Pharmacology Flashcards
What is pharmacodynamics?
what a drug does to the body so the biological effects and the mechanism of action
What is pharmacokinetics?
what the body does to a drug so the absorption, distribution, metabolism and excretion
What is an agonist?
a drug that binds to a receptor to produce a cellular response
What is an antagonist?
a drug that reduces or blocks the actions of an agonist by binding to the same receptor
What is affinity?
the strength of the association between a ligand and a receptor which is covered by binding and unbinding rate (latter is more significant) and chemical bonds between the ligand and receptor
What is efficacy?
the ability of an agonist to evoke a cellular response
Do antagonists have affinity or efficacy?
affinity but not efficacy as they don’t activate receptors
What is the relationship between receptor occupancy and agonist concentration?
hyperbolic
What is EC50 equal to?
the concentration of agonist that elicits a half maximal response
What happens to the receptor occupancy against agonist concentration graph if you make it semi-logarithmic?
it will be sigmoidal shape which is easier to use to calculate EC50
What does a lower or higher EC50 say about the potency of an agonist?
lower EC50 is more potent
higher EC50 is less potent
What does a higher maximal response say about the efficacy of an agonist?
- higher percentage maximum response is more efficacy so a full agonist
- lower percentage maximum response is lead efficacy so a partial agonist
What does equipotent mean?
the two drugs have equal potency but not necessarily efficacy so same horizontal reach along the graph
What is reversible competitive antagonism and what is it overcome by?
competition for the same arthosteric site and can be overcome by increasing agonist concentration
What is non-competitive antagonism?
binds to allosteric site and activation can’t occur when antagonist is bound
What does a competitive antagonist do to the sigmoidal graph?
rightward shift but no change in the maximum reached
What does a non-competitive antagonist do to the sigmoidal graph?
causes a depression of the slope but no sideways shift
What does an increasing concentration of antagonist do to the change in the graph?
- increased concentration of competitive gives a greater rightward shift
- increased concentration of non-competitive gives a greater depression
What are receptors the targets of?
neurotransmitters
hormones
other mediators and therapeutic agents
What do autocrine, paracrine and endocrine cells signal to?
- autocrine signal to itself
- paracrine signal to close neighbours
- endocrine signal over long distances using the blood
What are the four types of receptors?
- Type 1: ligand-gated ion channels/ inotropic
- Type 2: G protein-coupled receptors/ metabotropic
- Type 3: kinase-linked receptors/ enzyme-linked
- Type 4: nuclear receptors
What are the features of type 1 receptors?
- ligand-gated
- ionotropic
- on plasma membrane
- react quickly to hydrophilic signalling molecules
What are the features of type 2 receptors?
- G protein-coupled receptors
- metabotopic
- on plasma membrane
- react slowish to hydrophilic signalling molecules
What are the features of type 3 receptors?
- kinase-linked receptors
- enzyme-linked
- on plasma membrane
- slow reactions to hydrophilic protein mediators
What are the features of type 4 receptors?
- nuclear receptors
- intracellular
- targeted by hydrophobic signalling molecules
- very slow reactions
What are ion channels regulated by?
signals that cause channel to alternate between conducting and non-conducting states
What can ion channels be gated by?
- chemical signals
- transmembrane voltage
- physical stimuli
What is the main example of a ligand-gated ion channel?
- ACh receptor
- five subunits making a channel and rapid changes
- agonist binds, channel opens and ions flow down a gradient
How does signalling via a second messenger work?
eg GPCRs
- enzyme effectors increase or decrease the rate of synthesis of second messenger
- ion channel effectors cause changes in membrane electrical properties
What are GPCRs made up of?
- Receptor: integral membrane protein, 7 transmembrane spans, two together make a dimer
- G-protein: peripheral membrane protein, 3 polypeptide subunits, binding site holds GTP or GDP
How does GPCR activation occur?
- GDP is in binding site of alpha subunit in the inactive state
- activated by agonist binding to GPCR to which they couple
- alpha and gamma are covalently bound by lipid and beta is paired to gamma
- alpha contains GTPase with Raw and AH (to clamp nucleotide) domains
- activation by agonist causes conformational change so GDP released and GTP binds
- alpha and betagamma separate to give GTP-bound alpha subunit and betagamma dimer
What are the states that a GPCR can be in?
- no signal: receptor unoccupied, G protein alpha subunit binds GDP
- signal on: GDP off, GTP on, alpha and betagamma separation, alpha combines with effector
- signal off: alpha acts as enzyme to hydrolyse GTP to GDP, alpha recombines with betagamma
How does the process of heart rate change with Gi and Gs occur?
- M2 ACh activates Gi which stops ATP to cAMP by adenyl cyclase so decreased HR and force of atria
- beta 1 adrenoceptor activated Gs which activates ATP to cAMP by adenylyl cyclase, cAMP then activated protein kinase A so increased HR and force of atria and ventricles
How does Gq cause muscle contraction?
- alpha 1 adrenoceptor activates Gq which activates PLC making DAG
- activates PKC
- PLC converts PIP2 to IP3 so Ca2+ released from ER
What is an example of signalling by receptor kinase?
insulin binding causes autophosphorylation of intracellular tyrosine
What does signalling via nuclear receptors do?
switch on or off genes to change mRNA levels and rate of synthesis
What are the four mechanisms of drug disposition?
absorption
distribution
metabolism
excretion
Whats involved in the process of absorption?
process of a drug entering the body from its site of administration
What is involved in the process of distribution?
process of a drug entering the blood, tissues and then distribution within the tissues
What is involved in the process of metabolism?
tissue enzymes catalyse the conversion of drug to a less active and more polar form that can be readily excreted
What is excretion?
removing a drug by kidneys or another route
What do metabolism and excretion come together to form?
elimination
What are the factors influencing drug absorption?
- solubility: drug must first dissolve before absorption
- chemical stability: some drugs are destroyed by acid in the stomach or by enzymes in the GI tract
- lipid to water partition coefficient: rate of diffusion increases with lipid solubility of the drug
- degree of ionisation: only the unionised form of a drug readily diffuses across the bilayer, depends on pKa of drug and local pH
What conditions ionise acidic or basic drugs more?
acidic drugs are less ionised in acid and basic drugs are less ionised in base
What are the factors affecting GI absorption?
- GI motility
- pH at absorption site
- blood flow to stomach
- way that tablet is manufactured
- physciochemical interactions
- presence of transporters
What is oral availability?
the fraction of the drug that reaches the systemic circulation after oral ingestion
What is systemic availability?
the fraction of the drug that reaches that systemic circulation after absorption
What are the main routes of administration?
- Enteral: Oral Sublingual Rectal - Parenteral: IV IM SC Inhaled Transdermal Topical
What are the four main compartments for body water?
plasma
interstitial
intra-cellular
transcellular
What drugs move readily in the body?
- ionised and unionised drugs that aren’t bound to plasma proteins
- unionised in any form
What is the volume of distribution?
apparent volume in which a drug is dissolved
What does a Vd<10 mean?
the drug is in a vascular part and is too large to cross capillary walls or too bound to plasma proteins
What does a Vd 10-30 mean?
the drug is in the extracellular space so drugs with low lipid solubility
What does a Vd>30 mean?
there is distribution throughout total body water, for highly lipid soluble drugs or those that are very bound to tissue proteins
How do drugs leave the body?
in the urine
rendered more polar bu metabolism or unchanged
What does drug metabolism do?
changes drugs to more polar metabolites or less active compounds
What is the main organ of drug metabolism in the body?
liver
What is phase 1 of drug metabolism?
oxidation, reduction, hydrolysis which makes the drug more polar and adds a chemically reaction group permitting conjugation
What is phase 2 of drug metabolism?
conjugation which adds an endogenous compound to increase polarity
What are the steps in drug metabolism?
Drug –phase1–> Derivative –phase2–> Conjugate
What type of reaction is phase 1 and why is this important?
phase 1 are catabolic and introduce a part that can be attacked in phase 2
Where do the two phases take place?
liver
What is the CYP450 monooxygenase cycle?
drug enter
molecular oxygen provides two O atoms
one O added to the drug
other O makes water
Why does CYP450 change in different people?
individual variation and environmental factors
What are the features of phase 2 reactions?
result in inactive products
happen in the liver
glucuronidation occurs frequently
What are the processes in excretion?
glomerular filtration
active tubular secretion
passive reabsorption by diffusion
What do molecules have to be to enter the filtrate?
must be unbound to enter filtrate via glomerular filtration
What are the transporters that secrete drugs into the lumen of the nephron?
- Organic anion transporter
- Organic cation transporter
What so OAT and OCT transporters do?
- move drugs against electrochemical gradient
- each has a transport maximum
- can secrete highly-bound drugs
- some drugs compete for the sam etransporter
What are the factors influencing reabsorption of drugs?
lipid solubility
polarity
urinary flow rate
urinary pH
What does an alkaline or acidic pH do the the excretion of fluids?
alkaline pH increases exertion of acids
acidic pH increases excretion of bases
What is the therapeutic window?
sits in between the maximum tolerates concentration and the minimum effective concentration
What does a high or low therapeutic ratio mean?
high = safe low = unsafe
What is Ke?
the fraction of the amount of drug eliminated per unit time
What is first order kinetics?
the rate of elimination is directly proportional to the drug concentration so the graph will curve down
What changes the concentration in first order kinetics?
does administered changes it but not the time or how fast the elimination occurs
What is clearance?
the volume of plasma cleared of drug in unit time
What does clearance determine?
the dose rate
What happens at steady state?
the rate of drug administration = the rate of drug elimination
What is time to reach steady state determined by?
half-life not infusion rate
What is oral availability?
fraction of the administered dose that reaches the systemic circulation
What is the volume of distribution?
the volume into which a drug appears to be distributed with a concentration equal to that of plasma
How is loading dose estimated?
from the Vd of the drug
What is zero order kinetics?
drug is eliminated at a constant rate so the graph goes straight diagonally down
What order is elimination?
zero order then changes to first order at a lower concentration
What is plasma steady-state concentration not related to?
not linearly related to dose rate
What is depolarisation?
the membrane becoming less negative
What is hyper polarisation?
the membrane potential becoming more negative
Which way does Na+ move?
in because concentration gradient and electrical gradient are both inward
Which way does K+ move?
out because outward concretion gradient is larger than inward electrical gradient
What happens when Na+ or K+ channels are opened?
the gradient shifts toward Ena or Ek respectively
What are action potentials?
electrical signals where nerve cell membrane polarity is reversed momentarily
What are the features of Na+ channel activation?
it is self-reinforcing with positive feedback
What are the features of K+ channel activation?
it is self-limiting with negative feedback
What happens to Na+ channel after they have been activated?
they become inactive and go into refractory period so they can be closed and ready to open again
What is the absolute refractory period?
no stimulus can make an AP
What is the relative refractory period?
a very strong stimulus can make an AP as there is some inactivated and some closed and the membrane is hyperpolarised
What characteristics does a less leaky axon have?
greater the local current spread so increased AP conduction velocity
What increases passive current spread?
increased axon diameter
decreased leak by adding Schwaan in PNS or oligodendrocyte in CNS
How is conduction spread in unmyelinated or myelinated axons?
unmyelinated is by passive spread of current
myelinated is by saltatory conduction
What does the ANS do?
contraction and relaxation of smooth muscle heart rate and force secretions metabolism immune system regulation
What is the structure of the motor ANS?
synapse in the autonomic ganglion
What neurotransmitter is used in the sympathetic conduction?
preganglionic is ACh
postganglionic is NA
What neurotransmitter is used in the parasympathetic conduction?
both preganglionic and postganglionic are ACh
What is the structure of the sympathetic nerve chain?
short preganglionic which synapse at paravertebral or prevertebral ganglia
postganglionic are long
What is the structure of the parasympathetic nerve chain?
long preganglionic that are in the walls of the organ
postganglionic are short
What is sympathetic outflow?
thoracolumbar to the sympathetic chain
What is parasympathetic outflow?
craniosacral (CN3,7,9,10 and S2-4)
What is chemical transmission in ANS sympathetic?
- AP makes Ca2+ move in and ACh out by exocytosis
- ACh opens LGIC so depolarisation and Ca2+ entry and NA release
- NA activates GPCR so cellular response
What is chemical transmission in ANS parasympathetic?
- ACh is always neurotransmitter
- ACh activates GPCR (muscarinic ACh) to cause cellular response
What is NANC?
non-adrenergic non-cholinergic transmission
What are the neurotransmitters used in sympathetic NANC?
sympathetic:
ATP rapid
NA intermediate
NPY slow
What are the neurotransmitters used in parasympathetic NANC?
parasympathetic:
ACh rapid
NO intermediate
VIP slow
What are the two types of ACh cholinceptors?
- nicotinic = LGICs
- muscarinic = GPCRs, M1-5
What are NA or A receptors?
GPCRs
What does the sympathetic ANS do?
- increase HR and force in atria and ventricles
- relaxes bronchi and decreases mucus
- decreases intestinal motility and constricts sphincters
- increases release of adrenaline
- relaxes bladder
- ejaculation
What does the parasympathetic ANS do?
- decreases HR and force in atria
- constricts bronchi and increases mucus
- increases intestinal motility and relaxes sphincters
- contracts bladder
- erection
What are nicotinic ACh receptors made up of?
subunits
How can cholinergic transmission be blocked?
- competitive antagonism
- non-competitive antagonism
- depolarisation blocking
What is ganglionic transmission blocked by?
hexamethonium which does open channel block which in non-competitive
What are the types of M receptor for parasympathetic and their role?
M1- Gq- phospholipase C stimulation- increased acid secretion
M2- Gi- inhibition of adenylyl cyclase, opening of K+- decreased rate of heart
M3- Gq- phospholipase C stimulation- increased secretion in mouth and contraction of visceral smooth muscle in lungs
What are the types of M receptor for sympathetic and their role?
beta 1- Gs- stimulation of adenylyl cyclase- increase rate and force of heart
beta 2- Gs- stimulation of adenylyl cyclase- relaxation of bronchial and vascular smooth muscle
alpha 1- Gq- phospholipase C stimulation- contraction of vascular smooth muscle
alpha 2- Gi- inhibition of adenylyl cyclase- inhibition of NA release
