pharmacology Flashcards
types of drugs and their targets.?
Types of drugs
§ Small molecules
§ Peptides
§ Antibodies
§ Antisense oligonucleotides
§ Small interfering RNA
Common drug targets
receptors ( nuclear receptors, Ligand gated ion channels, G- protein coupled receptors, Kinase-linked receptors)
ion channels
enzymes
transporters
types of drugs that bind G coupled receptors.
antagonist, agonist, partial agonist , inverse agonist
Describe drug absorption.
§ Diffusion, passive transport
§ Diffusion via pores, ‘aquaporins’
§ Carrier protein (saturation kinetics)
- facilitated transport
- active transport (can get saturated)
§ Endocytosis
depending on the type of administration
-from there we have absorbtion -for example oral - absorbion from the gut-Hepatic portal vein- liver - free drug
intramascular- tissue reservoirs- free drug
Describe drug distribution.
Drug distribution is a critical pharmacokinetic process that occurs after a drug enters the bloodstream through absorption, whether via oral administration, injection, or other routes. This process involves the movement of a drug throughout the body, from the bloodstream to various tissues and organs, where it can exert its therapeutic effects or be metabolized and eliminated
some organs get more drug , it can also be stored , there are also barriers some drugs cannot cross
Describe drug metabolism
Metabolism – Biotransformation
CYP=very common
Catalyze Phase 1 metabolism: like ionization ( adding or subtracting small groups,oxidations, reductions and
hydrolysis reactions, to make molecules hydrophylic )
Liver and intestine
First pass metabolism
Higher dosage needed after
oral administration cf. other
routes of admin.
depends on the patient
And phase 2 Is conjugation
Describe drug excretion/elimination.
Renal excretion of drugs and drug metabolites
§ Glomerulus filtration
§ Active tubular secretion
§ Tubular reabsorption
Clearance is better in urine with the opposite PH
lipophilic drugs get reabsorbed
Clearance is a pharmacokinetic parameter describing drug
elimination
The volume of plasma that is cleared from a drug per unit time
Clearance is defined as the rate of elimination of a drug in
relation to the plasma concentration.
Clearance = Rate of drug elimination/
[Drug]plasma
Explain bioavailability.
Bioavailability
The fraction of an orally administered dose that
reaches systemic circulation as intact drug
§ Absorption
§ Efflux pumps (transporters)
§ First pass metabolism
LIVER:
Metabolism
(several enzymes
SMALL INTESTINE:
Absorption
Efflux pumps (P-gp)
Metabolism (CYP3A4)
Explain the general mechanisms of action of drugs.
Zero-order kinetics
Substrate saturation
Certain amount of drug is eliminated with time
No constant t1/2
Initial rate
Certain fraction of the drug is eliminated with time
Constant t1/2 F = bioavailability
D = dose (Q in Rang & Dale’s)
Vd = volume of distribution
ke = elimination constant
DT = dosing interval
Steady-state concentration
Csteady-state = Bioavailability x Dose/
Clearance x Dosing interval
Define drug affinity.
Affinity
How well does the key fit the lock? Some keys
do not fit, some keys can fit in the lock, but do
not open the door and other keys fit and open
the door.
This is defined by chemical interactions, size,
conformation
Affinity is the measured by the concentration of
drug required to occupy 50% of the drug target
at equilibrium (KD, equilibrium dissociation
constant)
Explain drug efficacy.
Efficacy
Full agonist – 100% efficacy
Partial agonist – less than 100% efficacy
Antagonist – zero efficacy
Inverse agonist – negative efficacy; reduce constitutive receptor
activity
Explain drug selectivity.
Define concentration-response relationship.
Potency
Amount of drug, expressed as the concentration or dose, required for
a given level of effect.
Potency depends on both target (affinity and efficacy) and tissue
(receptor number and drug availability) parameters.
The higher the potency, the lower the dose required for a given level
of effect.
Agonist potency is measured as the effective concentration required
to produce 50% of the maximal response (EC50).
SO THE concentration-response relationship. depends on potency but also Efficasy
Explain drug safety.
Selectivity and safety
All drugs can be dangerous; the dose is important
Highly potent drugs are often considered desirable because lower
doses can be used and therefore, less drug is available to cause offtarget
adverse effects.
Higher the drug dose àdecreased selectivity
Adverse drug reactions are unwanted effects at therapeutic doses
Describe drug tolerance.
Tolerance
Drug dose must be increased to maintain
clinical efficacy when tolerance develops.
Drug tolerance involves multiple
mechanisms including:
1. Upregulation of drug metabolism
(metabolic tolerance),
2. Desensitization of receptor signaling
and/or downregulation of receptors
3. Initiation of compensatory/opponent
processes
what is the therapeutic window?
Therapeutic window
Therapeutic index= ED50/TD50
Describe pharmacological homeostasis.
With these definitions in mind, “pharmacological homeostasis” could potentially refer to the use of pharmacological agents (drugs) to help the body maintain or restore homeostasis by influencing specific physiological processes. In other words, it could be the concept of using drugs to correct imbalances or dysregulations in the body’s internal environment.
Explain individual variation.
Interindividual differences in drug metabolism
§ genetic factors
§ drug-drug interactions
§ enzyme induction
§ dietary factors/inhibition
§ disease/inflammation
§ age
Induction
Induction of drug metabolizing enzyme:
§ decreased bioavailability
§ increased rate of elimination
§ can result in decreased plasma concentration
and therapeutic failure (cf. St John’s wort and
oral contraceptives)
opposite
Substances in grapefruit can bind to CYP3A4,
which might result in reduced metabolism
and too high plasma concentration
what is the interplay between drugs and complex systems?
System integration/modification of drug response
§ Individual variation
§ Pharmacological homeostasis
§ Complex systems
§ Therapeutic window
example
Complexity of GPCR signaling
§ Receptor intrinsic bias –
preference of receptor to
bind specific transducers
over others
§ Biased agonism – ligands
binding same receptor
differentially alter
downstream response
what is Volume of distribution?
The theoretical volume that a drug
would have to occupy (if it were
uniformly distributed), to provide
the same concentration as it
currently is in blood plasma.
Vd =F x D/C0
F = bioavailability
D = dose (Q in Rang & Dale)
Vd = volume of distribution
Co= initial concentration
Tc = target concentration
these two are interchagable
Low value – plasma volume
High value – very lipophilic
Not intact Blood brain barrier duo to inflammation influences bioavailability
P-gp does not allow to absorb through capillaries ( it throws it out )
pharmacodynamics
What the drug does to the body –
pharmacodynamics
§ Drug target
§ Mechanism of action
§ Affinity
§ Efficacy
§ Selectivity
§ Potency
§ Concentration-response
relationship
§ Safety
§ Tolerance
Allosteric modulators
Positive allosteric modulators
§ Binds to another site separate
from the orthosteric site
§ Increases potency and/or efficacy
Negative allosteric modulators
§ Binds to another site separate
from the orthosteric site
§ Decreases potency and/or efficacy
Biased agonism
Receptors can be coupled to two (or
more) intracellular responses
Different agonists can elicit similar
responses in both pathways (unbiased)
OR
A given drug can evoke a better
response in one pathway relative to
another compared to reference drug
