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Receptor definition
(a) receptors determine the dose-response relationship(b) are responsible for drug selectivity(c) they mediate the actions of drug agonists and drug antagonists TERM 2
Types of receptors
DEFINITION 2 regulatory proteins,enzymes,transport proteinsstructural proteins Lipid soluble drug directly on intracellular target.Activate intracellular enzyme domain.Activate intracellular tyrosine kinase.Ion gated channel.G Protein coupled receptor. TERM 3
Dose-response relationship (drug binds to
receptor and produces biological effect) =
hyperbolic curve
DEFINITION 3 at higher doses the curve flattens out and additional drug produces no further biological response Kd =drug concentration at which receptor occupancy is half maximalEC50 = drug concentration at which biological effect is half maximalDose response plots (Fig 2-2): drug effect (ordinate) against log dose concentration (abscissa) TERM 4
Spare receptor concept
DEFINITION 4 maximal biological response provided by a drug dose that does not result in all available receptors being occupied.4 receptors + 4 drug molecules = no spare receptors Kd is 50% max response Kd caused when 2 drug molecules bind40 receptors + 4 drug molecules = Kd is still 50% max response Kd still caused by 2 drug molecules bindingmany spare receptorschanges in receptor concentrations (numbers) changes the sensitivity of the tissues to the drug concentration TERM 5
Reversible Competitive Antagonistis
DEFINITION 5 propranolol (beta blocker antagonist) pushed off the receptor byincreasing concentrations of the endogenous ligand (epinephrine)propranolol at daily dose X works well to lower blood pressurewhen patient is under stress or exercises too much the increasedoutput of epinephrine replaces the drug and produces a biologicalresponse (increase blood pressure)
Irreversible Antagonists
May bind to receptor through covalent attachmentendogenous ligand can not knock off the drug phenoxybenzamine binds to alpha receptors and blocks the binding of excess epinephrine produced by a tumor of the adrenal gland (a pheochromocytoma). TERM 7
Partial Agonist
DEFINITION 7 drug produces lower response even when all receptors are occupied compared to a full agonist buprenorphine safer analgesic compared to morphine because itproduces less respiratory depression even at high doses (lessdanger of overdose). TERM 8
Chemical
antagonism
DEFINITION 8 drug A binds to Drug B and neutralizes the effects protamine binds to heparin and reverses heparin overdose (bleeding) TERM 9
Physiological
antagonism
DEFINITION 9 drug actions at one receptor type neutralizes(counteracts) the effects of an endogenous ligand at other receptor types insulin (the drug) counteracts the increase in blood glucose due to the actions of endogenous glucocorticoid hormones (natural andsynthetic, drug, glucocorticoids increase glucose levels) TERM 10
Intracellular Receptors
DEFINITION 10 (lipid soluble drug passes into cell and binds to cytoplasmic and/or nuclear receptors). also called gene-active receptorsmost drugs that use this type of receptor initiate transcription factors through release of inhibitory factors on the gene (regulators of gene expression) Ex: steroids (cortisol etc), thyroid hormones, vitamin Dresult is protein synthesis which takes 30 min to hourslag time characterizes the dose and the effectbiological effect can remain for days after the drug has left the system, the protein produced remains until it is removed from the body and its the protein which is producing the biological effectEx: corticosteroids for relieving joint pain an inflammation
Receptor Regulation
desensitization and/or receptor down regulation leads to reducedresponse to the usual drug dose after repeated administration TERM 17
cAMP Second Messenger
DEFINITION 17 cAMP acts through activation of an intracellular cAMP dependent protein kinasecAMP degraded by phosphodiesterase enzymes TERM 18
Quantal Dose Response Curves
DEFINITION 18 Unlike the graded dose response (Ex: blood pressure) the quantal dose response curve reduces all data to quantal (yes/no) results. For example a reduction in blood pressure of 10 mm Hg systolic is a Yes and less than10 mm Hg is a No. Quantal dose response curves apply to populations, a graded dose response applies mostly to individuals. Quantal dose response used to calculate LD50, therapeutic index (TI), TERM 19
Variation in drug response
DEFINITION 19 (a) Idiosyncratic drug response: allergy, genetics, unknown(b) Hyporeactive(c) Hypereactive(d) Tolerance develops after repeated dosing(e) Tachyphylaxis develops after the first couple of doses and diminishes rapidly TERM 20
Mechanisms that help explain variation in
drug response
DEFINITION 20 Altered drug concentration that reaches the receptor Variation in endogenous receptor ligands Alterations in receptor number or function
Variation in endogenous receptor
ligands
(epinephrine levels between patients and within the same patient at different times) saralsan blocks angiotensin II receptors, angio II can not bind, blood pressure is lowered but only in patients whose angioII levels are elevated. Saralsan raises blood pressure if angio II levels are normal. TERM 22
Alterations in receptor number or
function
DEFINITION 22 thyroid hormone excess increases beta receptor number, thismakes patient more sensitive to endogenous catecholamines, blood pressure increases, treat with a beta blocker drug ( propranolol). Note: down- regulation = reduced receptor number densensitization = reduced drug coupling efficiency up-regulation = increased number of receptorsGenetic factors (pharmacogenomics) can cause alterations in receptor number and function. Changes in components of response distal to the receptor (the most important and largest of all the reasons) cause is most often wrong drug for the condition, wrong diagnosis. TERM 23
Up-regulation
DEFINITION 23 a drug causes increase in the number of receptors,when the drug is stopped, the endogenous ligand causesa dramatic increase in the response (exaggerated response to a normal endogenous ligand conentration) TERM 24
Down-regulation
DEFINITION 24 a drug can induce reduced number of receptors, when drug is discontinued the number of receptors is too low for the endogenous ligand to produce a normal response. Clonidine an alpha2 receptor binder lowers blood pressure by blocking the outflow of norepinephrine (NE) in the CNS. The drug also reduces receptor number. When the drug is abruptly stopped a hypertensive crisis can occur because the resumption of NE outflow has reduced number of receptors to bind to, all receptors are filled with NE and blood pressure increases dramatically. TERM 25
Drug
Selectivity
DEFINITION 25 most drugs will not bind to only one specific type of receptor (side effects)any one single type of receptor is coupled in biological function to a wide (unknown number) of other biological processes
AGONIST
drug binds and activates the receptorhave high affinity for the Ra form of a receptor TERM 32
Full agonist
DEFINITION 32 drug binds and converts most of the receptors to the Ra form TERM 33
Partial agonist
DEFINITION 33 drug binds but can not shift the pool to mostlyRa form no matter how much drug is given themaximum response (in the patient) cannot be obtained TERM 34
Inverse agonist
DEFINITION 34 drug binds with greater affinity to the Ri form ofthe receptor the Ri pool is stabilized TERM 35
Pharmacologic antagonist
DEFINITION 35 drug binds to a receptor and prevents (blocks) other molecules from binding
Competitive antagonist
drug binds to a receptor but it can be removed by increasing concentrations of another drug (agonist)beta blocker drug at usual dose blocks receptors (antagonist) but is overcome (knocked off receptor) when patient is under great stress and produces much more than usual epinephrine (agonist), patients bp goes up. TERM 37
Irreversible antagonist
DEFINITION 37 drug binds and nothing can take it off phenoxybenzamine (irreversible antagonist) lowers bp even when a tumor in thepatient is surging out large amounts of epinephrine (special case). TERM 38
Special Types of Antagonists do not involve
typical receptors -chemical antagonist
DEFINITION 38 drug (chemical) binds to another drug(chemical) and blocks its actions protamine binds to and stops the actions of heparin EDTA binds to and stops the actions of lead TERM 39
Special Types of Antagonists do not involve
typical receptors -physiological antagonist
DEFINITION 39 insulin lowers blood glucose which has risen due to steroid administrationhere one drug (insulin) acts through a different physiological pathway (the individual body cells) to lower the blood glucose which was elevated due to the actions of the steroid on the liver. TERM 40
Causes of Variation in Drug Response
DEFINITION 40 Alteration of drug concentration that reaches the receptor.Changes in concentration of endogenous receptor ligand.Changes in number or function of receptors.Changes in components of response distal to target receptor.
Ligand
molecule that binds to receptor TERM 47
Specificity
DEFINITION 47 Atropine binds to Ach receptor only TERM 48
Affinity
DEFINITION 48 Strength of drug binding TERM 49
Selectivity
DEFINITION 49 Atropine binds to Ach receptors in exocrine glands and smooth muscle but not on skeletal muscle TERM 50
Five mechanisms of Drug Action
DEFINITION 50 Lipid soluble drug crosses membrane. Drug binds to outside face, allosteric enzyme activation. As in (2), enzyme is tyrosine kinase. Drug binds to outside face, alters ion channel. Drug binds outside stimulates intracellular message through G-Protein
Potency &
Efficacy
Potency is a comparative measure of the two doses of two different drugs required to produce the same effect.Efficacy is the maximum effect of a drug andClinically more important than potency when selecting patient drugpotency determines patient dose TERM 52
Therapeutic Range (Window)
DEFINITION 52 Therapeutic Range or Window is also sometimes called the Therapeutic Index but is different.Therapeutic Range is the range of Cp within which the drug will have maximum effect. Theophylline 10 - 20 ug/mL Digoxin 0.8 - 1.2 ng/mL TERM 53
Therapeutic Index
DEFINITION 53 The Therapeutic Index (TI) of a drug is a measure of the drugs toxicity.The TD50 = dose that is toxic in 50% of the animals that receive it. (Death is the ultimate toxicity)TI = LD50/ED TERM 54
Quantal Dose Response -
DEFINITION 54 ED50 now means the median effective dose at which 50% of patients exhibit the quantal effect.TD50 the median toxic dose, the dose that produces toxicity in 50% of the patients TERM 55
Quantal Dose Response -
DEFINITION 55 Used when response is digital instead of sigmoid dose-effect curves. Digital involves Yes/No response to drugs (headache gone, infection gone, seizures, increase in heart rate by 20 beats/minute etc.Used for population response.Population Gaussian distribution produced.ED50 and LD calculated.Margin of SafetyTherapeutic Index
Five Types of Transmembrane Signaling
Lipid-soluble drug crosses membrane and binds to intracellular receptors. Drug binds to outside membrane receptor and allosterically regulates intracellular enzyme Similar to (2) and enzyme is tyrosine kianse Drug opens or closes transmembrane ion channel. Drug binds to receptor and stimulates a G Protein which produces an intracellular second messanger. TERM 62
Intracellular Receptors
DEFINITION 62 N itric Oxide (NO) stimulates intracellular enzyme guanylyl cyclase which produces second messanger cGMP. Corticosteroids binds to intracellular DNA regulator proteins which alter and allow protein transcription to initiate. Drugs take hours to product effect and effects may last for days.Drugs highly lipid soluble.Action often regulates gene expression.Lag time 30 min to hours.Effects last for days after drug removed TERM 63
Ligand-Regulated Transmembrane Enzymes
DEFINITION 63 Insulin binds receptor.Insulin receptor consists of transmembrane polypeptide chain which inside the cell has enzyme attached.Insulin binding activates the intracellular enzyme TERM 64
Cytokine Receptors
DEFINITION 64 Growth hormone, interferon, IL2 etc (same actions as (2) but intracellular enzyme is tyrosine kinase which is not attached to the receptor polypeptide chain. Tyrosine kinase from Janus-Kinase (JAK) family of proteins. TERM 65
Ligand Gated Ion
Channels
DEFINITION 65 Ach, 5HT, GABA bind to their receptors and open ion channels.Ach opens AchR channels and sodium flows into muscle cell.
G Protein Coupled Receptors
Also called serpentine receptors.Actions are to increase intracellular Calcium, or cAMP, or phosphoinositides.Three parts to these receptors (a) extracellular receptor (b) G Protein on inner face of the membrane (c) Activated G protein activates an enzyme or opens/closes an ion channel. TERM 67
G-Protein Coupled Receptors
DEFINITION 67 drug binds to extracellular domain, activates an intracellular G-protein in the cytoplasmic side of the membranethese receptors are called serpentine receptors because of theirstructure (see Fig 2-11)the active G-protein then activates an enzyme or ion channel (theeffector)as many as 40% of all prescription drugs act through this type of receptor
