Drugs Flashcards
Types of drugs acting via GPCR
Antidepressants Antipsychotics Antiasthma Blood Pressure Glaucoma Abuse
The G protein Gq is coupled to
phospholipase
Structure of a ligand gated ion channel subunit
e.g. nicotinic acetylcholine receptor
4 transmembrane domains
N terminus extracellular
Large loop between TM3 and TM4
TM2 forms lining of channel
The most diverse receptor class
G protein coupled receptors
G protein
Protein that links GPCRs to intracellular signalling pathways.
They are trimeric and come in different forms.
Have GTPase enzyme activity.
3 most common forms of G protein
Gs
Gi
Gq
G proteins are trimeric
They contain alpha, beta and gamma subunits
IP3
Inositol tris-phosphate
A second messenger produced in the PLC pathway. (coupled to Gq)
Phospholipase C
PLC - hydrolyses PIP2 into Diacyl glycerol and IP3
Orphan receptor
Receptor for which the endogenous ligand is not known
Adenylate cyclase is linked to which G proteins
Gs and Gi
Structure of a voltage gated sodium or calcium channel
24 TM domains, arranged into 4 pseudosubunits.
TM4 is the voltage sensor.
There is a membrane dipping loop between TM5 and TM6.
N terminus intracellular
G protein Gi is coupled to
adenylate cyclase (negatively)
The receptor class that is most frequently targetted by drugs
G protein coupled receptors
Before entering the nucleus, transactivation nuclear hormone receptors must…
Bind ligand, dissociate from heat shock proteins and dimerize
G protein coupled receptor
Receptor for a neurotransmitter, hormone or other signalling molecule that is coupled to intracellular signalling pathways via G proteins
G proteins
guanine nucleotide binding proteins
Structure of a GPCR subunit
7 transmembrane domains
N terminus extracellular
Large loop between TM5 and TM6
The G protein Gs is coupled to
adenylate cyclase (positively)
What is gating
process by which ion channel opening and closing is controlled.
Transrepression
Process by which nuclear hormone receptors decrease expression of a protein
Ligand gated ion channel
Ion channel with a binding site for a ligand built into it.
The ion channel is opened by actions of the neurotransmitter.
Nuclear hormone receptors are usually present in the
cytoplasm
Phospholipase C is linked to
Gq
Transactivation
The process by which nuclear hormone receptors increase expression of a protein
The time to onset of a functional effect following binding of an agonist to its binding site in a ligand-gated ion channel is
less than a second
What is the major inhibitory neurotransmitter in the CNS
GABA
How many subunits do nicotonic receptors contain
five
Structure of nicotonic receptors in foetal tissue
2 alpha
1 beta
1 delta
1 gamma
Structure of nicotonic receptors in a adult tissue
2 alpha
1 beta
1 delta
1 epsilon
Where are GABA receptors found in the cell?
Cell surface
Where are glucocorticoid receptors found in the cell?
Intracellular
Where are muscarinic acetylcholine receptors found in the cell?
Cell surface
Where are nicotinic acetylcholine receptors found in the cell?
Cell surface
Where does adrenaline act in the cell
G protein coupled receptors
Agonist
Activating substances.
Bind to receptors and activate by mimicking the effects of a transmitter at receptors, due to structural similarities
Drug binding domain
a. Point on receptor protein where drug interaction is most favourable
Antagonist
bind the receptor but does not transduce a response
Amiodarone
Class III antidysrhythmic drug which targets K+ channels
Verapamil
Class IV antidysrhytmic drug which targets Ca2+ channels
Unclassified antidysrhythmic drugs
adenosine
atropine
digoxine
Lidocaine
Class Ib antidysrhythmic drug which targets Na+ channels
Atenolol
Class II antidysrhythmic drug which targets Beta 1 adrenoreceptors
Drug X has a Kd of 5nm
Drug Y has a Kd of 50nm
Which has a higher affintiy
Drug X has 10x higher affinity than drug Y.
Kd / dissociation constant
Concentration that gives 50% of maximal occupancy
EC50
Concentration giving 50% maximum effect
Potency
The concentration of drug required to give a specified response. Often enough is given to achieve the EC50.
Ligand
A molecule that binds to something
Receptor
Binds a ligand and transduces information
Is a enzyme a receptor?
NO
Orthosteric antagonism
Reversible binding of antagonist to the same site on the receptor as the agonist. Not activating receptor.
IC50
Concentration of antagonist giving 50% of control response
Issue with IC50
Changes with agonist concentration. Doesn’t only measure antagonist.
Selectivity
The relative potency or affinity at one receptor compared with another
efficacy
Ability of a drug to produce desired result
What kind of response does a partial agonist give?
A submaximal response
Constitutive activity
Model explaining an agonist has a higher affinity for its receptor when in its active state
Tone or Basal activity
Occurs due to ongoing underlying neurotransmitter release
Non-competitive inhibitor
Binds at site other than agonist site (allosteric)
Reduces maximum effect
Not affected by agonist concentration
Un-competitive inhibitor
Use-dependent - more effective at higher agonist concentrations.
Heart failure
Failure of the heart to meet the body’s oxygen demands. Often due to failures of contractile mechanisms.
A small EC50 tells you what about a drugs potency/affinity?
It is high
Role of calcium in cholinergic transmission
Stimulates vesicle fusion with the presynaptic membrane - thus exocytosis of ACh.
Device used to measure polarised light
polarimeter
d- / (+) enantiomer
Rotates polarised light clockwise
If an enantiomer rotates polarised light anticlockwise, it is…
i- / (-)
What’s a method of classifying the stereochemistry of a molecule, that can determine structure of amino acids?
D/L
(+)/(-) is a method of identification in stereochemistry which classifies based on…
direction a molecule rotates polarised light when in solution
Give a type of isomer that can be readily interconverted
Chair/boat
Why are doses expressed in mg/kg?
Patients may differ in body weight and size. Using this type of dose means the plasma conc. of the drug should be about the same no matter how big or small the subject.
Rectangular hyperbola
Curve that rises and then smoothly reaches a plateau. Characteristic of conc.-response/binding relationships. Predicted by Hill-Langmuir
Competitive antagonist
Drug that binds to the same site as an agonist, but doesnt activate the receptor. Presence of competitive antagonist will reduce occupancy by agonist. In a functional assay, it will cause a parallel rightward shift in the agonist conc. response curve.
Ki
Term used to define the affinity of a competitive antagonist, or to define the affinity of a ligand derived from a competitive binding assay.
Sigmoid curve
S shaped curve
Seen with conc.response relationships
A large EC50 tells you what about a drugs potency/affinity?
it is low
A low kd for a drug
high potency/affinity
A high pkd for a drug means
high potency/affinity
A high EC50 means
high potency/affinity
A low pA2 means
A low drug potency
How does adrenaline differ from how NA interacts
Acts as hormone, released by adrenal medulla into bloodstream
Monoamine oxidase
Enzyme responsible for metabolism of various neurotransmitters - adrenaline and serotonin
Paravertebral ganglia
sympathetic ganglia lying close to the spinal cord
Amlodipine
Calcium antagonist used to treat hypertension
Perindorpil
ACE inhibitor used to treat hypertension, alongside calcium blockers.
ACE inhibitor
Reduce activity of ACE in blood, preventing formation of AGII, reducing high BP
Three main classes of diuretics…
Thiazide
Loop
K+ sparing
Spirinolactone
Potassium sparing diuretic works by blocking aldosterone receptors
Amiloride
Potassium sparing diuretic works by inhibiting Na+ channels in luminal membrane
How does aldosterone increase Na+ absorption in principal cells?
- Increases Na+/K+ ATPases
- Increase Na+ channels
- Stimulate Na+ channels via protein mediator
Examples of ACE inhibitors
Captopril
Lisinopril
AGII receptor types
type 1 - vascular effects and aldosterone release
type 2 - growth and development
Propranolol
Non-selective competitive antagonist at β-adrenoreceptors
lipid soluble, penetrates CNS causing vivid dreams
Atenolol and Bisopropol
Competitive β1-adrenoreceptor antagonists.
Water soluble.
What pain mediators might cardiac muscle cells release when they become ischaemic?
adenosine
bradykinin
K+
Features of LDL and VLDL making them bad?
- fatty streak formation
- inhibit fibrinolysis
- activate platelets
Dietary changes to treat hyperlipidaemia
- Reduce saturated fat
- Increase unsaturated fat
- Increase fibre
- Avoid trans-fats
- Avoid hydrogenated fats
Lipid lowering drugs to treat hyperlipidaemia’s
Statins
ezetimibe
Statins
Inhibit HMG-CoA reductase.
Interfere body’s ability to produce cholesterol.
Causes more LDL receptors.
salbutamol interacts with what receptor
Agonist at beta 2 adrenoreceptors
Atropine
mAChR antagonist
beta1 adrenoreceptors
control heart rate and force of contraction
chronotropic drugs
Affect heart rate
Ionotropic drugs
affect strength of heart contractions
Thrombin
Enzyme which converts soluble fibrinogen to insoluble fibrin. produced from prothrombin.
according to VW system, class I drugs are:
sodium channel blockers
According to VW system, class II drugs are:
beta-adrenoceptor antagonists
According to VW system, class III drugs are:
amiodarone
sotalol
According to VW system, class IV drugs are:
Calcium channel blockers
Statins
Lipid lowering drugs
Cause muscle inflammation and damage.
Plasmin
Enzyme which breaks down fibrin into soluble products. Precursor is plasminogen.
ECG showing ST elevation suggests…
STEMI
Blood markes in ACS suggests
NSTEMI
No blood markers in ACS suggests
Unstable angina
Drugs to prevent thrombosis
Aspirin
Ticagrelor/clopidogrel
Heparins
Atorvastatin
What type of drugs would be prescribed to someone with arterial thrombosis?
Drugs which modify platelet aggregation
What drugs would be prescribed to some with venous thrombosis?
Ones which modify coagulation
e.g. heparins
What does antithrombin act on?
Factor X
and thrombin
PLATO trial
Showed ticagrelor more effective than clopidogrel
Re-entry dysrhythmia
A disorder of impulse generation, e.g. atrial fibrillation
Disorders of impulse conduction
WPW syndrome
Atrio-ventricular block.
Ectopic focus
Abnormal impulse generation
Ventricular fibrillation
Abnormal impulse generation in ventricles
Class IV drugs
Block L-type VSCC
Slow SA & AV node conduction
Suppress ectopic pacemaker
forward symptoms of congestive heart failure
inability of heart to pump blood efficiently.
Low output symptoms
backward symptoms of congestive heart failure
inability of heart to fill with blood efficiently.
Congestive symptoms
glucocorticoid receptor
GPCR involved in gene regulation.
