Pharmacology Flashcards
What is pharmacodynamics?
What a drug does to the body (biological effects and mechanism of action)
What is pharmacokinetics?
What the body does to a drug (absorption, distribution, metabolism and excretion of drugs and their metabolites).
What is a drug?
A SINGLE synthetic or natural substance of known structure - everyday substances, substances used for treatment and illicit substances.
What is a medicine?
A chemical preparation containing one or more drugs used with the intention of causing a therapeutic effect. Usually includes agents additional to the active drug.
Must act with a degree of selectivity
What is selectivity?
-the ability to distinguish between different molecular targets within the body and allows drugs to interact with select tissues to get the intended effect.
How do drugs act?
By binding to regulatory proteins to modify their function - enzymes, carrier molecules, ion channels, receptors
Or by binding to other targets - RNA and DNA
Very rarely there is no specific target
What are receptors?
Macromolecules in or within cells that mediate the biological actions of hormones, neurotransmitters and other endogenous substances
What is an agonist?
A drug that binds to a receptor to produce a cellular response. They bind reversibly to receptors to activate them temporarily by inducing a reversible confrontational change. Possess affinity (rate of agonist binding/rate of agonist unbinding) and efficacy (rate of receptor activation / rate of receptor deactivation)
What is an antagonist?
A drugs that reduces, or blocks the actions of an agonist by binding to the same receptor.
- bind but do not activate receptors
- posses affinity but not efficacy
Describe the relationship between affinity and dissociation in agonists.
Low affinity - ‘fast’ dissociation rate
High affinity - ‘slow’ dissociation rate
What is efficacy in agonists?
The ability of an agonist to evoke a cellular response.
Low efficacy = small response
High efficacy = big response
What happens when drug dose is too high?
Selectivity no longer works and negative effects can occur
What is the relationship between receptor occupancy and agonist concentration?
As agonist conc. increases the receptor occupancy increases correspondingly and the relationship of hyperbolic.
What is EC50 ?
The concentration of agonist that elicits a half maximal effect.
What is the relationship between concentration (dose) and effect?
The relationship is sigmoidal
Describe reversible competitive antagonism
Binding of antagonist and agonist (both reversible) occurs at the same (orthosteric) site and are competitive and mutually exclusive
It can be overcome by increasing concentration of agonists
Describe non-competitive antagonism
Agonist binds to orthosteric sure and antagonist binds to separate allosteric site and thus is not competitive.
Both may occupy the receptor reversibly and simultaneously but activation cannot occur when antagonist is bound
What do competitive antagonist do to the graph?
Cause a parallel rightward shift of the agonist concentration response curve but maximum response is unchanged
What do non competitive antagonists do to the graph?
Depress the slip and maximum of the concentration response curve but do not cause a rightward shift.
What are receptors and what are they targets of?
They are sending elements of chemical communication within the body and are the targets of ; -neurotransmitters, hormones, other mediators, therapeutic agents (agonists and antagonists, modulators)
What are autocrine, paracrine and endocrine signalling?
Autocrine - cell signals to itself
Paracrine - cell signals to its close neighbour
Endocrine - cell signals via molecules transported in the blood to target distant cells
Describe ligand gated ion channels
Located at the plasma membrane
Targeted by hydrophilic signalling molecules
Consists of separate glycoprotein subunits that form a central, ion conduction channel where ions flow down their electrochemical gradient.
Allows very rapid changes in permeability > Action in milliseconds
Eg. Nictonic acetylcholine
Describe G protein-coupled receptors
Located at the plasma membrane
Targeted by hydrophilic signalling molecules
Signal in seconds
Receptor - integral membrane protein, single polypeptide with extracellular NH2 and COOH terminus, contains seven transmembrane helical spans
Describe kinase linked receptors
Located at plasma membrane
Targeted by hydrophilic protein mediators (eg insulin)
Work on hours time scale
Describe nuclear receptors
Located intracellularly in the nucleus (or cytoplasm)
Targeted mainly by hydrophobic signalling molecules
Very slow action - hours/day time scale
Describe ion channels
Transmembrane pores formed by glycoproteins that span the membrane to create an ion conducting pathway for selected ions
Usually gated
When open, ions cross passively down conc. gradient
May be gated by chemical signals, transmembrane voltage and physical stimuli
What is signalling via second messengers?
Receptor activation modulates the activity of an effector (generally an enzyme)
GPCRs (G protein coupled receptors) are linked to a cell membrane located effector by intermediary G proteins
Enzyme effectors change the rate of synthesis of second messenger molecules affecting activity of targets
Ion channel effectors cause changes in membrane electrical properties
What is a G protein?
Peripheral membrane protein
Consists of 3 polypeptide subunits
Guanine nucleotide binding subunit that can hold GTP or GDP
Exists as multiple types according to their alpha subunit
How are G proteins activated?
By agonist binding to the GPCR
Inactive state = the guanine nucleotide binding site of the alpha subunit is occupied by GDP
Active state = it’s occupied by GTP and alpha and beta-gamma subunits separate from each other
What does the activation of G proteins cause?
Confrontational change which causes the G protein alpha subunit to release GDP and allow GTP to bind in its place > separation of receptor and Beta-gamma dimer > generates free GTP bound alpha subunit and beta-gamma diner, both of which are signalling molecules
How do G protein coupled receptors work?
After the G protein is activated > G protein alpha subunit combines with and modifies activity of effector> agonist molecule may dissociate from receptor but signalling can persist.
Turning off: alpha subunit acts as an enzyme to hydrolyse GTP to GDP and the signal is turned off > the G protein alpha subunit recombined with the beta gamma subunit completing the G protein cycle
describe ADME (absorption, distribution, metabolism and elimination)
absorption - drug is absorbed from the site of administration and enters the plasma
distribution - drug reversibly leaves the bloodstream and is distributed into interstitial and intracellular fluids
metabolism - drug transformation by metabolism
excretion - drug elimination in urine, faeces or bile.
how can small molecules cross the cell membrane.
passive diffusion, facilitated diffusion, active transport or endocytosis
what is facilitated diffusion?
specialised carrier proteins bind the drug on the side which is outside of the membrane and due to a conformational change, then release it on the other side (inside).
Does not require energy, is how water soluble drugs enter. can show saturation kinetics
what is active transport?
movement via specialised carrier proteins and requiring energy to move the drug against its concentration gradient.
can be used for water soluble drugs. requires energy. can show saturation kinetics.
what are the principle sites for carrier mediated drug transport?
blood brain barrier GI tract placenta renal tubule biliary tract
what is endocytosis?
the drug is encased in a small vesicle the “released” inside the cell.
useful for transport of large drugs across the cell membrane.
what is the pKa?
the pH at which 50% of drug is ionised and 50% unionised.
what happens to acids and bases in drug absorption?
weak bases accumulate in compartments of low pH, weak acids accumulate in compartments with high pH.
low pH facilitates absorption of weak acids and high pH facilitates absorption of weak bases.
how does drug distribution vary with different body compartments?
total body water - small water-soluble molecules
extracellular water - later water soluble molecules
blood plasma - highly plasma protein bound molecules, large and highly charged
adipose tissue - highly lipid soluble molecules
bone and teeth - certain ions.
what is the apparent volume of distribution?
it describes the extent to which a drug partitions between the plasma and tissue compartments.
vd =dose/ [drug]plasma
[drug]plasma = amount added / volume of beaker.
(not a physical volume, can be greater than body volume. more ionised = vd closer to 41L whereas in lipophilic drugs the vd is greater)
describe plasma protein binding.
albumin is the most abundant plasma protein, many drugs bind with low affinity albumin via electrostatic and hydrophobic forces.
plasma protein binding reduces the availability of the drug for diffusion to the drug target organ. it may also reduce the transport of the drug to non-vascular compartments.
describe drug metabolism
enzymatic conversion of the drug to another chemical entity is metabolism. the liver is the most important in this process but kidney, gut mucosa, lungs and skin are also involved.
metabolism in the liver reduces the bioavailability of drugs when administered by enteral (oral) route.
where are hepatic drug metabolising enzymes found?
embedded in the smooth endoplasmic reticulum of the liver hepatocytes.
what are phase one metabolism reactions?
change in a drug by oxidation, reduction or hydrolysis. usually forms chemically reactive metabolites that can be pharmacologically active and/or toxic.
what happens in phase 1 oxidation reactions?
oxidation reactions are accomplished by cytochrome p450 enzymes (microsomal haem proteins). during oxidation the drug molecule incorporates one atom of 02 to the drug to form a hydroxyl group.
this can produce harmful metabolites.
what do cytoplasmic enzymes do in phase 1 metabolism?
they have the ability to metabolise drugs.
what bonds are susceptible to hydrolysis in phase 1 metabolism?
ester and amide bonds.
which genes are involved in drug metabolism in the human liver?
CYP genes - CYP1 CYP2 and CYP3.
P450s activity is also genetically determined leading to higher or lower plasma levels.
what are phase 2 metabolism reactions?
reactions involving the combination of the drug with one of several polar molecules to form a water-soluble metabolite.
conjugation, involving reactive group from phase 1, usually terminates all biological activity and is then excreted via the kidney. (some drugs go straight to phase 2 metabolism)
describe drug elimination.
drug elimination is mostly accomplished via renal filtration of blood plasma. water and most electrolytes are reabsorbed into blood circulation in the renal tubules.
drug metabolites rendered polar by phase 2 metabolism are not reabsorbed and are excreted in urine.
what happens if drug plasma concentrations are too high or too low?
too high = toxic effects
too low = sub-therapeutic effects
what is clearance (Cl) ?
the volume of blood removed of drug per unit time.
it is important as it helps determine the dosage rate needed to maintain a desired drug plasma conc.
how do you estimate clearance?
rate of drug elimination / drug plasma conc.
what is zero order kinetics?
when the rate of clearance/elimination is independent of the total drug conc. in the plasma and a constant amount is eliminated per unit time.
this occurs when Vmax is reached.
what are first order kinetics?
rate of elimination is proportional to the drug plasma concentration in the body. occurs at low levels of drug plasma conc. (up to Km) and follows michaelis-menten kinetics.
what is the elimination equation for michaeil-menten kinetics?
Re = [Vmax x drug plasma conc.] / [Km + drug plasma conc.]
how is dosage rate worked out?
drug plasma conc. X clearance
what is the equation for elimination half life?
t1/2 = 0.693 X Vd/CL
what does elimination half life tell us?
- the time required for drug plasma concentration to achieve its maximum
- determines how much time is required fro the drug to be eliminated from the body.
what are factors affecting volume of distribution (and therefore elimination half life)?
- ageing - decrease in muscle mass means a decrease in t1/2
- obesity increases t1/2
- pathological fluid increases t1/2
what are factors affecting clearance (and therefore elimination half life)?
- cytochrome P450 induction = decrease and inhibition = increase in t1/2
- cardiac /hepatic /renal failure increases t1/2
what is depolarisation?
when the membrane potential becomes less negative
what is hyperpolarisation?
the membrane potential becomes more negative
how do sodium ions move across the membrane?
through sodium selective channels.
they flow inwardly following their concentration and electrical gradients.
Ena = +60 mv
what is the membrane potential for many neurones?
-70 mv
how do potassium ions move across the membrane?
- potassium selective channels
- they flow outwardly as the concentration gradient has an outward energy which exceeds the inward energy of the electrical gradient. (Ek = +30mv)
describe the membrane potential when movement of potassium and sodium ions occurs.
see action potential graph.
what are action potentials?
- brief electrical signals in which the polarity of the nerve cell membrane is momentarily reversed.
- they propagate along nerve cell axons with constant magnitude and velocity allowing signalling over long distances.
- generated when the threshold is reached.
what type of feedback do sodium ion channels display?
- positive feedback
- they are self-reinforcing - the opening of a few channels causes further depolarisation.
what type of feedback do potassium ion channels display?
- negative feedback
- they are self-limiting - movement of ions causes repolarisation which turns off the stimulus for opening.
what is the refractory period?
after sodium channels initially open they enter a non-conducting, inactivated state. repolarization is required to enter the closed state, inactivation contributes to the repolarisation phase and is responsible for the refractory period.
absolute refractory period = no stimulus can elicit a second action potential.
relative refractory period = a stronger than normal stimulus may elicit a second action potential.
why do passive signals not spread far from their origin?
the nerve cell membrane is ‘leaky’ and so current is lost across the membrane and there is a reduced change in potential.
how does passive conductance affect action potential velocity?
the less leaky the axon the greater the local current spread, and greater the action potential velocity.
hoe can passive current speed be increased?
- increasing the axon diameter
- decreasing the leak of current across the axon (adding insulating material such as myelin provided by schwann cells and oligodendrocytes)
what is the PNS made up of?
- somatic efferent sends signals away from the CNS (motor fibres, skeletal muscle etc)
- somatic afferent sends signals towards the CNS (sensory fibres)
- autonomic nervous system
what is the ANS made up of?
- enteric
- sympathetic
- parasympathetic
what does the ANS do?
- supplies every peripheral muscle except skeletal muscle.
- regulates functions that do not require conscious effort and are involuntary
describe the organisation of the motor ANS
preganglionic neuron > post ganglionic neuron > effector cells
- pre ganglionic neuron is inside the CNS and the post ganglionic neuron is outside the CNS.
- in the autonomic ganglia the preganglionic neuron uses a synapse to communicate with the postganglionic neuron.
what does the sympathetic ANS do?
- orchestrates the stress response (fight or flight reactions)
- also has important ongoing activity.
- e.g increases heart rate, relaxes bronchi, releases adrenaline etc.
what does the parasympathetic ANS do?
- regulates many functions, some of which are restorative and energy conserving (rest and digest)
e. g decreases heart rate, relaxes sphincters, constricts bronchi etc
what neurotransmitters are used in sympathetic division?
- from preganglionic neuron to post ganglionic neuron acetylcholine (ACh) is released.
- from postganglionic neuron to effector cells noradrenaline is used.
what neurotransmitters are used in parasympathetic division?
- acetylcholine (ACh)
describe chemical transmission in the ANS
action potential originating in the CNS travels to the the preganglionic neurone triggering Ca2+ entry through voltage-gated channels and the release of ACh by exocytosis
- ACh binds to and opens ligand-gated ion channels in the postganglionic neurone, causing depolarization and the initiation of action potentials triggering Ca2+ entry and the release of noradrenaline (in sympathetic) or ACh (parasympathetic)
- noradrenaline activates G-protein coupled adrenoreceptors in the effector cell membrane to cause a cellular response via ion channel/enzymes.
if the transmitter is not noradrenaline or acetyl choline, what is it likely to be?
- non-adrenergic, non-cholinergic (NANC) transmission
- co released with a NANC co-transmitted (ATP of NO)
what is ACh?
- endogenous agonist of cholinoreceptors that are nicotinic, or muscarinic
- nicotinic = ligand gated ion channels which occur in the ganglia, skeletal muscle and CNS
- muscarinic = G-protein coupled receptors with 5 distinct subtypes. (m1-3 most important in ANS)
what are NA and adrenaline?
- endogenous agonists of a family of G protein coupled receptors
- there are two divisions alpha and beta
- alpha adrenoreceptors rank of potency = noradrenaline> adrenaline > isoprenaline.
- beta adrenorecrptoes rank of potency = isoprenaline > adrenaline > noradrenaline.
what are the clinically important subclasses of adrenoreceptors?
- a1, a2,b1,b2,b3
- all are selectively targeted by current therapeutic agents.
what are GPCRs?
- G protein coupled receptors are integral membrane proteins with extracellular NH2 and intracellular COOH termini.
contains 7 transmembrane a helical spans.
what are the steps in neurochemical transmission in the ANS?
- Uptake of precursor
- synthesis of transmitter or intermediate
- storage of transmitter or intermediate
- depolarisation by action potential
- calcium 2+ ions entry via voltage channels
- calcium ions induces release of transmitter
- receptor activation
- enzyme mediated inactivation of transmitter or reuptake of transmitter.
what are ACh receptors?
consists of 5 glycoprotein subunits that form a central, cation channel.
- exists as subtypes for skeletal muscle, ganglia and two for the CNS
what is the ratio of postganglionic neurons to preganglionic neurons?
a single postganglionic one can have input from many preganglionic neurons.
what is an open channel block?
when ganglionic transmission is selectively blocked by hexamethonium (uncompetitive antagonism)
how can blockages of ganglionic transmission be achieved?
- depolarisation
- competitive antagonism
- non competitive antagonism
what drugs work in stroke prevention?
- warfarin
- thrombin inhibitors
- Xa inhibitors
