Pharmacology Flashcards
What is pharmacodynamics?
The effect a drug has on the body- biological effects and mechanism of action)
What is pharmacokinetics?
What the body does to a drug (absorption, distribution, metabolism/excretion)
What do drugs act by binding to?
Specific target molecules
What do receptors do?
Mediate the action of hormones and neurotransmitters
What is an agonist?
A drug that binds to a receptor to produce a cellular response
What is an antagonist?
A drug that blocks the action of an agonist
What do agonists possess?
Efficacy and affinity
What is affinity?
The strength of association between a ligand and receptor
What is efficacy?
The ability of an agonist to produce a cellular response
What do antagonists possess?
Affinity not efficacy
What does increasing agonist concentration do?
Increases the number of receptors occupied
What is EC50?
The concentration of agonist that elicits a half maximal response
What is a full agonist?
Produce a maximal response
In terms of a graph of agonist concentration against response, what direction would the curve move for increased/decreased potency?
Shifting left for increased potency and right for decreased potency
In terms of a graph of agonist concentration against response, what would a taller curve show in terms of efficacy?
Increased efficacy
What is competitive antagonism?
Binding of agonists and antagonists at the same binding site and therefore is competitive (whichever binds first will elicit a response)
What is non-competitive antagonism?
The agonist and antagonist bind to different sites so it is not competitive
Can the agonist and antagonist bind at the same time?
They can bind at the same time- but activation cannot occur when the antagonist is bound
What does antagonist binding in non-competitive antagonism do?
Depresses the maximum response
What is potency?
The amount of a drug required to produce a given response (smaller potency is best)
What are the 4 main factors involved in drug movement through the body?
Absorption, distribution, metabolism, excretion
What 4 factors does drug absorption depend on?
Solubility, chemical stability, lipid to water partition coefficient, degree of ionisation
What is the relationship between rate of diffusion and lipid solubility?
As one increases, the other increases
What can unionised drugs do that ionised ones can’t?
Diffuse across the lipid bilayer
What is the pKa?
pH at which half a drug is ionised and half isn’t
When is an acid ionised?
pH>pKa
When is a base ionised?
pH
How is pKa worked out for an acid?
pH-pKa= log(AH/A-)
How is pKa worked out for a base?
pH-pKa= log (BH+/B)
Where does the absorption of weak acids take place?`
Stomach lumen
Where does absorption of bases occur?
Small intestine
Why does most absorption occur in the small intestine?
Large surface area
Which is absorbed better, weak or strong acids/bases?
Weak
What factors affect GI absorption?
GI motility, blood supply, pH, physiochemical interactions, presence of transporters, how drug is manufactured
What is oral availability?
The fraction of a drug that reaches the systemic circulation after oral ingestion
What is systemic availability?
The fraction of a drug that reaches the systemic circulation after absorption
What drugs have 100% systemic availability?
IV
What are disadvantages of oral drugs?
Some can be inactivated by enzymes/acid, GI irritation, difficulty swallowing
What is an advantage of sublingual administration?
Bypasses the portal system and first pass metabolism
When is rectal administration used?
Nocturnally or when oral is compromised
What are disadvantages of giving drugs IV?
Must be sterile, risk of sepsis and embolism
What are the disadvantages of intramuscular administration?
Painful, tissue damage, variable absorption
What is an advantage of intramuscular administration?
Rapid onset of lipid soluble drugs
What type of drugs are able to move between fluid compartments?
Free drugs
What can ionised/unionised drugs not bound to proteins do?
Move freely
What drugs move by diffusion?
Only unionised drugs
What type of drugs can move out of the plasma?
Those that are not bound
What is the apparent volume in which a drug is dissolved known as?
Volume of distribution (Vd)
How is Vd worked out?
amount of drug in body/plasma concentration
What does a Vd < 10 mean?
Drug is mainly contained in the vascular compartment
What does a Vd between 10 and 30 mean?
Drug is largely restricted to extracellular fluid
What does a Vd > 30 mean?
There is distribution throughout total body water or accumulation in certain tissues
What is the concentration a drug must reach to achieve an effect known as?
Minimum effective concentration
What is the concentration at which a drug causes significant unwanted effects known as?
Maximum tolerated concentration
Where does the ideal drug concentration lie?
Between the minimum effective concentration and maximum tolerated concentration
What is the difference between the MEC and MTC known as?
Therapeutic ratio
What is significant about having a greater therapeutic ratio?
It means the drug is safer
How is the therapeutic ratio worked out?
MTC/MEC
What is first order kinetics?
The rate of drug elimination is directly proportional to the drug concentration
How does a graph of first order kinetics fall?
Exponentially
What is the half life of a drug?
The time taken for drug concentration to fall by 50%
What does doubling the concentration of a drug NOT do?
Change the half life
What does doubling the concentration of a drug do to the duration of the drug?
Doubles it
What is clearance?
The volume of plasma cleared of a drug in unit time
What does clearance apply to?
Drugs with first order kinetics
How do you work out the rate of elimination?
Clearance x plasma conc
What are the units of clearance?
l/hr
What does clearance determine?
The maintenance dose rate
What is the maintenance dose rate?
Dose per unit time required to maintain a given plasma concentration
When is steady state concentration reached?
After approx. 5 half lives
What is an initial dose of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose known as?
The loading dose
What is the relationship between clearance and half life?
Shorter clearance= faster half life
What is meant by zero order kinetics?
Drugs are eliminated at a constant rate rather than proportional to their concentration
What two different ways can drugs be excreted in urine?
Unchanged, highly charged molecules or chemically transformed compounds rendered more polar by metabolism
Why are drugs rendered more polar before excretion?
So they are not reabsorbed by the kidneys
What other ways can drugs be excreted besides urine?
Bile, and minor ways are through sweat or milk
What organs are involved in drug metabolism?
Primarily the liver but also the GI tract, lungs and plasma
What is phase 1 of drug metabolism?
Catabolic- oxidation/reduction/hydrolysis occurs to make drugs more polar. Adds a chemical group to permit conjugation
What is phase 2 of drug metabolism?
Anabolic- conjugation, adds an endogenous compound which increases polarity
In terms of metabolism, if a drug is already polar what can it do?
Skip straight to phase 2 metabolism
Are all drugs excreted polar?
No some are excreted unchanged
Where does oxidation of lipid soluble drugs take place?
Haem proteins in the endoplasmic reticulum of liver hepatocytes and elsewhere
What are the superfamily of haem proteins classified on the basis of and what are they known as?
CYP proteins- amino acid sequence similarities
What does the first number after CYP signify?
Gene family
What does the first letter after CYP signify?
Gene subfamily
What does the second number after CYP signify?
Individual gene
What are the main gene families in the liver?
CYP1, 2 and 3
What subfamily do 50% of prescribed drugs come from?
CYP3A
What does a drug enter the complex monooxygenase P450 cycle as?
Drug substrate (RH)
What are two atoms of oxygen provided via to the dug substrate in the monooxygenase P450 cycle?
Molecular oxygen O2
What happens to the first oxygen atom in the monooxygenase P450 cycle?
Added to the drug to yield the hydroxyl product (ROH) which leaves the cycle
What happens to the second oxygen atom in the monooxygenase P450 cycle?
Combines with hydrogen to form H2O
What do phase 2 reactions usually result in?
Inactive products
Where do phase 2 reactions largely occur?
The liver
What is glucuronidation?
Common reaction in phase II involving transfer of glucuronic acid to electron rich atoms of the substrate
What are examples of endogenous substances subject to glucuronidation?
Bilirubin, adrenal corticosteroids
What is the ANS responsible for?
Carrying output from the CNS to the whole of the body except skeletal muscle
What are some involuntary visceral functions of the ANS?
Contraction/relaxation of smooth muscle, all exocrine and some endocrine secretions, heartbeat, some metabolism
What does the parasympathetic system coordinate?
The body’s basic homeostatic function
What does the sympathetic system coordinate?
The body’s response to stress
Describe the outflow and ganglionic fibre of the sympathetic system?
Thoracolumbar outflow- short preganglionic, long postganglionic
Describe the outflow and ganglionic fibre of the parasympathetic system?
Craniosacral- long preganglionic and short postganglionic
What is the postganglionic neurotransmitter in the sympathetic system?
Usually noradrenaline
What is the postganglionic neurotransmitter in the parasympathetic system?
Acetylcholine
What is the preganglionic neurotransmitter for all of the ANS?
Acetylcholine
What does noradrenaline activate in target cell membranes to produce a cellular response?
G protein coupled adrenoceptors
What does acetylcholine activate in target cell membranes to produce a cellular response?
G protein coupled muscarinic acetylcholine receptors
What do ligand gated ion channels consist of?
Separate glycoprotein subunits that form a central, ion conducting channel
What do ligand gated ion channels allow?
rapid changes in the permeability of the membrane to certain ions and rapid changes in membrane potential
What are the 3 separate proteins of GPCRs?
Receptor, G protein, effector
What occurs after G protein coupling?
receptor activation and effector modulation
Describe the structure of the receptor protein
Integral membrane protein. A single polypeptide chain with extracellular NH2 and intracellular COOH. There are 7 transmembrane spans with 3 extra and 3 intracellular connecting loops
Describe the structure of the G protein
Peripheral membrane protein. 3 polypeptide subunits (alpha, beta, gamma)
What does the alpha subunit of a G protein contain?
Guanine nucleotide binding site that can hold GTP or GDP
What happens to the receptor, G protein and effector when there is no signalling?
Receptor unoccupied, G protein alpha subunit binds GDP, effector not modulated
When a signal is on, what happens once the G protein has coupled the receptor?
GDP dissociates and GTP binds to the alpha subunit, G protein dissociates to alpha and beta-gamma subunits,
What subunit combines with and modulates the activity of the effector when a signal is on?
Alpha
If an agonist dissociates from a receptor, what can happen?
Signalling can persist
What does the alpha subunit act as when the signal is off?
GTPase to hydrolyse GTP to GDP + Pi to turn signal off
What happens to the alpha subunit when the signal is off?
It binds with the beta-gamma subunit again
What are receptors which contain 5 glycoprotein subunits that form a central cation conducting channel?
Nicotinic acetylcholine receptors
What is cholinergic transmission activated by?
Synthesis of acetylcholine by choline acetyl transferase
What is cholinergic transmission terminated by?
Degradation of acetylcholine into choline via acetylcholinesterase
What do M1 muscarinic ACh receptors do and how?
Increase acid secretion through stimulation of phosphoesterase C
What do M2 muscarinic ACh receptors do and how?
Decrease heart rate through inhibition of adenyl cyclases and opening of K+ channels
What do M3 muscarinic ACh receptors do and how?
Increase secretion from the mouth and contract bronchiolar smooth muscle through stimulation of phosphoesterase C
What do beta1 adrenoceptors do and how?
Increase heart rate and force through stimulation of adenyl cyclase
What do beta2 adrenoceptors do and how?
Relaxation of bronchial/vascular smooth muscle via stimulation of adenyl cyclase
What do alpha1 adrenoceptors do and how?
Contraction of vascular smooth muscle through stimulation of phosphoesterase C
What do alpha2 adrenoceptors do and how?
Inhibition of noradrenaline release through inhibition of adenyl cyclase
What is prazosin?
Selective, competitive antagonist of alpha1 which acts as an anti-hypertensive
What is atenolol?
Selective, competitive antagonist of beta1 which acts as an anti-hypertensive and anti-anginal
