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Fundametals of pharmacology (Pharmacodynamics (Affinity (Measure of how…
Fundametals of
pharmacology
Pharmacodynamics
Agonist
Chemical that binds to target to increase its activity
Endogenous agonists present in the body
e.g. hormones
Partial agonist has a lower max response
compared with a full agonist; can compete
with full agonists to dampen a response
Affinity
Measure of how well a drug binds to its receptor
Drug binding is related to the drug concentration
Drug unbinding is related to chemical properties
of the drug-receptor complex
Binding of drug to receptors occurs in a exponential fashion
as the drug concentration increases
Antagonist
Chemical that binds to target to oppose its activity
Only exert noticeable effects in the presence of an agonist
e.g. propranolol opposes B-receptor activation to cause activity
e.g. naloxone little activity as mu activation usually v low
Competitive and non-competitive types; most
are competitive (compete with agonist to bind target)
Small molecules and
action sites
Most drugs are small molecules,
allowing them to easily enter tissues and cells
Antibodies and gene therapies are larger,
so harder to get to target before being metabolised
Chemically sensitive sites are the areas of the body
(usually proteins) that are sensitive to the drug
Efficacy
How well an agonist achieves a response at the target
Different drugs with same MOA need different doses
to achieve the effect
Potency
Concentration needed for an effective response
i.e. the ED50 (conc needed to get 50% max response)
Higher potency will have lower ED50
Dose-response
relationships
Allosteric modulators
Alter affinity of binding site for agonist, or change
efficacy of the response when the agonist binds
Can be positive or negative
Bind to a site away from the target site for the agonist
Effectively change the set point for normal activity
Confounding
factors
Tolerance
Alterations over time result in
increased requirement to achieve same effect
E.g. long-term opiate analgesia needs increasing
after time to have same effect
Tachyphylaxis means decline in response to
repeated doses of an agonist
Chemical structure
Lipophilic versus hydrophilic has
large impact on body distribution
Method of metabolism and excretion
Desensitisation
Use of drug can lead to reduced response
of the target to the drug or downregulation of the target
E.g. in smoking, nicotine acts at nACh;
over time same dose has less effect
Action on
ion channels
Voltage-dependent Ca
channels and cardio
Part of neuro system to release
neurotransmitter at synapse
Involved in muscle contraction
in smooth and cardiac muscle
Different types of Ca channel made up from
different subunits, which can be specifically targetted
CCBs
Act as vasodilators for treatment of HTN
and angina prophylaxis
Different CCBs have differential action on cardiac contractility, vasodilatation, SAN/AVN depression by targeting different variants of the voltage-dependent Ca channels
Dihydropyridines e.g. amlodipine, nifedipine
more selective for vascular smooth muscle
Non-dihydropyridines e.g. diltiazem, verapamil
have more pronounced inotropic effect on heart
Voltage-dependent
ion channels
Ion channels conduct passage of ions
across a membrane in presence of
electrochemical gradient
Voltage gated ion channels
are opened by voltage change
Ligand gated channels are
opened by a ligand binding
Action on carrier
transport molecules
Monoamine
transporters
NA, 5HT, DA important
neurotransmitters in CNS
Drugs can target the neurtransmiters
to affect amount of transmitter
Some drugs are selective for one type of transporter,
while others target all three e.g. amphetamines
Each has their own transporter responsible
for reuptake into presynaptic membrane
Increased DA from drugs of abuse causes euphoria
Antidepressants generally select for
5HT transporter, so no euphoria
Antidepressants
SNRIs e.g. venlafaxine affect DA and 5HT,
but no ACh SEs
SSRis are fairly selective for 5HT
TCAs agonise 5HT, DA and NA,
also ACh antaonism (antimuscarinic SEs)
Increase 5HT elevates mood
Action of drugs
on enzymes
Enzyme inhibition
Competitive (drug binds to
active site, blocks substrate)
Non-competitive (drug binds
elsewhere, substrate can still bind)
Reversible (enzyme goes back
to normal function after)
Irreversible (permenant loss of function)
E.g. aspririn to COX1 (non-competitive, irreversible)
E.g. ramipril to ACE (competitive, reversible)
E.g. statins on HMG Co-A reductase
May need to be intracellular or extracellular,
may need enzyme activity to exert effects
Nuclear receptors
Adrenal cortical hormones act
on steroid receptors
Nuclear receptors affect
transcription and translation
Steroid hormones are lipophilic,
so enter cells to access nuclear receptors
Biologicals
Recombinant proteins
Cells used to synthesise MAbs
E.g. TNF-a for RA
Can also replace faulty proteins with synthesised
version e.g. imiglucerase in Gaucher's disease
Gene therapy
Aim is to replace a defective
gene with a functioning one
E.g. glybera for lipoprotein lipase deficiency
(adeno-associated virus)
Difficulty is finding an appropriate vector
Concerns - immune response to virus,
cancer from random gene insertion
