biochemical basis Flashcards
what is an example of reversible competitive antagonist?
propranolol
what is example of irreversible antagonist?
aspirin
what are the 4 super-families of receptors?
- ligand-gated ion channel
- G-protein coupled receptors
- kinase-linked receptors
- nuclear receptors
what are ligand-gated ion channels?
super efficient signalling systems
- ion channel opens and allows ions to move in/out of cell
- hyperpolarisation and depolarisation
- neurotransmitters bind to the channel that changes conformation to open
what is an example of ligand-gated ion channels?
nicotonic & ACh receptor
(nicotine acetyl choline receptor = permeable to Na+. K+. Ca2+ = non-specific = modulate fast synaptic excitation)
-> through cholinergic synapse
what is positive of ligand-gated ion channels in comparison to other receptor classes?
time scale!
- takes milliseconds for ligand-gated ion channels (G-protein coupled takes seconds and kinase-linked & nuclear receptors take hours)
what is G-protein coupled receptor?
membrane-bound receptors that then have downstream action
G -proteins interact with other molecules, 2 categories:
- adjacent enzymes - activate or inhibit - the enzymes would evoke second cascade which would lead to response
- adjacent ion channels, example/ beta-adrenoceptors, always activate certain molecules
what are G-proteins and how are they activated/inactivated?
proteins coupled to receptors in G-coupled receptors
- made of alpha, beta & gamma subunit
- when alpha binds to GDP - 3 subunits remain together & inactive
- when alpha binds to GTP- alpha subunit seperates from beta & gamma and is free to activate/inhibit other proteins
to inactivate again - alpha subunit consumes energy from GTP and turns it into GDP
what is process of alpha-1 adrenoceptor?
-catecholamine binds to adrenoceptor
- stimulates Gq to release GDP & bind to GTP, activating alpha Gq
-activated Gq activates phospholipase C (PLC)
- PLC cleaves PIP-2 to IP3 & DAG
IP3 = moves to ER and opens calcium channels, calcium moves into cytoplasm -> depolarisation
DAG = binds to PKC (which needs calcium to function) and PKC phosphorylates & activates proteins which triggers cellular response = MLCK activity(enzyme involved in the regulation of smooth muscle contraction) & vasoconstriction
how does 1 molecule make big response in G-protein coupled receptor?
signal amplification
what are the G proteins for each adrenoceptor?
alpha 1 = Gq
alpha 2 = Gi
beta 1, 3 & 3 = all Gs
(principal transduction = like the start bit of process)
what is principal transduction for the beta adrenoceptors?
they all have the same principal transduction
= G alpha s stimulates adenylyl cyclase which increases cyclic AMP
what is principal transduction of alpha adreno-ceptors?
alpha 1 = Gq activates phospholipase C which increases IP3 and DAG
alpha 2 = Gi inhibits adenylyl cyclase which decreases cAMP and calcium channels and increases K+ channels
what is physiological effect of alpha 1 adreno-ceptors?
vasoconstriction of blood vessels
what is physiological effect of alpha 2 adreno-ceptors?
- presynaptic inhibition of noradrenaline
- when in GI tract they can contribute to the inhibition of gastrointestinal motility and secretion (since digestion is not key for fight or flight response)
what is physiological effect of beta 1 adreno-ceptors?
increased heart rate & cardiac muscle contraction
what is physiological effect of beta 2 adreno-ceptors?
dilation of bronchi
- increased heart rate & cardiac muscle contraction (less than B1)
- also decreased gut motility
what is physiological effect of beta 3 adreno-ceptors?
thermogenesis in skeletal muscle, lipolysis
what affect does adrenaline have on adrenoceptors?
binds/activates all adrenoceptors
= full sympathetic physiological response
what affect does isoprenaline have on adrenoceptors?
binds/activates beta 1 & 2 adrenoceptors
= tachycardia (big side effect)
= bronchodilation
what affect does salbutamol have on adrenoceptors?
binds/activates beta 2 adrenoceptors
= bronchodilation
= desired therpeutic effect for asthma
what is the process of alpha 2 adrenoceptors?
- adrenaline etc bind and changes conformation of adrenoceptor
- stimulates Gi to release GDP & bind to GTP, activating Gi
-activated Gi inhibits adenylyl cyclase - negative feedback on effect of Gs which important for inactivation of un-important cells for fight or flight
- also inhibits noradrnaline release -> relaxation of GI tract
*G beta gamma (part of G protein) reacts with K+ channel
(beta 2 and alpha 2 both relax Gi tract, just through different mechanisms)
what is process of beta receptors?
- beta receptor coupled with Gs
- binding of adrenaline etc changes conformation of adrenoceptor
- stimulates Gs to release GDP & bind to GTP, activating Gs
- activated Gs, activates adenyl cyclase which converts ATP to cAMP
- cAMP moves through cytoplasm causing phosphorylation of PKA which inhibits MLCK activity
- cellular response triggered = depens on what beta receptor
what is salbutamol?
- given as an inhaler, beta 2 adrenoceptor
- it will phosphorylate PKA, cAMP = gives bronchodilation
what is phosphodiesterase function?
terminates action of cAMP
what is theophylline function?
phosphodiesterase inhibitor
- maintains bronchodilation as phosphodiesterase inactivates cAMP and cAMP needed for cascade of bronchodilation
what is kinase-linked receptor general process?
-also called enzyme-coupled receptors
binding to receptor (cytokine receptor)
- protein phosphorylation
- gene transcription
- protein synthesis
- cellular effects
has MULTIPLE PARALLEL signalling pathways
(insulin= example)
what is an example of kinase-binding receptor and what is process?
insulin receptor
- insulin secreted after meal
- results in cellular responses
- tyrosine residues phosphorylated
- ATP floating around and ATP drops off phosphate group at tyrosine
- phosphorylates this part of protein that allows attachment of relay proteins to receptor = now ready to activate lots of different pathways like GLUT4 -> glucose enter cell
what are the different cellular responses of insulin?
insulin receptor = kinase-linked receptor = multiple signalling pathways
- recruitment of glucose transporters
- increased formation of glycogen
- increased formation of fat
- changes in gene expression
- decreased formation of glucose from glycogen
- increased formation of protein
what are nuclear receptors general process?
intra-cellular receptors that are generally bound by steroid hormones
- these receptors are protein monomers located in nucleus of target cell and contain DNA-binding domains that allow for control for gene transcription
what type of molecule is for nuclear receptors?
agonist that can get into plasma membrane - must be very lipophillic
like steroid hormones (example - osetrogen)
what process do steroid hormones initiate in nuclear receptors?
2-step process:
- Activated hormone-receptor complex forms within the cell
- The complex binds to DNA & activates specific genes ->Gene activation leads to production of key proteins
what is structure of nuclear receptor?
- part that binds to sterioid (agonist, signalling molecule)
- part that binds to DNA
what are examples of receptor molecules for nuclear receptors?
- androgen, testosterone ligand
- oestrogen
- glucocorticoid
- progesterone
- mineralocorticoid, aldosterone ligand
all lipophillic so easily pass through membrane
what is process of aldosterone hormone (mineralocorticoid)?
- aldosterone promotes increase in ENaC(sodium channel) expression (by binding to receptor that changes gene expression) which increases sodium absorption therefore increasing blood pressure
- aldosterone normally secreted in response to hyponatremia (where you get resistance to thiazides - which are used to lower arterial blood pressure by blocking sodium reabsorption)
what is mechanism of action of ibuprofen?
has NSAID which inhibits COX-1 and COX-2 therefore decreases fever & gastric protection
*COX-2 converts arachidonic acid to prostaglandin E2 which leads to pain pyrexia (fever)
COX-1 converts arachidonic acid to prostanglandin G2 which leads to gastric protection
what type of drug is ibuprofen?
non steroidal anti-inflammatory drug
- act’s at cyclooxegenase enzymes (COX)
what is mechanism of action for amlodipine?
calcium channel blocker - which reduces cardiac contractibility, drugs interact with channels ->reduction in arterial blood pressure
How is calcium involved in cardiac contractibility?
because Ca2+ involved in cardiac cell contraction and propagation of cardiac impulse - contraction of vascular smooth muscle cells requires influx via Ca2+ voltage-gated channels so increased Ca2+ which -> activation of myosin & actin -> muscle contraction
what are SSRI’s?
selective serotonin re-uptake inhibitors
- anti-depressant drugs (inhibit re-uptake of serotonin so have more serotonin in body)
*you might think of amitryptyline - it works in similair way but amitryptyline is tricycline anti-depressant which is different family that is less common than SSRI’s as more side effects
what are some examples of SSRI’s?
- citalopram
- escitalopram
- fluoxetine
- fluvoxamine
- paroxetine
- sertraline
what is negative of SSRI’s?
lots of adverse side-effects
what is sodium valproate an example of?
a drug that can have multiple mechanisms of action
what is formoterol?
= beta blocker
- commonly used as a maintenance medication for the long-term management of asthma and chronic obstructive pulmonary disease (COPD)
- It is used to provide sustained bronchodilation and control of symptoms = it has higher potency than salbutamol
what happens if taking sertraline & ibuprofen at the same time?
sertraline inhibits enzyme that metabolises ibuprofen so increasing plasma conc of ibuprofen which inhibits cox-1 which evokes GI side-effects
what is relationship between Ki and affinity?
- Ki = the concentration of a drug needed to occupy half of the available receptors
- lower Ki indicates higher affinity but as pKi it means opposite since -ve so higher pKi indicates higher affinity
