Pharmacology Flashcards
Give some examples of mAChR agonists and antagonists.
AGONISTS: Pilocarpine (activates constrictor pupillae muscle - drains aqueous humor therefore treats glaucoma)
ANTAGONISTS:
- Ipratropium bromide (dilates bronchioles - asthma)
- Homatropine (belladonna - dilates pupils)
- Atropine (increases heart rate, bronchial dilation, pupil dilation)
Give some examples of nAChR agonists and antagonists.
AGONIST: Nicotine (+?)
ANTAGONISTS:
- Trimethaphan (autonomic ganglia)
- Pancuronium (NMJ - muscle relaxant)
- Tubocurarine (poison)
Give some examples of alpha-1 receptor agonists and antagonists.
AGONISTS:
- Phenylephrine (decongestions)
- Adrenaline (vasoconstriction, therefore increases blood pressure - cardiac arrest & anaphylactic shock)
ANTAGONISTS:
- Prazosin (anti-hypertensive: inhibits action of noradrenaline on vascular smooth muscle - vasodilatation)
Give some examples of alpha-2 receptor agonists and antagonists.
AGONISTS:
- Clonidine (hypertension)
ANTAGONISTS:
- Yohimbine (?aphrodisiac)
Give some examples of beta-1 receptor agonists and antagonists.
AGONISTS:
- Dobutamine (increases force of contraction - treats cardiogenic shock)
ANTAGONISTS:
- Atenolol (reduces heart rate and force of contraction)
- Propanolol (reduces heart rate and force of contraction & bronchoconstriction; therefore astma is a contraindication)
Give some examples of beta-2 receptor agonists and antagonists.
AGONISTS:
- Salbutamol (bronchodilation - treats asthma)
ANTAGONISTS:
- Butoxamine
- Propanolol (reduces heart rate and force of contraction & bronchoconstriction; therefore asthma is a contraindication)
How can local anaesthetics affect Na+ channels? In what order are axons blocked?
Competitive antagonist: blocks open Na+ channels (use-dependent, hydrophilic pathway)
Pain increases the amount of open Na+ channels, therefore more of the anaesthetic will be able to block them
Small myelinated -> unmyelinated -> large myelinated
Give some examples of agonists and antagonists of muscarinic receptors.
M1 antagonist = pirenzipine (reduces gastric acid & muscle spasms)
M2 antagonist = gallamine (muscle relaxant)
M3 antagonist = hexahydrosiladiphenol
Define the affinity of a drug.
AFFINITY = ability of drug to bind to a receptor
What is the difference between intrinsic efficacy and efficacy?
INTRINSIC EFFICACY = ability of drug to activate receptor
EFFICACY = relationship between receptor occupancy and the ability to initiate a response at the molecular/cellular level (determined by cell/tissue dependent factors)
Define an agonist and antagonist.
AGONIST = has both affinity and intrinsic efficacy
ANTAGONIST = has affinity only (prevents activation by agonists)
How can you measure drug-receptor interactions?
Bind radiolabelled ligands to cells/membranes
Describe the appearance of a receptor/drug graph and what values can be measured on it.
Hyperbolic (sigmoidal if logarithmic)
Bmax = maximum binding capacity (gives information about receptor no.)
Kd = dissociation constant ([ligand] at 50% occupancy) (measure of affinity)
Describe the appearance of a concentration/response graph and what values can be measured on it.
Hyperbolic (sigmoidal if logarithmic)
Emax = maximal response (100%) (indicates intrinsic activity)
EC50 = effective concentration of drug giving 50% of the maximal response (measure of potency)
Define potency.
POTENCY = measure of drug activity (amount of product required to produce an effect of given intensity)
Depends on affinity and efficacy (intrinsic and otherwise) - therefore is affected by no. of receptors present
Define dose. How does it differ from concentration?
Concentration refers to the known concentration of a drug at site of action (i.e. how much of drug reaches tissue)
DOSE = concentration at site of action unknown (i.e. amount administered)
Use asthma drugs to show the difference between selectivity and specificity.
SALBUTAMOL (acute) = poor beta-2 selectivity (similar affinity for both beta-1 and beta-2 receptors) but good beta-2 efficacy
- inhaled (bronchi beta-2 adrenceptors affected only - IV salbutamol causes problems in those with angina by activating beta-1 receptors)
SALMETEROL (chronic) = no selective efficacy but has a higher affinity for beta-2 adrenoceptors than beta-1 adrenoceptors
Why can <100% occupancy allow 100% binding in some cases? Why is this useful?
Spare receptors present
Allow signal amplification
Increases sensitivity to allow responses at low concentrations of agonist
What can changing the receptor no. do? In what circumstances does this occur?
Changes the agonist potency which can affect the maximal response
Receptor no. increases with low activity (up-regulation) and decreases with high activity (down-regulation -> tolerance)
What is a partial agonist?
Agonist that does not elicit the maximal response as there are no spare receptors (insufficient efficacy)
(EC50 ~ Kd)
Give an example of the clinical uses of partial agonists.
Buprenorphine = partial u-opioid agonist (higher affinity but lower efficacy than morphine, therefore causes less respiratory depression but still controls pain)
Antagonises effects of heroin by competing for receptors but efficacy is too low to produce maximal effect
Can a partial agonist ever become a full agonist?
Yes - by increasing receptor no.
Still has low intrinsic efficacy at each receptor but there are sufficient receptors to contribute to a full respone
What is the effect of increasing efficacy on a response/drug curve? Increasing reversible antagonists? Increasing irreversible antagonists?
Increase efficacy -> curve moves to the left
Increase [reversible antagonist] -> curve moves to the right (higher EC50)
Increase [irreversible antagonist] -> curve moves to the right and down (receptors permanently blocked)
Give an example of a reversible antagonist.
Naloxone: high affinity competitive u-opioid antagonist
Reverses opioid-mediated respiratory depression (competes with heroin for receptors)
Treats heroin overdose
Give an example of an irreversible antagonist.
Phenoxybenzamine: alpha-1 adrenoceptor antagonist
Prevents vasoconstriction and treats hypertension caused by pheochromocytoma
Give an example of a non-competitive antagonist.
Ketamine: binds to allosteric site at NMDA receptor in brain (ligand-gated ion channel which allows memory and learning)
Causes analgesia at low concentrations by reducing CNS excitation
How do local anaesthetics block APs?
Hydrophilic: block open Na+ channels e.g. tubocurarine
Hydrophobic: inactivate Na+ channels (depolarising blockers) e.g. succinylcholine
How do tetrodotoxin and aminopyridine affect APs?
Tetrodotoxin: AP cannot be generated -> paralysis (death due to respiratory paralysis)
Aminopyridine: AP constantly transmitted (no repolarisation) -> static depolarisation until neurotransmitters run out
How can a cell’s responsiveness to drugs change? What is the difference between tachyphylaxis and suprasensitivity?
- change in receptor no.
- change in receptor coupling to secondary messengers
- change in the availability of secondary messengers (or other downstream components)
- change in cell responsiveness (cell efficacy)
TACHYPHYLAXIS = desensitisation due to down-regulation of receptors (excessive exposure to an agonist -> reduced sensitivity)
e.g. repeated opioid use (tolerance)
SUPRASENSITIVITY = agonist deprivation/excessive antagonist exposure -> up-regulation of receptors
e.g. giving long-term beta blockers -> withdraw drugs suddenly -> increased number of receptors means sympathetic activation relatively increases
Note: metabolism may be needed to obtain active drug (therefore people without the polymorphism for the specific enzymes will not respond to this drug) e.g. Clopidogrel
e.g. Alcohol: repeated exposure -> up-regulation of liver enzymes -> more alcohol required to elicit the same response
Why doesn’t tachyphylaxis occur with a pheochromocytoma?
Adrenoceptors do not up-regulate
Catecholamine secretion is intermittent
How does increasing age affect catecholamine sensitivity?
Reduced sensitivity to endogenous catecholamines
Reduced responsiveness to exogenous catecholamines e.g. heart rate in response to adrenaline
Reduced renin-angiotensin-aldosterone system (reduced clearance of drug)
Therefore it’s sometimes better to start with a smaller dose (increased efficacy)
Why would you specifically look for over-expressed receptors such as HER before giving the agonist (herceptin), instead of just giving it just in case?
Without enough receptors the response to the drug will be too high
