F. Pharmacology & ADME Flashcards by Liz Boateng

What are the molecular targets on cells which drugs usually interact with? and give examples

Proteins:
* Enzymes
* Transporters/pump proteins
* Ion Channels
* Receptors

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What is a receptor?

Proteins which respond to a endogenous (native) messenger by initiating a a signal

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What are the common characteristics of receptors?

Selective binding site for native hormones/ transmitter
Act as molecular switches-inactive and actives states

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What is the ANS?

A component of the perhipheral nervous system that regulates unconcious physiological control of organ systems.

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What are the divisions of the nervous system?

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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)

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What are the divisions of the ANS

Sympathetic NS
(fight or flight)
Parasympathetic NS
(rest and digest)
Enteric NS
(GI tract)

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what type of sympathetic receptors are found in the heart?

beta-1 AR

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What type of sympathetic receptors are in the lungs and skeletal muscle?

beta-2 AR

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What type of sympathetic receptors are in skin, GI tract and brain?

alpha-1 AR

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What type of sympathetic NS receptors are in the skin for sweat gland secretion?

MR -Ach

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Define an agonist

a drug or natural substance tht binds to and activates a receptor

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define an antagonist

a drug or natural molecule that binds to a receptor but doen’t activate the receptor

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agonist have both …. and …. for a receptor

affinity and efficacy for a receptor

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antagonists have only …. and not … for a receptor

affinity but not efficacy

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What is an on-site side effect?

a drug bind to the same type of receptor but at a different site

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what is an off-site side effect?

binds to a different type of receptor and somewhere else from the target

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which type of g-protein are alpha-1 ARs coupled to

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What type of G-protein are alpha-2 ARs coupled to

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what type of of g-proteins are beta AR coupled to

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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

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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 ## Footnote easier to remove from body

Where does excretion mainly take place?

* Kidney

Stages of excretion in the kidney where do they occur

1. Passive filtration-glomerelus 2. Active secretion-proximal tubule 3. 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