pharmacodynamics Flashcards
define pharmacodynamics
- drugs acting on body
- interaction with receptor
- to reduce symptoms and disease
example of drugs non-receptor mechanism
- metal chelators = reduce metal ions overload
- antacids = neutralize gastric acid
- osmotic diuretics eg: mannitol
- bile acid binding resins eg: colestipol
- general anaesthetics
characteristics of drugs
- size range 100-1000
- shape and charge that complement binding site of receptor
- many are weak acids/weak bases
- unionized form that being absorb
types of receptors
- proteins
- nucleic acids (DNA/ RNA)
drug-receptor interaction
- lock and key fit 3D structure
- non-covalent chemical interactions
- usually reversible
what is Ka?
- equilibrium dissociation constant
- drugs that binds 50% of available receptors at equilibrium
name of drugs for using in industries
code name eg: D365
name of drugs for using in worlwide
generic (non-proprietary) name eg: verapamil
what happen when 2 ligands bind at the same receptor?
cause competition thus reduce the time spent receptor-bound for each ligand
what is side effects?
- unwanted reactions eg: nausea
- when drugs act on non-target receptors
- increase when doses increase
4 types of receptor proteins
- ion channels
- G protein-coupled receptors
- kinase-linked receptors
- intracellular receptors
what is ion channels?
- 4-5 subunits
- ligand-gated
- conduct Na, K, Cl, Ca
- fast communication
examples of ion channels
- nAChR
- GABA(a) receptor
- Glycine receptor
- Glutamate receptor
- Purine receptor
what is G protein-coupled receptors?
- receptors that linked to effectors via G protein
- single polypeptide chain
- spanning membrane 7 times
- third intra loop couples to G protein
- small ligands bind to helix cluster
- larger ligands bind to extracellular surface
- process seconds to minutes
examples of GPCR
- mAChR
- adrenoceptors
- Serotonin receptor
- GABA(b) receptor
- dopamine receptor
- histamine receptor
- opiod receptor
- eicosanoid receptor
function of 2nd messengers
activate protein kinases that phosphorylate target proteins
types of 2nd messengers
- cAMP
- cGMP
- Diacylgylcerol (DAG)
- IP3
- Ca2+
cAMP?
- formed from ATP by adenylate cyclase
- activates PKA
- hydrolysis by phosphodiesterase
cGMP?
- formed from GTP by guanylate cyclase
- activates PKG
- hydrolysis by phosphodiesterase
DAG and IP3?
- formed from phosphoinositides by phospholipase C
- IP3 triggers Ca release from ER
- DAG co-activates PKC
Ca2+ activates?
- PKC
what is kinase-linked receptors?
- intracellular part of receptor has catalytic activity
- especially for hormones
types of kinase-linked receptor
- tyrosine kinase receptor
- serine/threonine kinase receptor
- guanylate cyclase
tyrosine kinase receptor
- regulate growth, differentiation, development
- receptors for insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) etc
serine/threonine kinase receptor
eg: tumour growth factor (TGF) Beta receptor
what is intracellular receptors?
- in cytosol/nucleus
- activated receptor bind to DNA and alter genes transcription
- process minutes to hours
- for therapeutic consequences
intracellular receptors response to
- steroids and vitamin D
- thyroid hormone
- inducers of drug metabolism eg: barbiturates
functions of peroxisome proliferator-activated receptor
regulate genes for lipid, carbohydrate metabolism and transport
define desensitization
decrease in response to drug with repeated doses
examples of desensitization
- accelerated drug clearance
- reduced receptor response due to modification
- reduced no. of receptors due to lower expression
- depletion of mediators eg: NA
- physiological adaptation
- drug resistance
characteristic of linear plot graph drug-receptor
- hyperbolic curve
- potency
characteristic of semi-log graph drug-receptor
- sigmoidal curve
- efficacy
define full agonist
- drug that restore maximal response
- shifting resting state to activated state of receptor
- efficacy =1
define partial agonist
- agonist if work alone
- act as antagonist when act with other agonist drugs
- efficacy = less than 1
define inverse agonist
- shifting activated receptor to resting state
- cause inactivation of receptor and no response
define antagonist
- give equal affinity to both resting and activated receptor
- inhibit action of agonist but not on itself
- response not affected and on graph 0
2 types of antagonists
- competitive
- non-competitive
effect of competitive antagonist
- can be overcome by increasing [agonist]
- maximal response not affected
- shifts curve to the right
effect of non-competitive antagonist
- cannot be overcome
- reduces maximal response
- decrease efficacy
candidates for new drugs derive from:
- chemical modification of known molecules
- screening of natural products
- rational drug design
- biotechnology
steps of drug development and testing
- in vitro studies
- animal testing
- clinical testing/trials (human)
- marketing
phases in clinical trials
- is it safe?
- does it work?
- does it work double-blind?
types of tests in preclinical
- molecular screening
- cellular and tissue screening
- whole animal studies
types of toxicity testing
- acute toxicity
- subacute and chronic toxicity
- reproductive toxicity
- carcinogenicity
- mutagenicity
acute toxicity?
effect of large dose up to lethal level
subacute and chronic toxicity?
effects of multiple doses
reproductive toxicity?
affect fertility, teratology, lactation, postnatal development
mutagenicity?
genetic stability of bacteria and mammalian cells in culture
limitations of preclinical testing?
- time and cost for toxic test
- need large no. of animals
- limits on extrapolation of animal data to humans
- rare adverse effect not detected
what to do when variable disease happen?
use cross-over
what happen when other disease influence the test result?
- use cross-over
- proper selection of patients based on medical histories
what happen when subject and observer bias?
- use placebo response
- use single and double blind design
elaborate phase 1 clinical trials
- is it safe?
- dose versus effect
- pharmacokinetics
- ~ 1 year
elaborate phase 2 clinical trials
- does it work?
- safety and efficacy
- include single blind crossover design
- ~ 2- 5 years
explain phase 3 clinical trials
- does it work double blind?
- to verify effectiveness and monitor safety for long term use
- include double blind crossover design
- ~ 2- 4 years
explain phase 4 post-marketing surveillance
- monitor drug safety under actual use
- to detect any rare adverse effects
