General principles of pharmacology (L1&2) Flashcards
what is pharmacodynamics?
the effects of a drug on the body
what is pharmacokinetics?
what the body does to the drug
what are the principles of pharmacodynamics?
molecular interactions by which drugs exert their effects
influence of drug concentration on the magnitude of response
what does the study of pharmacodynamics allow us to do?
determine the appropriate dose range for patients
compare the effectiveness and safety of one drug to another
what is the journey of the drug? (pharmacokinetics)
absorption
distribution
metabolism
excretion
what does the study of pharmacokinetics allow us to do?
design and optimise treatment regimes for individuals
what are the sources of drugs?
naturally occurring
synthetic
what is biologics?
new source of drug development - allows us to manufacture naturally derived products
can genetically modify them
how does a drug interact with its target?
a drug will not work unless its bound
due to:
1) shape
2) charge distribution
what does the shape of a drug determine?
the ability of the drug to bind
lock and key mechanism
what does the charge distribution of the drug determine?
the type of bonds that hold the drug to the target
what are the type of bonds from weakest to strongest?
van der waals
hydrogen
ionic
covalent
what are van der waals forces?
shifting of electron density in a molecule results in the generation of transient positive and negative charges.
these react with transient areas of opposite charges on other molecules
bond strength = +
what are hydrogen bonds?
H atoms bound to O or N become more positively polarised
these bond with more negatively polarised atoms
bond strength = ++
what are ionic bonds?
atoms with an excess of electrons (negatively charged) are attracted to atoms with a deficiency of electrons (positively charged)
bond strength = +++
what are covalent bonds?
2 bonding atoms share electrons
bond strength = ++++
what are the further considerations to drug binding?
hydrophobicity
ionisation of drug (pKa)
conformation of target
stereochemistry of drug molecule
what are the targets for drug action?
receptors
enzymes
ion channels
carrier molecules
what are receptors?
targets for endogenous transmitters
eg. hormones and neurotransmitters
what are enzymes?
biological catalysts which facilitate biochemical reactions
what are ion channels?
pores which span the membranes to allow the selective passage of ions
what are carrier molecules?
transport ions and small organic molecules across cell membranes
what drugs act by virtue of their physiology-chemical properties?
antidotes
antiacids
laxatives
what do drugs do to receptors?
agonists activate the receptor
antagonists block the action of agonists
what do drugs do to ion channels?
either block or modulate the opening and closing
what do drugs do to enzymes?
either inhibit them or act as a false substrate
what do drugs do to carrier molecules?
either transported in the place of endogenous substrate or inhibit transport
how does the allosteric action of benzodiazepines (BZ) have on the GABAa receptor?
decrease excitability of the channel by stopping Cl- moving through
BZ binds allosterically to the GABA binding site (orthosteric)
doesn’t change Cl- activity without the GABA
enhances the effect of GABA
what are NSAIDs?
non steroidal inflammatory drugs
e.g. ibuprofen and aspirin
inhibit cyclooxygenase preventing prostaglandins being released
what are prostaglandins?
inflammatory mediators
lead to inflammation, pain and fever
what are agonists?
a ligand that combines with receptors to elicit a cellular response
what is an antagonist?
a drug which blocks the response of the agonist
what are receptor subtypes?
receptors within a given family generally occur in several molecular varieties
often have similar structures but significant differences in their pharmacological responses
how are receptor subtypes identified?
on the basis of selectivity of agonists and/or antagonists
or
by cloning techniques
what are the types of receptor signal transduction?
ligand gated ion channels
GPCR
enzyme (kinase) linked receptors
intracellular receptors
what is the fastest signal transduction?
ligand gated ion channels
what are the 2 types of channel linked (inotropic) receptors?
ligand gated
voltage gated
how do ligand gated ion channels work?
they require an agonist to open the channel
eg. nicotinic acetylcholine receptor
acetylcholine causes skeletal muscle to contract by opening ligand-gated ion channels
how do voltage gated ion channels work?
are not linked to receptors
they require a change in electrical charge across a membrane to open/close
e.g. Na+ channels in nerve cell membranes
local anaesthetics work by blocking VG Na+ channels
how do nicotinic acetylcholine receptors work?
pentameric structure
inward kink - allows ion channels to stay shut: stops ions flowing through ion channel in resting state
on extracellular binding we get a twist to open so the inward kink falls out - allows passage of cations
inside of channel is negatively charged so only cations can flow through
what are used as muscle relaxants?
nicotinic ACh receptor antagonists
what are GPCR?
largest family of receptors 7 transmembrane helices consists of 3 subunits: • alpha • beta • gamma
examples of drugs that GPCRs?
endogenous agonists
α/β adrenoceptors – epinephrine (natural)
β2 adrenoceptors – salbutamol (drug based)
how is specificity achieved in GPCRs?
molecular variation in alpha subunits
different subunits have different signalling systems
what are the different subunits in GPCRs?
Gs, Gi, Gq, G0
whats the action of Gs?
stimulatory
activates adenylyl cyclase
activates Ca++ channels
whats the action of Gi?
inhibitory
inhibits adenylyl cyclase
activates K+ channels
whats the action of Gq?
activates phospholipase C
whats the action of Go?
doesn’t work on the alpha subunit
uses beta and gamma subunits to bring about transduction
how does Gs protein signalling transduction work?
1) unoccupied receptor does not interact with the Gs protein
2) hormone/neurotransmitter binds to the receptor
3) occupied receptor changes shape and interacts with the Gs protein
4) Gs protein releases GDP and binds GTP
5) adenylyl cyclase catalyses formation of cAMP
6) when hormone or drug is no longer present, the receptor reverts to its resting state. GTP I hydrolysis and adenylyl cyclase is deactivated
what does atenolol do to GPCR?
it is a B1 receptor antagonist
what does salbutamol do to GPCR?
it is a B2 receptor agonist
what are enzyme liked receptors?
large extracellular ligand-binding domain connected to intracellular domain by single membrane-spanning helix
ligand binding –> dimerisation –> autophosphorylation
examples of drugs that target enzyme linked receptors?
endogenous agonists
insulin receptor – insulin
tyrosine kinase – imatinib
how do insulin receptors work?
1) insulin binding activates receptor tyrosine kinase activity in the intracellular domain of the beta subunit of the insulin receptor
2) tyrosine residues of the beta subunit are auto-phosphorylated
3) receptor tyrosine kinase phosphorylates other proteins, eg. insulin receptor substrates (IRS)
4) phosphorylates IRSs promote activation of other protein kinases & phosphatases, leading to biologic actions of insulin – lowered blood glucose levels
5) can take hours – longer timeframe
how do intracellular receptors work?
no extracellular binding site
drug has to get into the nucleus
family of 48 soluble receptors
important for expression of cholesterol and hormones
examples of drugs that target intracellular receptors
Estrogen receptors – estradiol & tamoxifen
what are the 2 major classes of intracellular receptors?
class 1 - located in the cytoplasm, form homodimers, ligands are endocrine - class 1 binds to class 1 only
class 2 - present in nucleus, form heterodimers, ligands are lipids (fatty acids)
how does class 1 nuclear receptor signal transduction work?
1) unoccupied receptor does not provide intracellular signal
2) lipid-soluble drug diffuses across the cell membrane
3) drug binds to receptor – occupied receptor changes shape & is activated
4) activated receptor moves to nucleus
5) the drug-receptor complex binds to chromatin, activating the transcription of specific genes
6) mRNA is translated into specific proteins that result in a specific biological response
how many binding sites do drugs have?
most have multiple
binding at 1 site will alter the binding at another site - positively or negatively
what binds at allosteric sites?
allosteric antagonists - positive or negative
what binds at orthosteric sites?
full and partial agonists
inverse agonists
reversible competitive antagonists
irreversible competitive antagonists
what binds at effector region?
non competitive antagonists
channel activators
