Pharmacology Flashcards
What is the difference between pharmacodynamics and pharmacokinetics?
Pharmacodynamics - what the drug does to the body
Pharmacokinetics - what the body does to the drug
Drugs which act on receptors can be either _________ or ______________
Agonists
Antagonists
What is affinity?
The strength at which a ligand will bind to its receptor
What is efficacy?
The ability of an agonist to evoke a cellular response
What is EC50?
The concentration of agonist that elicits half maximal response
This is the Michaelis-Menten constant
What is competitive antagonism?
The antagonist and agonist compete for the same binding site
What is non-competitive antagonism?
The agonist binds to the orthosteric site and the antagonist bings to a separate allosteric site
Activation cannot occur when the antagonist is bound
What is potency?
The effectiveness of a drug at a given concentration
How do competitive antagonists affect the concentration response curve?
Competitive antagonists cause a parallel rightward shift of the agonist concentration response curve with no depression of the maximal response
How do non-competitive antagonists affect the concentration response curve?
Non-competitive antagonists depress the slope and maximum of the concentration response curve, but do not cause a rightward shift
What is the therapeutic window?
Any concentration of drug between the minimum effective concentration (MEC) and maximum tolerated concentration (MTC)
How is the therapuetic ratio calculated?
TR - MTC/MEC
Drugs with ____ therapeutic ratios are unsafe
Low
When a drug is given by IV, how is the initial concentration calculated?
C0 = D/Vd
D - dose (mg)
Vd = volume of body plasma
The drop in concentration of a drug in the body over time depends on what?
The rate of removal or elimination (Kel)
What is first order kinetics?
Most drugs express this
It is when the rate of elimination is directly proportional to drug concentration
What is “clearance”?
This is the volume of plasma filtered clear of the drug in unit time
How is rate of elimination calculated?
Rate = Cl x Cp
Cl - clearance
Cp - plasma concentration
Rate of elimination is measured in l/hr
At a stead state the rate of drug administration will equal what?
The rate of elimination
(drug concentration remains constant)
Changing the rate of drug administration does not change the time to reach a steady state, it will change what instead?
It will change the concentration of the steady state
How many half lives does it take to reach a steady state?
5
What is a loading dose?
An initially higher administered dose given at the beginning f treatment.
It accelerates the time at which a steady state can be reached and when plasma concentration becomes adequate
How does a larger Vd affect half life?
It increases it
How can half life be shortened?
If Cl is reduced
What is zero order kinetics?
This describes drugs that are eliminated at a constant rate, regardless of their concentration
An increase in drug concentration will have no effect on the rate of elimination
(at very low concentrations some drugs may initially function at first order kinetics because concentration is the limiting factor)
What is the reason for some drugs functioning at zero order kinetics?
The enzyme that breaks them down has a Km that is lower than the concentration of the drug in the body
What is a ganglion?
A group of cells at which a synpase is present
Why is the sympathetic innervation of the adrenal gland unusual?
It is innervated by a preganglionic neurone
Acetylcholine is released
The adrenal gland acts as the postganglionic neurone, by releasing adrenaline
Where does the sympathetic outflow originate?
The sympathetic chain (thoracolumbar outflow)
Between the levels of T1 and L2
Where does parasympathetic outflow originate?
Cranial nerves III, VII, IX and X
Cranio-sacral outflow
Thoraco-lumbar outflow
Sacral spinal nerves
How is noradrenaline cleared from the synaptic cleft?
It is reabsorbed
How is acetylcholine cleared from the synaptic cleft?
Broken down and re-synthesised
Describe how action potentials are sent via the sympathetic system
. The action potential causes volatge gated calcium ion channels to open allowing for calcium influx into the preganglionic neurone
. Acetylcholine is released into the synaptic cleft
. Acetylcholine bins to receptors (nicotinic) on the postsynaptic neurone and ligand gated ions channels open
. The postsynaptic neurone becomes depolarised and calcium ions enter via voltage gated ion channels
. Noradrenaline is released at the effector site
. Noradrenaline activates G-protein coupled adrenoceptors
How is transmission of an action potential different in the parasympathetic system when compared with the sympathetic system?
. Acetylcholine is released at effector sites
. Acetylcholine activates muscarinic acetylcholine receptors on the target cell instead of nicotinic receptors - this is a slower process
Which is faster, ligand gated ion channels or G-protein coupled?
Ligand gated channels
What is G-protein?
Guanine nucleotide binding protein
It is a peripheral membrane protein with 3 subunits, alpha, beta and gamma
It contains a binding site for GTP/GDP
Describe how G-proteins function
. When the receptor is bound, the G-proteins couples with the receptor
. GDP dissociates from the G-protein (bound in inactive state) and will bind to the alpha subunit
. The alpha subunit then combines with the effector altering its activity
. The receptor and effector are not linked so the signal can still be exerted even after the agonist dissociates
. The signal stops when the alpha subunit hydrolyses GTP releasing energy to rembine to subunits and cause dissociation from the effector
What are nicotinic acetylcholine receptors constructed of?
Up to 5 different glycoprotein subunits
They form a transmembrane channel that allows conduction of cations
What are the peripheral variants of nicotinic receptors?
Skeletal ((α1)2βγε)
Ganglionic (α3β4)
What are the CNS variants of nicotinic receptors?
α4β2
α7
Describe cholinergic transmission
- Uptake of choline via transporter
- ACh synthesisedvia choline acetyltransferase (CAT) – choline combines with acetyl CoA provided by mitochondria
- ACh packaged into vesicles
- Depolarization by action potential – must be present for exocytosis
- Ca2+ influx through voltage-activated Ca2+ channels – must occur for exocytosis
- Ca2+- induced release of ACh (exocytosis)
- Activation of ACh receptors (nicotinic or muscarinic) causing cellular response
- Degradation of ACh to choline and acetate by acetylcholinesterase (AChE) – terminates transmission
- Reuptake and reuse of choline
Which two receptors can ACh activate?
. Nicotinic (ligand gated receptors)
. Muscarinic (G-protein coupled receptors)
What are the individual roles of muscarinic receptors M1, M2 and M3?
. M1 – signals to specific G-protein (Gq) which stimulates phospholipase C which causes increased acid secretion in the stomach.
. M2 – signal to specific G-protein (Gi) which stimulates inhibition of adenylyl cyclase which opens K+ channel causing decreased heart rate.
. M3 – signals to specific G-protein (Gq) which stimulates phospholipase C production which causes increased secretion of saliva or contraction of visceral smooth muscle.
Describe noradrenergic transmission
- Synthesis of NA (multiple steps) – L-Tyrosine is converted through a variety of steps to noradrenaline
- Storage of NA by transporter (concentrates) – into vesicles
- Depolarization by action potential
- Ca2+ influx through voltage-activated Ca2+ channels
- Ca2+-induced release of NA - exocytosis
- Activation of adrenoceptor (receptors for noradrenaline) subtypes causing cellular response (tissue dependent)
- Reuptake of NA by transporters uptake 1 (U1) or uptake 2 (U2)
- Metabolism of NA by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
What are the different G-protein coupled adrenoceptor subtypes and their functions at sympathetic neuroeffector junctions?
- B1 – stimulates through Gs stimulating adenylyl cyclase increasing heart rate and force
- B2 – stimulates through Gs stimulating adenylyl cyclase causing relaxation bronchial and vascular
- a1 – stimulates through Gq stimulating phospholipase C causing contraction of vascular smooth muscle
- a2 – stimulates through Gi stimulating inhibition of adenylyl cyclase causing inhibition of NA
What are pre-synaptic autoreceptors and give an example?
. Pre-synaptic auto-receptors are either muscarinic or G-protein coupled (based on type of synapse)
. Instead of being present exclusively on the post synaptic neurone, they also occur on the pre-synaptic neurone
. This leads to the control of further neurotransmitter release by means of a negative feedback loop.
. When stimulated, the pre-synaptic muscarinic receptor for acetylcholine, causes the reduction of calcium influx into the pre-synaptic terminal through calcium channels.
What is a prodrug?
An inactive precursor of a drug
How many phases are there in drug metabolism?
2
What is the purpose of the drug phases that result in a metabolised drug?
To increase polarity and add functional groups increasing chance of excretion
Where may drugs be excreted from the body?
Bile
Sweat
Breast milk
Urine
What is the name of the family of proteins in the liver responsible for metabolism of drugs
Cytochrome P450 monooxygenase
Which two components make up the elimination step of a drug?
- Metabolism
- Excretion
What is the pKa of a drug?
The pH at which 50% of the drug is ionised and 50% is not
What is Vd?
The theoretical volume necessary to contain the total amount of drug at the same concentration that it is observed in the blood plasma
