F. Pharmacology & ADME Flashcards
What are the molecular targets on cells which drugs usually interact with? and give examples
Proteins:
* Enzymes
* Transporters/pump proteins
* Ion Channels
* Receptors
What is a receptor?
Proteins which respond to a endogenous (native) messenger by initiating a a signal
What are the common characteristics of receptors?
- Selective binding site for native hormones/ transmitter
- Act as molecular switches-inactive and actives states
What is the ANS?
A component of the perhipheral nervous system that regulates unconcious physiological control of organ systems.
What are the divisions of the nervous system?
- CNS
- PNS
describe the features each divison of the nervous system
what connects the PNS to the CNS
CNS
- Brain + spinal cord
PNS
-sensory nerves (afferent fibres)
-motor nerves (somatic efferent fibres)
-autonomic nerves ( nerves involved in unconcious physiological control of organ systems)
What are the divisions of the ANS
- Sympathetic NS
(fight or flight) - Parasympathetic NS
(rest and digest) - Enteric NS
(GI tract)
what type of sympathetic receptors are found in the heart?
beta-1 AR
What type of sympathetic receptors are in the lungs and skeletal muscle?
beta-2 AR
What type of sympathetic receptors are in skin, GI tract and brain?
alpha-1 AR
What type of sympathetic NS receptors are in the skin for sweat gland secretion?
MR -Ach
Define an agonist
a drug or natural substance tht binds to and activates a receptor
define an antagonist
a drug or natural molecule that binds to a receptor but doen’t activate the receptor
agonist have both …. and …. for a receptor
affinity and efficacy for a receptor
antagonists have only …. and not … for a receptor
affinity but not efficacy
What is an on-site side effect?
a drug bind to the same type of receptor but at a different site
what is an off-site side effect?
- binds to a different type of receptor and somewhere else from the target
which type of g-protein are alpha-1 ARs coupled to
Gq
What type of G-protein are alpha-2 ARs coupled to
Gi
what type of of g-proteins are beta AR coupled to
Gs
what effects does each type of Gprotein cause?
Gs-increases cAMP and PKA, relaxation of smooth muscle
Gi-decreases cAMP, PKA- inhibition of sympathetic NS acts as a regulator
Gq- increases calcium levels, contration of smooth muscle
Describe the signal transduction pathway of Gs PCRs
NA binds, Gs binds to adenylyl cyclase, Atp to cAMP, inactive PKA to active PKA, target protein is phosphorylated
Describe signal transduction in Gq PCRs
NA binds, Gq moves to PL C, PIP2 binds to PL C, hydrolyses to products are IP3 and DAG , IP3 bind to receptor channels to open ca 2+ stores
DAG does it’s own stuff
What is affinity
The ability of a drug to bind to it’s receptor
What is efficacy?
The ability of a drug, once bound, to activate the receptor via onformational change
What is the law of mass action?
rates of binding/dissociation are proportional to concentration of drug and receptors
what is Kd + equation
equilibrium dissociation constant- the concentration where of frug needed to occupy 50% of receptor binding sites at euilibrium = conc. dxr/ conc dr
what is Rmax
Max effect of the drug determined by conc of drug
what is Ec50
- the conc that produces the half of max effect of the drug
what is a full agonist?
produces the same max effect, as good as counterpart’s response
what is a partial agonist
an agonist with lower efficacy-ability to activate
anatagonists can be …. and ….
competitive (receptor binding is competed by both agonist and antag.) and reversible (bonding non-covalently and dissocitation)
What is surmountable antagonism?
In the prescence of the antagonist the maximmal agonist response is the same Rmax doesn’t change
what is non-surmountable antagonism
in the prescence of an antagonist the maximal agonist response reduces, Rmax reduces
due to non-competitive/irreversible antagonists
what is an irreversible antagonist?
forms covalent bond and doesn’t dissociate, blocking the binding site for the agonist and reduces the Rmax
The Rmax depends on two things
- Affinity and efficacy of the drug
- properties of the response aka receptor reserve e.g. amplification even when not even 50% of receptors are occupied
What determines drug distribution?
- affinity to binding sites in plasma proteins
- structure of cppillary endothelium
- accumlating in cetain tissue (tissue depots)-which may be the target or not
what are the phases of metabolism?
- phase 1: redox reactions
- phase 2: conjugation
increased hydrophilicity, reactivity,size less likelyto bind selectively
easier to remove from body
Where does excretion mainly take place?
- Kidney
Stages of excretion in the kidney where do they occur
- Passive filtration-glomerelus
- Active secretion-proximal tubule
- Reabsorption-distal tubule
Parameters of ADME
- Absorption: Bioavailability (F), Cmax, Tmax
- Distribution: Volume distribution (Vd)
- Elimination: Half life( t1/2), clearance (CL)
Explain bioavailablility, Cmax and Tmax
- Bioavailability=the fraction of dose got into circulation
- Cmax=max conc in circulation, and time taken for drug to reach circulation
What is the therapeutic window?
the plasma concentration range, where there is a min. conc for therapeutic effct to occur and a max where beyound this concentration there’s an onset of side effects
What is first pass metabolism?
drug passes through the hepatic portal system before in enters sytemic circulation, some of it is metabolised here so drug conc decreases
3 different types of capillaries
- continuous-inetrcellular clefts
- fenestrated-fenetrations/pores, intercellular clefts
- dicontinuous- very large intercellular space, very leaky, basement membrane incomplete (liver and glomerulus)
Which enzymes are involved with metabolism in liver?
CYP450-redox
UGT-conjugation
Ciliary muscles and pupillary sphinter muscles are part of which branch of the ANS
Parasymp
Pupillary dilator muscles are part of which branch of ANS
Symp.
receptor super families
- GCPRs
- Nuclear receptors
- Ligand-gated ion channels
- Catalytic receptors
What two main ways drug is absorbed in gut/small intestine?
- passive diffusion
- Active transport
There are many different G-proteins. They are heterotrimetric which means what?
Composed of 3 subunits: alpha, beta and gamma
What is the alpha subunit of a g-protein bound to and how does this change when a signal binds to the GPCR ?
- A GDP molecule
- when the change happens GDP is swapped for GTP
- trimeric form breaks and alpha subunit of g protein seperates and moves towards the adenylyl cyclase.
Where is adrenaline produced?
Adrenal medulla gland which sits above the kidney
