Pharmacology
Pharmacokinetics
Pharmacodynamics
Pharmacodynamics
• The biochemical and physiologic
mechanisms of drug action
What the drug
does when it gets there.
Drug Mechanisms
• Receptor interactions
• Non-receptor mechanisms
HOW DRUGS ACT :
MOLECULAR ASPECTS
• TARGETS FOR DRUG ACTION
* receptors
* ion channels
* enzymes
* carrier molecules
• PHYSICO-CHEMICAL INTERACTIONS
Targets for drug action
A drug = a chemical that affects physiological function in
a specific way.
With few exceptions, drugs act on target proteins namely:
–
–
–
–
enzymes
carriers
ion channels
receptors
Specificity is reciprocal:
individual classes of drug bind only to certain targets,
and individual targets recognize only certain classes of
drug.
No drugs are completely specific in their actions
SPECIFICITY
• NONspecific drug action - Not all drugs act via
receptors:
– e.g., antacids neutralize excess gastric acid. general
anaesthetics, osmotic act by virtue of their physico-chemical
properties
– Interaction with various macromolecules (Na-K-ATPase,
inhibition acetylcholinesterase, as false substrates or inhibitors
for certain enzymes).
• Specific drug action - most drugs produce effects by
acting on specific protein molecules called
RECEPTORS
• according to interactions with targets, effects of drugs
are:
– nonspecific
– specific
RECEPTORS
• Protein molecules, normally activated by
transmitters or hormones.
• Many receptors have been cloned.
• Drug receptor = specialized macromolecule
that binds a drug and mediates its
pharmacological action.
• Many synthetic drugs that act either as agonists
or antagonists on receptors for endogenous
mediators.
Receptor Interactions
Drugs that activate receptors and produce a response are
called AGONISTS.
Lock and key mechanism
Agonist
Receptor
Agonist-Receptor
Interaction
Receptor Interactions
Induced Fit
Receptor
Perfect Fit!
Interaction of receptors with
ligands
• Formation of chemical bonds
– mostly electrostatic and hydrogen bonds and van
der Waals forces
– i.e., mostly noncovalent bonds (covalent are
important in toxicology mostly)
– The bonds are usually reversible.
• The closer the fit and the greater the number of
bonds - the stronger are attractive forces
between them - the higher the affinity of the
drug for the receptor.
Basic principles
• The first step of drug action on specific receptors is the
formation of a reversible drug-receptor complex, the
reactions being governed by the Law of Mass Action –
rate of chemical reaction is proportional to the
concentrations of reactants:
k+1
[R] + [A]  [RA]
stimulus

EFFECT
k-1
•
•
•
•
•
R = receptor
A = drug
RA = drug-receptor complex
k+1 = constant of association
k-1 = constant of dissociation
Modify factors
Receptor Interactions
Drugs called ANTAGONISTS - combine with receptors, but do
not activate them.
Competitive
Inhibition
Antagonist
Receptor
DENIED!
Antagonist-Receptor
Complex
Receptor Interactions
Non-competitive
Inhibition
Agonist
Antagonist
Receptor
DENIED!
‘Inhibited’-Receptor
MAJOR RECEPTOR FAMILIES
•
Mostly proteins that are responsible for transducing
extracellular signals into intracellular responses.
1)
2)
3)
4)
ligand-gated ion channels
G protein-coupled receptors
enzyme-Iinked receptors
intracellular receptors.
•
(Note: Pharmacology defines a receptor as any biologic
molecule to which a drug binds and produces a
measurable response. I.e., enzymes and structural
proteins can be considered to be „pharmacologic
receptors“) .
Time scale: ms
Examples:
Nicotinic
GABA receptor
s
Muscarinic
Ach receptor
hours
Cytokine R
hours
Oestrogen R
Video
• http://pharmamotion.com.ar/pharmacolog
y-animations/
• http://pharmamotion.com.ar/videoanimation-mechanism-of-ionotropicreceptors-or-ligand-gated-ion-channelslgics/
Non-receptor Mechanisms
• Actions on Enzymes
– Enzymes = Biological catalysts
• Speed chemical reactions
• Are not changed themselves
– Drugs altering enzyme activity alter processes
catalyzed by the enzymes
– Examples
• Cholinesterase inhibitors
• Monoamine oxidase inhibitors
• COX
Non-receptor Mechanisms
• Changing Physical Properties
– Mannitol
– Changes osmotic balance across membranes
– Causes urine production (osmotic diuresis)
Non-receptor Mechanisms
• Changing Cell Membrane Permeability
– Lidocaine
• Blocks sodium channels
– Verapamil, nefedipine
• Block calcium channels
– Bretylium
• Blocks potassium channels
– Adenosine
• Opens potassium channels
Non-receptor Mechanisms
• Combining With Other Chemicals
– Antacids
– Antiseptic effects of alcohol, phenol
– Chelation of heavy metals
Non-receptor Mechanisms
• Anti-metabolites
– Enter biochemical reactions in place of normal
substrate “competitors”
– Result in biologically inactive product
– Examples
• Some anti-neoplastics
• Some anti-infectives
Drug Response Relationships
• Time Response
• Dose Response
Time Response Relationships
Maximal (Peak) Effect
Effect/
Response
Latency
Duration of Response
Time
Time Response Relationships
IV
IM
SC
Effect/
Response
Time
Dose Response Relationships
• Potency
– Absolute amount of drug required to produce
an effect
– More potent drug is the one that requires lower
dose to cause same effect
Potency
A
B
Therapeutic
Effect
Effect
A!
Why?
Dose
Which drug is more potent?
Dose Response Relationships
• Threshold (minimal) dose
– Least amount needed to produce desired effects
• Maximum effect
– Greatest response produced regardless of dose
used
Dose Response Relationships
B
A
Therapeutic
Effect
Effect
Dose
Which drug has the lower threshold dose?
A
Which has the greater maximum effect?
B
Dose Response Relationships
• Loading dose
– Bolus of drug given initially to rapidly reach
therapeutic levels
• Maintenance dose
– Lower dose of drug given continuously or at
regular intervals to maintain therapeutic levels
Therapeutic Index
•
•
•
•
Drug’s safety margin
Must be >1 for drug to be usable
Digitalis has a TI of 2
Penicillin has TI of >100
LD50
TI 
ED50
Therapeutic Index
Why don’t we use a
drug with a TI <1?
ED50 < LD50 = Very Bad!
Factors Altering Drug
Responses
• Age
– Pediatric or geriatric
– Immature or decreased hepatic, renal function
• Weight
– Big patients “spread” drug over larger volume
• Gender
– Difference in sizes
– Difference in fat/water distribution
Factors Altering Drug
Responses
• Environment
– Heat or cold
– Presence or real or perceived threats
• Fever
• Shock
Factors Altering Drug
Responses
• Pathology
–
–
–
–
Drug may aggravate underlying pathology
Hepatic disease may slow drug metabolism
Renal disease may slow drug elimination
Acid/base abnormalities may change drug
absorption or elimination
Influencing factors
• Genetic effects
– Lack of specific enzymes
– Lower metabolic rate
• Psychological factors
– Placebo effect
Pediatric Patients
• Higher proportion of water
• Lower plasma protein levels
– More available drug
• Immature liver/kidneys
– Liver often metabolizes more slowly
– Kidneys may excrete more slowly
Geriatric Patients
• Chronic disease states
• Decreased plasma
protein binding
• Slower metabolism
• Slower excretion
• Dietary deficiencies
• Use of multiple
medications
• Lack of compliance
Web Resources
• Basic Pharmacokinetics on the Web
– http://pharmacy.creighton.edu/pha443/pdf/Defa
ult.asp
• Merk Manual: Overview of Drugs
– http://www.merck.com/pubs/mmanual_home/se
c2/5.htm
Web Resources
• Merk Manual: Factors Affecting Drug
Response
– http://www.merck.com/pubs/mmanual_home/se
c2/8.htm
• Merk Manual: Pharmacodynamics
– http://www.merck.com/pubs/mmanual_home/se
c2/7.htm