: β = Gs protein
1. Cell Membrane Mnemonics: qiqs qiq
2. Nucleus intracellular Secondary messengers
3. Cytoplasm • cAMP (Cyclic Adenosine Monophosphate)
a) G-Protein Coupled Receptors • cGMP (Cyclic Guanosine Monophosphate)
• aka Metabotropic Receptors • IP3 (Inositol Triphosphate)
• most common receptor • DAG (Diacylglycerol)
• 7-transmembrane spanning receptor G-proteins
o the ligand passes through the receptor 7 times • location: cell membrane
• Metabotropic: effects due to its metabolites (or • onset: within seconds
secondary messengers) Gs – protein
• involved in signal transduction • Gs = stimulates
• stimulates (+) Adenyl cyclase (AC)
• receptors: β receptors
• blockers: β blockers
• stimulators: EPI, NE, Salbutamol
• as the ligand binds to the receptor, it will pass 7 times
• cAMP = inhibited by PDE3 (phosphodiesterase 3)
 there will be an increase in secondary messengers
 GDP will phosphorylate  GTP (effect of 2°
messengers)
• if the G-proteins are not activated, there will be a
decrease in secondary messengers and stays in the
cytoplasm for a period of time and will eventually be
metabolized and be depleted
Gi - protein
• Signal Transduction
• Gi = inhibits
o drug or ligand binds to the receptor and to G-
• inhibits (-) Adenylyl cyclase (AC)
protein of 2° messengers
 • inhibitory = ex. Presynaptic a2 receptors o Cations – positive (+)
o further release of neurotransmitters o Anions – negative (-)
• receptors: presynaptic a2 receptors and M2 receptors • the gate undergoes conformational changes
• receptors that are G-linked are also autoreceptors o Polarized (-) - if negative charge is greater
• role: regulation or autoregulation  cells are at REST
o Depolarized (+) – if positive charge is greater
 cells are at WORK
o Hyperpolarized ( ) – if negative charge is much
greater
Gq - protein I. Voltage-gated
• Gq = qontraction a) Voltage-gated Na+ channel
• (+) phospholipase (PLC)  causes contraction • blocked by Class I antiarrhythmics, local
• acts on Phosphatidylinositol-4,5-biphosphate (PIP2) anesthetics, tetrodoxin, and saxitoxin
• receptors: a1 receptors, M1 receptors, M3 receptors. and • the gate is regulated by a change in the potential of
postsynaptic a2 receptors the membrane
• Phospholipase – breaks down phospholipids • has 2 types of gates
(triglycerides) to remove 1-3 fatty acid derivatives o M gate – out gate
o Phospholipase C (PLC) – removes 1 fatty acid o H gate – in gate
derivative 3 Conformations
 removes Inositol Triphosphate (IP3) 1) Open Conformation – m gate and h
 removal of IP3 will become gate are BOTH open
Diacylglycerol (DAG) 2) Inactive Conformation – m gate is
• location: smooth muscles EITHER open or closed, and h gate is
•  IP3/DAG = smooth muscle contraction ALWAYS closed
• involved in the phosphorylation of MLCK (Myosin light- 3) Closed Conformation – m gate is
chain Kinase) closed, and h gate is opened
o MLCK – increases calcium inside the smooth
b) Voltage-gated K+ channel
muscles that causes the contraction
b) Ion Channels • blocked by Class III antiarrhythmics
c) Voltage-gated Ca2+ channel
• conduct charges in electrical signals
• blocked by Class III CCBs (Dihydropyridine, and
• Ions - charged particles
Non-dihydropyridine CCBs)
II. Ligand-gated o Autophosphorylation – the molecules will
• aka Ionotropic Receptor phosphorylate each other
• if the ligand binds to the ionotropic receptor, there will  Phosphorylation – addition of phosphate
be movement of ions and the channel will open group
• examples: Nicotinic Receptors and GABAA o Downstream signaling – produce its intended
Receptors EFFECT
Nicotinic Receptors  aka Signal Transduction
• associated with Na+ channels  involves the non-receptor kinases
• blocked by neuromuscular blockers  ex: Receptor Tyrosine Kinase (RTKs),
o Neuromuscular blockers – NMBs or Receptor Serine Threonine Kinase (RSTKs)
Curare derivatives o Drug targets
o Tubocurarine – used in arrowheads to o Bevacizumab – drug that acts on ligand (VEGF)
cause paralysis to targets o Cetuximab – drug that acts on the receptor
GABAA Receptors binding site (EGFR)
• associated with Cl- channel o Erlotinib – drug that acts on the kinase domain
• stimulated by benzodiazepines (BZDs) and (EGFR TK)
barbiturates (BRBs) o Dabrafenib – drug that acts on the downstream
III. Kinases and Catalytic Receptors molecules (BRAF)
IV. Enzymes
• they exist as isolated units (Monomers)
o Monomers react with other molecules to form a • examples: ACE, COX, MAO
very large molecule a) Angiotensin Converting Enzyme (ACE)
o Kinase – located within the integral parts of the • aka Kininase II
receptor • responsible for RAAS pathway for
• once the ligand binds to the receptor, there will be a hypertension
dimerization • blocker: ACEi (ACE inhibitors)
• Dimerization – receptors and kinase will stick b) Cyclooxygenase (COX)
together • blocker: NSAIDs
o after dimerization, there will be an activation of c) Monoamine Oxidase (MAO)
the kinase  AUTOPHOSPHORYLATION  • Non-specific: inhibits both MAOA and MAOB
downstream signaling o ex: Tranylcypromine, Isocarboxazid,
Phenelzine
 • MAOA
o used to treat depression (reversible
inhibitor of MAOA)
o ex: Moclobemide
• MAOB
o used to treat Parkinsonism
o ex: Selegiline, Rasagiline, Safinamide
V. Transporters
• aka carriers
• examples: Sodium-Potassium ATPase Pump,
Potassium-Hydrogen Pump
1. Sodium-Potassium ATPase Pump (Na+ - K+
ATPase Pump)
• responsible for Ca2+ extrusion
• ex: Digoxin – inotropic drug
o used for cardiovascular diseases
o inhibits the Na+ - K+ ATPase pump
o source: Digitalis purpurea or Digitalis
foxglove
2. Potassium-Hydrogen Pump (K+ + H+ Pump)
• present in parietal cells
• mediates the release of gastrin,
acetylcholine, and histamine
o responsible for the hydrochloric
release for the acidic environment of
the stomach
• ex: Proton Pump Inhibitors, H2 Receptor
Antagonists
o Proton Pump Inhibitors
 drugs that end in -azole
> except Aripiprazole
(antipsychotic)
 inhibits the K+ + H+ pump
 addresses hyperacidity
o H2 Receptors – inhibits histamine
VI. Structural Proteins and Other Molecules
• examples: Microtubules, Tubulins
Microtubules
• responsible for the cytoskeleton of the cells
• also responsible for the organelle
movement that forms the mitotic spindle
Tubulins
• chena chena chena
• drug examples: Vinca Alkaloids (Vincristine),
Taxols (Paclitaxel), Colchicine, Griseofulvin
Vincristine
• antineoplastic
• targets the mitotic phase of the cell cycle
Colchicine
• first-line agent for acute gout
• inhibits microtubule synthesis
o X microtubules = X organelle movement
= X neutrophil movement (inflammation
mediator) = no pain and inflammation
Griseofulvin
• antifungal
• inhibits fungal mitosis
VII. Nuclear Receptors
• aka Gene-Transcription Linked Receptor
• located intracellularly, specifically in the nucleus
• examples: Thyroid Hormones, Steroid Hormones
 Drug Receptor Interaction > primary binding site
1. Affinity > considered as the endogenous ligand binding
• ability of the ligand to bind to active site of receptor site
b) Allosteric Site
> binding site of other molecules
> can alter the binding of endogenous ligands to
the orthosteric site
> can enhance or inhibit the binding of
endogenous substances to the orthosteric site
> “secret passage” – Ma’am Kath hehez
4. Drug Receptor Conformation
Bile Acid Sequestering Agents • depends on whether to stabilize the active or the inactive
• addresses hyperlipidemia form
• lowers the bad cholesterol a) Inactive Receptor Form
• lowers the absorption of fat-soluble drugs > downstream signaling is attached to the receptor
• ex: Colesevelam, Colestipol b) Active Receptor Form
• Colesevelam – cannot lower the absorption of fat-soluble > downstream signaling is attached to the receptor
drugs because it has higher affinity to its receptor * both exists at equilibrium/ has the same concentration
Fat-soluble drugs c) Agonist
• Vit. A, D, E, K > stabilizes active receptor state
• Warfarin > AFFINITY + INTRINSIC ACTIVITY
> drug binding to the binding site
• Digoxin
d) Inverse Agonist
• Levothyroxine
> stabilizes inactive receptor
2. Intrinsic Activity
> focuses on binding of the drug to the inactive site
• ability to generate a series of biochemical events leading
> ex: Diphenhydramine
to an effect AFTER receptor-binding
e) Antagonist
• ability to stimulate active response
> maintains equilibrium between the inactive and
3. Constitutional/ Constitutive Activity active receptor state
• ability to generate a SERIES of biochemical response
even in the absence of a ligand Ri ⇄ Ra
Receptor Binding Sites:
a) Orthosteric Site
5. Allosteric Modulators
a) Allosteric Agonist
> improve/ enhance binding of endogenous ligand to
the orthosteric site
b) Allosteric Antagonist
> reduce/prevent binding of endogenous ligand to the
orthosteric site
6. Agonists
a) Full Agonists
> produce the maximal clinical effects expected with
receptor interaction
b) Partial Agonists
> produce less than the maximal clinical effects
expected with receptor interaction
c) Mixed Agonist – Antagonist Activity
> produce some of the anticipated effects attributed to
receptor interaction
> example: Tamoxifen – Estrogen Receptor Partial
Agonist Effect:
o both have agonist and antagonist effect
o used for breast cancer patients
o Agonist Effect: facilitates Ca2+ deposition and
overstimulation of Estrogen in the uterus
o long-term usage can cause uterine cancer
Antagonist Effect:
o antagonist effect in the breast tissues
o can block the estrogen receptor = no  of
cancer cells in the breast tissues
7. Antagonists
• other term: Inverse Agonist
Antagonists
• drugs that produce clinical effects that are opposite of
another drug or of the endogenous agonist
• ex: Beta blockers
o stimulator: EPI (produced by the neurons; important in
neuron signal transduction)
Classification of Antagonists:
a) based on mechanism of antagonist action
Pharmacologic
• aka Receptor Mechanism
o 2 ligands acting on the same receptor
• opposite effects are produced by binding to the same
receptor or receptor system
ex: Stress or Anxiety
• stress and anxiety are due to epinephrine (or
adrenaline)
• EPI – stimulate β1 receptor which causes increased
heart rate and to β2 receptor which causes tremors
ex: Stage Fright
• treatment: Propranolol – decreases heart rate by
binding to β1 receptor and decreases the tremors by
binding to β2 receptors
Physiologic
• aka Functional Mechanism of Antagonist Action
o 2 ligands acting on 2 different receptors
• produce opposite effects by binding to different
receptors
ex: Anaphylactic shock
• due to massive histamine release
 • causes vasodilation = hypotension
• bronchospasm – tightening of airways
o due to histamine binding to H1 receptors
o treatment: EPI
o EPI binding to α1 receptor = vasoconstriction
o EPI binding to β1 receptor = bronchodilation
b) based on ability to surmount antagonist/opposite effect
Competitive Antagonists
• the effect of the antagonist can completely
overcome the dose or the concentration of the
agonist
• quantity-based
• surmountable
Non-competitive Antagonists
• agonist cannot overcome the effect of the antagonist
c) based on the reversibility of drug-receptor interaction
Note: Reversibility is dependent on the type of bond/
interaction formed between the drug and the receptor
Reversible
• interaction that involves IMFAs
• the bond is temporary
• only lasts <24 hours
• Non-covalent bonding: weak bonding
• ex: Propranolol (reversible antagonist)
o can decrease heart rate in less than 8 hours
Irreversible
• interaction involves a permanent bond
• Covalent bond
• usually lasts days or weeks
• ex: Aspirin in 325 mg (antiplatelet)
o COX
Drug Receptor Theories
1. Clark Hypothesis
• the pharmacologic effect of the drug depends on the
percentage of the receptors occupied
• aka Clark Occupancy Theory
• “all receptors are occupied” – to reach the
pharmacologic effect
2. Hypothesis of Paton
• effectiveness of a drug does not depend on the actual
occupation of the receptor but by obtaining proper
stimulus
• depends on the Rate Theory
• effectiveness of the drug is dependent on the stimulus
3. Hypothesis of Ariens and Stephenson
• effectiveness of a drug lasts as long as the receptor is
occupied
• many substances possess different effect, some have
high affinity for the receptor, some have low affinity, and
some are not effective, and those ineffective substances
block or inhibit the receptor
• focuses on the “Occupancy Theory”
Dose-Response Relationship
• relationship between concentration/ dose and effect
• comparison of agonist and effect
• Hill Equation:
𝐸𝐸 [𝐴𝐴]𝑛𝑛𝑛𝑛
o = [𝐴𝐴]𝑛𝑛𝑛𝑛 +[𝐴𝐴]
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 50 𝑛𝑛ℎ
where:
E = Effect
Emax = Maximum Effect
[A] = Concentration of the Agonist
 [A]50 = Concentration of the Agonist producing half the •  agonist =  degree of binding
maximal effect • Hyperbolic
nH = Hill Coefficient A. Graded-Dose Response
**Plateau shape • Efficacy: maximum achievable response
• Ceiling dose: smallest dose that produces the maximum
response
• Potency: dose needed to achieve 50% of maximum response
• Mid-slope: degree of changes in response with a change in
dose

Steep slope
• Hill-Langmuir Equation:
[𝐴𝐴−𝑅𝑅] [𝐴𝐴] • a small increase in dose leads to a large change in
o 𝑝𝑝𝑝𝑝𝑝𝑝 = = [𝐴𝐴]+𝐾𝐾 response that may lead to serious toxicity
𝑅𝑅+[𝐴𝐴−𝑅𝑅]
where: • “Start low, go slow”
A = Agonist • example: SBP = 200 mmHg
R = Receptor Drug A Drug B
[A - R] = Agonist – Receptor Complex
K = Equilibrium Dissociation Constant 10 mg 180 mmHg 180 mmHg
pAR = proportion of binding sites occupied by ligand at
equilibrium 20 mg 60 mmHg 120 mmHg
 3. Differentiates competitive from non-competitive
antagonism

Applications:
1. Differentiates potency and efficacy

B. Quantal Dose-Response Relationship/ Graph

Quantal – “all or none” response
Parameters:
Effective Dose 50% Population (ED50)
• median effective dose
Toxic Dose 50% Population (TD50)
• median toxic dose
Therapeutic Index (TI/I)
• measure of the relative safety of drug
2. Differentiates partial agonist from full agonists • ratio of ED50 and TD50
• X clinical margin of safety
TD50
• TI=
ED50
•  TI = safer
Margin Of Safety
• allowable range