pharmacology Flashcards
Define pharmacodynamics
What a drug does to the body
Define pharmacokinetics
what the body does to a drug
What is a receptor?
Protein macromolecules
What is an agonist?
drug that binds to a receptor to produce a cellular response
define affinity
strength of association between ligand and receptor
Define efficacy
ability of an agonist to evoke a cellular response
What is an antagonist?
drug that blocks the effects of an agonist - has affinity but no efficacy
What is competitive antagonism?
binding of an agonist and antagonist occur at same (orthosteric) site and is thus competitive
What does competitive antagonism do to the potency and efficacy graph?
parallel rightward shift of agonist concentration response curve with no depression in maximal response(efficacy)
What is non competitive antagonism?
agonist binds to normal site but antagonist binds to a separate (allosteric site)
can occur simultaneously but cant be activated if antagonist is bound
How does a non competitive antagonist effect the graph?
depress slope and maximum curve response, does not cause rightward shift
Potency
the amount of drug required to permit a cellular response
Define absorption
process by which a drug enters the body from its site of administration
distribution
process by which drug leaves circulation and enters the tissues perfused by blood
How is a drug more readily excreted by the body?
tissue enzymes catalyse chemical conversion of a drug to a more polar form that is more readily excreted by the body
What are some factors that control drug absorption?
solubility - must dissolve
chemical stability - some drugs are destroyed by acid
lipid to water partition coefficient - rate of diffusion of drug increases with lipid solubility
degree of ionisation - only unionised forms can diffuse across lipid bilayer
What does the degree of ionisation depend on?
pKa of the drug and local pH
What is the pKa?
pH at which 50% of the drug is ionised and 50% isnt
What equation is used to determine how active a drug will be in the body?
What happens when Ka is large?
henderson-hasselbalch (pH - pKa = log(A-/AH) = acid
is Ka is large then it is a strong acid
What are some routes of administration?
Enteral - oral, sublingual and rectal
paraenteral - IV, intramuscular etc
What is the volume of distribution?
Apparent volume in which a drug is dissolved
IV - Vd = dose/ plasma
What does MEC stand for
Minimum effective concentration
What does MTC stand for?
maximum tolerated concentration
What is the therapeutic ratio
MTC/MEC - the higher the TR the safer the drug
What is first order kinetics?
Rate of elimination is directly proportional to drug concentration
plasma concentration falls exponentially
half-life is inversely proportional to elimination rate constant
What is clearance?
The volume of plasma cleared of drug in unit time
What does the rate of elimination equal?
clearance x plasma concentration
What does a constant plasma steady state equal?
maintenance dose rate/ clearance
when is a constant steady state reached?
after approximately five half lives
What is volume of distribution?
volume into which a drug appears to be distributed with a concentration equal to that of plasma
What is loading dose?
initial higher dose of drug before stepping down to maintenance dose
employed to decrease time to steady state for drugs with long half-life
what is half life?
time for concentration of drug in plasma to half
dependant upon Vd and Cl
What is zero order kinetics?
initially eliminated at a constant rate, then return to first first order kinetics
What affects drug distribution?
ADME - absorption, distribution, metabolism, excretion
What are the two phases of drug metabolism?
1st phase - RHS of the liver - oxidation, reduction and hydrolysis
makes drugs more polar, adds a chemically reactive group permitting conjugation
2nd phase - LHS of liver
conjugation, adds an endogenous compound increasing polarity
What are drugs converted to to facilitate excretion
more polar metabolites that are not readily absorbed iin renal tubules
WHat are the three basic processes of reanl excretion fo drugs?
glomerular filtration
active tubular secretion
passive reabsorption across tubular epithelium
Define depolarization
the membrane potential becomes less negative (positive)
Define hyperpolarization
membrane potential becomes more negative
What are some characteristics of sodium channels?
Na flows inwardly
140mM outside of cell
negative driving force = inward movement of sodium
Potassium channels?
K moves outwardly
when positive - outward movement of potassium
What are some characteristics of ion channels?
Protein complexes spanning lipid bilayer, central pathway to allow rapid flow of selected ions
How are voltage activated Na and K channels activated?
membrane depolarisation - sodium channels rapidly but potassium channels with a slight delay
opening of a few sodium channels causes causes further depolarisation ( positive feedback - upstroke of graph)
How do potassium channels work?
Self-limiting, outward movement of K causes repolarisation which turns off the stimulus ( negative feedback)
Where is there an undershoot on the graph when (potassium channels)
Delayed closure of potassium channels
What are some characteristics of closed state channels? (depolarisation to open)
Open state (maintained depolarisation to closed)?
Inactivated state? (repolarized to closed)
Activation gate close, inactivation gate open - non(conducting)
Activation gate open, inactivation gate open
CONDUCTING
Activation gate open, inactivation gate closed
non-conducting
What is absolute refractory period?
no stimulus can elicit a second action potential
all Na channels are closed
What is relative refractory period?
Stronger than normal stimulus may elicit a second action potential
possive conduction is a factor in the propagation of the action potential - longer the length constant - greater the local spread (increases AP velocity)
What are oligodendrocytes?q
Produce myelinated cells in CNS (Schwann cells do it in PNS)
Astrocytes?
star shaped - support homeostasis and maintain BBB
Microglia?
Immune surveillance - macrophage of the CNS
What are the functions of the ANS
- Carries output from the CNS to the whole of the body other than skeletal muscle
- Regulates visceral functions that are largely involuntary
- Subdivided into sympathetic and parasympathetic divisions
What do sympathetic nerves do?
- Coordinates the body’s response to stress, associated with fight, flight and fright reactions
- Preganglionic neurones always ACh
- Post ganglionic neurone usually noradrenaline
- Thoraco-Lumbar outflow (T1-L2)
- Increases HR and force of contraction
- Relaxes bronchi, decreases mucus production
- Reduces GI motility and constricts sphincters
- Vasoconstriction but relaxation in skeletal muscle
- Release of adrenaline from adrenal gland
- Ejaculation
What do parasymapthetic nerves do?
- Coordinates the body’s basic homeostatic functions
- Preganglionic and post ganglionic neurones ACh
- Cranial Nerves 3/7/9/10
- Decreases HR
- Bronchoconstriction, stimulates mucus production
- Increases GI motility and relaxes sphincters
- No effect on blood vessels or adrenal glands
- Erection
How are neurochemicals transported in the body?
- Precursor taken up
- Transmitter synthesised and stored
- Action potential depolarises
- Calcium influx through voltage-activated channels
- Calcium induced release of transmitter
- Receptor activation
- Enzyme-mediated inactivation of transmitter or reuptake of transmitter
How are sympathetic chemicals transmitted in the body?
- Sympathetic
o Action potential from CNS
o Travels to presynaptic terminal of preganglionic neurone triggering Calcium entry and release ACh
o ACh opens ligand-gated ion channels in the postganglionic neurone
Causes depolarisation and generation of action potentials that travel to presynaptic terminal of the neurone, triggering calcium entry and release, usually of noradrenaline
o Noradrenaline activates G protein coupled receptors - adrenoceptors
How are parasympathetic signals transferred?
- Parasympathetic
o Pretty much the same as sympathetic BUT
o ACh always the transmitter used by postganglionic neurones
o ACh activates G protein coupled muscarinic acetylcholine receptors in target cell membrane
Ligand gates ion channels ?
- Consist of separate glycoprotein subunits forming a central, ion conducting channel
- Allow rapid changes in the permeability of membrane to certain ions
- Rapidly alter membrane potential
G-protein Coupled Receptors – Muscarinic ACh receptors ?
- Receptor, G-protein and effector are separate proteins
- G protein couples receptor activation to effector modulation
- Signalling slow in comparison to transmitter-gated ion channels
Structure of G protein Coupled Receptors ?
- Receptor
o Integral membrane protein
o 7 transmembrane spans joined by 3 extra cellular and 3 intracellular connecting loops - G-protein
o Peripheral membrane protein
o 3 polypeptide subunits (alpha = binding site)
o Contains guanine nucleotide binding site which can hold GTP
How do G-protein coupled receptors work? (no signalling, turning on signal and turning off signalling)
- No signalling
o Receptor unoccupied
o G protein binds GDP
o Effector not modulated - Turning on the signal
o Agonist activates receptor
o G protein couples with receptor
o GDP dissociates from and GTP binds to alpha subunit
o G protein dissociates
o Alpha subunit combines with and modifies activity of effector
o Agonist may dissociate from the receptor, but signalling persists - Turning off the signal
o Alpha subunit acts as an enzyme to hydrolyse GTP GDP
o G protein alpha subunit recombines with the By subunit completing G protein cycle
Nicotinic Acetlycholine Receptors (Ligand-gated)?
- Consist of 5 glycoprotein subunits forming a central, cation conducting, channel
- Diverse range of subunits
- Alpha 1-10, beta 1-4, gamma, delta, epsilon
- Binding of transmitter opens gate
Cholinergic Transmission
- Uptake of choline
- Synthesis of ACh
- Storage of ACh
- Depolarisation by action potential
- Calcium influx through voltage-activated calcium channels
- Calcium induced release of ACh – exocytosis
- Activation of ACh receptors causing cellular response
- Degradation of ACh to choline and acetate by AChE which terminates transmissions
- Reuptake and reuse of choline
- Nicotine acts as an agonist – mimics the action of ACh
Cholinergic Transmission at Parasympathetic Neuroeffector Junctions
- Synthesis and storage of ACh
- Depolarisation by action potential
- Calcium influx through voltage-activated calcium channels
- Calcium induced release of ACh
- Activation of muscarinic ACh receptor subtypes (M1-M3) causing cellular response
- Degradation of ACh to choline and acetate by AChE – terminates transmission
- Reuptake and reuse of choline
What is the process of M1 receptors?
Gq – stimulates phospholipase C – increased stomach acid secretion
M2 receptors?
Gi – inhibition of adenylyl cyclase, opening of K+ channels – deacreased HR
M3 receptos?
Gq – stimulates phospholipase C – increased saliva secretion and bronchoconstriction
Noradrenergic Transmission at Sympathetic Neuroeffector Junctions
- NA synthesis and storage
- Depolarisation by action potential
- Calcium influx through voltage activated calcium channels
- Calcium induced release of NA
- Activation of adrenoceptor subtypes causing cellular response
- Reuptake of NA by transporters U1/U2
- Metabolism of NA by MAO and COMT
What do Beta 1 receptors do?
- B1 – Gs – stimulation of adenylyl cyclase – Increased HR and force
What do beta 2 receptors do
- B2 – Gs – stimulation of adenylyl cyclase – Relaxation of bronchial and vascular smooth muscle
What do alpha 1 receptors do
- A1 – Gq – stimulation of phospholipase C – contraction of vascular smooth muscle
What do alpha 2 receptors do?
- A2 – Gi – inhibition of adenylyl cyclase – inhibition of NA release
Amphetamine?
- U1 substrate
- Inhibits MAO
- Displaces NA into cytoplasm
- NA accumulates in synaptic cleft causing increased adrenoceptor stimulation
Prazosin?
- Selective, competitive antagonist of a1
- Vasodilator used as anti-hypertensive
Atenolol
- Selective, competitive antagonist of B1
- Used as an anti-anginal and anti-hypertensive agent
Atropine?
- Competitive antagonist of Muscarinic ACh receptors, does not block nicotinic ACh receptors
- Blocks parasympathetic division of ANS
- Used to reverse bradycardia post MI and in AChE poisoning
Which neurotransmitter acts on muscarinic receptors and what is its action in
the airways?
Acetylcholine, constriction of the airways
Muscarinic receptors in airway smooth muscle
cause constriction when activated.
In gastric parietal cells, which secretagogue acts on the M3 receptor?
Acetylcholine acts on M3 muscarinic receptors.
What does gastrin bind to?
Gastrin binds to G/CCK2 receptors,
What does histamine bind to?
histamine acts via H2 receptors
What is ghrelin?
is the “hunger hormone”
How does a steroid hormone work?
Binding to an intracellular receptor that then activates gene expression in the nucleus
What substance directly stimulates protein kinase A?
Cyclic AMP
What is the primary target of a statin?
liver cells - hepatocytes
What do ligand gated ion channels conduct more quickly ?
Conduct ions more quickly compared to carrier molecules
How is signalling terminated in the G protein cycle?
hydrolysis of GTP to GDP at the alpha subunit
What is the mechanism of action of glyceryl trinitrate?
Arginine is converted into a neurotransmitter that activates guanylate cyclase
How does hypotension in sepsis occur?
vasoactive mediators that are released to maintain tissue oxygenation - nitric oxide released by activated endothelium is one of the central mediators
What oncogene is tested for in breast cancer?
HER2
What is obesity a risk factor for?
Cancer
