Pharmacodynamics Flashcards
1
Q
What is pharmacodynamics
A
It is the study of the biochemical and physiological effects of drugs and their mechanisms of action at organ level and cellular level
Also a study of dose/effect relationship
Also it is modification of action of one drug by another drug.
2
Q
What are the 2 states a receptor can be in
A
active (Ra) & inactive (Ri) which are in equilibrium.
3
Q
What shifts the equilibrium of the receptor
A
Binding to a drug shifts the equilibrium to either direction
4
Q
What’s a ligand
A
any molecule which attaches selectively to particular receptors.
5
Q
What’s affinity
A
The strength of the reversible interaction between a drug and its receptor, as measured by the dissociation constant, is defined as the affinity of one for the other.
6
Q
What is intrinsic activity
A
capacity of a drug to induce a functional change in the receptor.
7
Q
What is specificity
A
A drug that interacts with a single type of receptor that is expressed on only a limited number of differentiated cells will exhibit high specificity.
the measure of a receptors ability to respond to a single ligand
8
Q
What are agonists
A
Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds
9
Q
What are primary agonists
A
drugs that bind to the same recognition site as the endogenous agonist (the primary or orthosteric site on the receptor)
10
Q
What’s a primary agonist
A
drugs that bind to the same recognition site as the endogenous agonist (the primary or orthosteric site on the receptor)
11
Q
Difference between selectivity and specificity
A
Selectivity is the degree to which a drug acts on a given site relative to other sites while Specificity is the measure of a receptors ability to respond to a single ligand
12
Q
What’s an allosteric agonist
A
bind to a different region on the receptor referred to as an allosteric site.
13
Q
What’s an allosteric agonist
A
Agonist that bind to a different region on the receptor called an allosteric site
14
Q
What’s an antagonist
A
Drugs that block or reduce the action of an agonist are termed antagonists.
15
Q
What is a syntopic interaction
A
competition for the same or overlapping site on the receptor
16
Q
What are the types of agonists
A
Inverse
Partial
17
Q
What are physical antagonists
A
Antagonists that bind to the drug and prevents its absorption
18
Q
Example of physical antagonist
A
Charcoal binding to alkaloids to prevent absorption
19
Q
What are chemical antagonists
A
antagonists that combines with an agonist chemically like chelating agents binds with the metals
This antagonism is the combination of agonists with antagonists, with resulting inactivation of the agonists
20
Q
What are physiological antagonist
A
Physiological antagonist produces an action opposite to a substance but by binding to the different receptors e.g. adrenaline is a physiological antagonist of histamine because adrenaline causes bronchodilatation by binding to β2 receptors, which is opposite to bronchoconstriction caused by histamine through H1 receptors
21
Q
What is a partial agonist
A
Agents that are only partly as effective as agonists regardless of the concentration employed.
22
Q
What are inverse agonists
A
Many receptors exhibit some constitutive activity in the absence of a regulatory ligand; drugs that stabilize such receptors in an inactive conformation are termed inverse agonists (produce effect opposite to that of agonist).
23
Q
What is Efficacy
A
A maximal effect (Emax) an agonist can produce.
24
Q
How is efficacy mead
A
measured with a graded dose-response curve only.
25
What is potency
The amount of the drug needed to produce a given effect.
26
What determines potency
affinity of the receptor for the drug.
27
What is EC50 and how is it gotten
The dose causing 50% from the maximal effect and can be obtained from graded dose-response curve.
28
What’s ED50, TD50 and LD50
ED50 is the dose causing an effect in 50% of the population (mean effective dose)
TD50 is the dose causing therapeutic effect in 50% of the population (mean therapeutic dose)
LD50 is the dose causing lethality in 50% of the population (mean lethal dose)
29
In what I’m what graph do you see TD50, ED50, LD50
quantal dose response curve
30
What is Tolerance
Repeated administration of a drug results in diminished effect
31
What is tachphylaxis
a type of tolerance which occurs very rapidly.
32
What is desensitization
decreased response to the agonist after its repeated injection in small doses.
33
What could be the cause of tolerance
1- Masking or internalization of the receptors.
2- Loss of receptors (down regulation)- decreased synthesis or increased destruction.
3- Exhaustion of mediators (depletion of catecholamine).
34
What is synergism
When the action of one drug is facilitated or increased by the other, they are said to be synergistic.
35
What is additive
The effect of the two drugs is in the same direction and simply adds up:
effect of drugs A + B = effect of drug A + effect of drug B
36
Give 5 examples of additive drug combinations
1. Aspirin + paracetamol = as analgesic / antipyretic
2. Nitrous oxide + halothane = as general anaesthetic
3. Amlodipine + atenolol = as antihypertensive
4. Glibenclamide + metformin = as hypoglycaemic
5, Ephedrine + theophylline = as bronchodilator
37
What’s Supra additive
The effect of combination is greater than the individual effects
of the components:
effect of drug A+ B > effect of drug A+ effect of drug B
This is always the case when one component is inactive as such
38
Give 6 examples of Supra additive drugs
Acetylcholine + physostigmine = Inhibition of breakdown (treat antimuscarinic toxicity)
Levodopa + carbidopa/benserazide = Inhibition of peripheral metabolism (treat Parkinson’s $
Adrenaline + cocaine/desipramine = Inhibition of neuronal uptake (of adrenaline) (intranasal vasoconstriction)
(5) Sulfamethoxazole + (1) trimethoprim = Sequential blockade
(Treat bacterial infections)
Antihypertensives (enalapril+hydrochlorothiazide) = Tackling two
contributory factors
Tyramine + MAO inhibitors = Increasing releaseable CA store
39
What are the types of antagonists mists
Competitive and non competitive
40
Give 6 characteristics of competitive antagonist
•Same binding site as of agonist
•resembles chemically with agonist
•Right shift of DRC
•Surmountable antagonism by increasing agonist dose
•Inactivation of certain agonist molecules
•Response depends on concentration of both
41
Give 2 examples of competitive antagonists
1. Ach – Atropine,
2. Morphine - Naloxone
42
Give 6 characteristics of non competitive inhibitors
•Different binding site as of agonist.
•Not resembles chemically with agonist.
•Flattening/downward shift of DRC.
•Unsurmountable antagonism (Maximum response is suppressed).
•Inactivation of certain receptors.
•Maximum response depends on concentration of antagonist
43
Give 2 examples of non competitive antagonists
1. ketamine -NMDA-glutamate receptor.
2. Diazepam - Bicuculline
44
Give 6 examples of physiological receptors
•GPCR
•Ion channels
•Transmembrane enzymes
•Transmembrane, non-enzymes
•Nuclear receptors
•Intracellular enzymes
45
What are Cellular Pathways Activated by Physiological Receptors
Signal Transduction Pathways
46
What are the 2 major functions of the physiologic receptors
ligand binding and message propagation
47
What are the 2 functional domains within the receptor
-ligand-binding domain and
-effector domain.
48
How are the regulatory functions of a receptor exerted
may be exerted •directly on its cellular target(s), on effector protein(s), or may be conveyed by •intermediary cellular signaling molecules called transducers.
49
What are the functional family under ion channels
Ligand gated
Voltage gated
50
What are physiological ligands under ligand gated
GABA,
5-HT3, nicotinic cholinergic, glycine, NMDA
51
What are effectors and transducers for ion channels
Na*, Ca?*, K*, CI-
52
Example of drugs with ligand gated ion channel
Nicotine,
gabapentin
53
What are physiological ligands under voltage channel
None (activated by membrane depolarization)
54
Effectors and transducers for voltage channel
Na*, Ca?*, K*, other ions
55
Drugs with voltage gated ion channels
Lidocaine, verapamil
56
Drugs with voltage gated ion channels
Lidocaine, Verapamil
57
What are Receptors with intrinsic ion channel
Ligand gated ion channels.
58
Give 2 characteristics of receptors with intrinsic ion channels
•No intervention of G-protein or second messenger.
•Response is fastest (in milliseconds)
59
Give 5 examples of receptors with intrinsic ion channels
5HT3, GABA, glycine, Ach(N), NMDA
60
In the voltage activated Na channels, what open and closes it
Depolarization opens it, leading to an influx of ions, the depolarization closes it
61
Describe the structure of the nicotinic cholinergic receptor
The five receptor subunits (α2, β, γ, δ) form a cluster surrounding a central transmembrane pore.
Each subunit have a large extra cellular domain, and four trans membrane helices
62
What are the functional families under GCPR
β Adrenergic receptors
Muscarinic cholinergic receptors
Eicosanoid receptors
63
Physiological ligands of β Adrenergic receptors
Epinephrine
Norepinephrine
DA
64
Physiological ligands under Muscarinic cholinergic receptors
Ach
65
Physiologic ligands under Eicosanoids
Prostaglandin
Thromboxane
Leokotrianes
66
Physiologic ligands under Eicosanoids
Prostaglandin
Thromboxane
Leoktrienes
67
Transducers for β Adrenergic receptors
Gs:AC
68
Transducers for Muscarinic cholinergic receptors
Gi, Gq : AC, PLC, , ion channels
69
Transducers for Eicosanoids
Gs, Gi, Gq proteins
70
Example of drugs with β Adrenergic receptors
Dobutamime
71
Example of drugs with Muscarinic cholinergic receptors
Atropine
72
Example of drugs with Eicosanoids receptors
Montelukast
Misoprostol
73
What is GPCR
Large family of cell membrane receptors linked to the effector enzyme/channel/carrier proteins through one or more GTP activated proteins (G-proteins i.e. guanine nucleotide binding protein)
74
What are G proteins
signal transducers that convey the information that agonist is bound to the receptor from the receptor to one or more effector proteins
75
What is the G protein heterotrimer
a guanine nucleotide-binding ‘α’ subunit, which confers specific recognition to both receptors and effectors, and an associated dimer of β and ϒ
76
What are G protein regulated effectors
Adenylyl cyclase
Phopholipase C
Cyclic GMP phosphodiesterase (PDE6)
Membrane ion channels selective for Ca+ and K+
77
How does GPCR span the membrane
GPCRs span the plasma membrane as a bundle of seven alfa-helices.
78
The GPCR is a binding site for what
•Extracellular binding site for ligand.
•Cytosolic binding site for transducer G-protein.
79
How many subunits do ligand gated receptors have and what are they
Five
2 α, β, γ, δ
80
How many subunits do GPCR receptors have and what are they
3
α, β, γ,
81
What do Gs, Gi , Gq and G12/13 do respectively for α-subunits
•The Gs α-subunit uniformly activates adenylyl cyclase; ***and Ca++ channels in myocardium and skeletal muscles***
•the Gi α-subunit can inhibit certain isoforms of adenylyl cyclase; and *** open K+ channel in heart and muscle and close Ca+ in neurones***
•the Gq α-subunit activates all forms of phospholipase C;
•and the G12/13 α-subunits couple to guanine nucleotide exchange factors (GEFs), such as p115RhoGEF for the small GTP-binding proteins Rho and Rac.
82
What’s the Adenylyl cyclase-cAMP pathway
↑ cAMP (2nd messenger)
⬇️
PKA phosphorylation
⬇️
Various functions
-↑ heart contraction
-Smooth mus relaxation
-Glycogenolysis
-lipolysis
-inhibition of secretion/mediator release
- hormone secretion, among others.
- Modulation of junctional transmission
- Opens specific type of Ca++ channel - Cyclic nucleo tide gated channel (CNG) - - -heart, brain and kidney
83
What’s the Phospholipase C: IP3-DAG pathway
PIP2
⬇️
IP3 + DAG
⬇️. ⬇️ Mobilize Ca 2+ PKc activation
Via Calmodulin and PKC
Activation of CCPK, MLCK, PKc
-contraction
-neural excitation
-cell proliferation, secretion
-transmitter release
-eicosanoid synthesis
84
Explain Resensitization and Down regulation
I. Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins (Gs) located in the cytoplasm.
2. Agonist-activated receptors are phosphorylated by a G protein-coupled receptor kinase (GRK), preventing receptor interaction with Gs and promoting binding of a different protein, - β arrestin (β-Arr), to the receptor.
3.The receptor- β arrestin complex binds to coated pits, promoting receptor internalization.
4.Dissociation of agonist from internalized receptors reduces - β Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase.
5.Return of receptors to the plasma membrane result in the efficient resensitization of cellular responsiveness.
6. Repeated or prolonged exposure of cells to agonists favor the delivery of internalized receptors to lysosome , promoting down regulation rather than resensitisation
85
What are the 2 types of enzyme linked receptors
•With intrinsic enzymatic activity.
•Without intrinsic enzymatic activity (but bind a JAK-STAT kinase on activation
86
What’s the therapeutic index
That’s the LD50/ ED50
The larger the the T.I( farther from 1) the easier to take
87
Examples of drugs that are competitive
Neostagmine-acetylcholine esterase
88
Examples of drugs that are non competitive
Omeprazole
Imipramine
Aspirin
89
Examples of ions channel blocking drugs
Niphedipine
Quinidine
Amiodarone
90
Ion channel modulators
Amlodipine
nateglinide
repaglinide
sulfonylureas
alprazolam
zolpidem,
91
What is phenoxybenzamine
An antagonist for alpha adrenoceptor
92
Drugs with high and low therapeutic index
Penicillin: High therapeutic index (100)
Digoxin : Low therapeutic index (0.8–2.0)
93
Factors that affect dose response relationship
absorption,
metabolism, and elimination of the drug;
the site of action of the drug in the body;
and the presence of other drugs or disease.
94
What’s the proportional relationship between dose Abd response
At low doses, relatively directly proportional
At higher doses the amount of change in response to an increase in the dose gradually decreases until a dose is reached that produces no further increase in the observed response (i.e., a plateau).
95
What kind of curve is the d/r curve
Sigmoid
96
What’s the d/r curve
Measurement of the relationship between the quantity/concentration of a substance and its overall effect on an organism.
97
How is the d/r curve plotted
the response (ordinate) is plotted against the logarithm of the drug concentration (abscissa
98
How is the curve plotted
the response (ordinate) is plotted against the logarithm of the drug concentration (abscissa
99
How is the curve plotted
the response (ordinate) is plotted against the logarithm of the drug concentration (abscissa
100
How is the scale of the drug conc determined
the scale of the drug concentration axis is expanded at low concentrations where the effect is rapidly changing, while compressing the scale at higher doses where the effect is changing more slowly
101
What are the salient features of the curve
i.Threshold
ii.Slope
iii.Emax
102
When are there no no adverse effects from exposure to the chemical. ( the human body can take some toxic insult )
At a dose below threshold
103
What thresholds are easier and more difficult to determine
Thresholds based on acute responses, such as death, are more easily determined, while thresholds for chemicals that cause cancer or other chronic responses are more difficult to determine.
104
How do technologist determine the toxicity when the threshold is difficult to determine
, toxicologists look at the slope of the dose-response curve to give them information about the toxicity of a chemical.
105
What does the slop say about the toxicity
A sharp increase in the slope of the curve can suggest increasingly higher risks of toxic responses as the dose increases, A relatively flat slope suggests that the effect of an increase in dose is minimal
106
How can you define the potency of a chemical
The potency of a chemical is a measure of its strength as a poison compared with other chemicals
The more potent the chemical, the less it takes to kill
107
What does the slope of the curve say about the potency of a drug
A steep curve that begins to climb even at a small dose suggests a chemical of high potency
108
List 3 characteristics of DR curve
•i. curves are sigmoid, having between 20 and 80 % as straight lines for statistical analysis.
•ii. Drugs with a similar mechanism of action have parallel curves.
•iii. Beyond Emax, further increase in drug concentration cannot produce any increase in response
109
What are the 2 types of D/R curve
Graded D/R curve
Quantal D/R curve
110
Give 3 characters of GRADED D/R curve
• Measured in a single biologic unit
• Continuous scale (⬆️dose -› ⬆️effect)
• Relates dose to intensity of effect
111
List 3 characteristics of QUANTAL D/R curve
• Population studies
• All-or-none pharmacologic effect
• Relates dose to frequency of effect or % of population showing a specific result
112
How do you define the potency of a drug
A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity
A highly potent drug evokes a given response at a low concentration. A drug of lower potency evokes the same response only at higher concentrations.
113
Example of a highly potent drug
Fentanyl
114
Example of a drug with low potency
Miperidine
115
How is the potency usually measured
Often measured at 50 % concentration or dose leve
116
Is the potency of a drug clinically important
Relatively unimportant in clinical use of drugs.
117
What is efficacy of a drug
Ability of the drug to produce effect. Emax is the maximal effect that can be produced by a drug.
118
What determines the efficacy of a drug
determined mainly by the properties of the drug and its receptor-effector system
119
Is the efficacy of a drug important clinically
Yes efficacy is an Important clinical measure
120
What’s the max efficacy of a partial agonist in comparison to an agonist
Partial agonist have lower maximal efficacy than full agonists.
121
How does the D/R curve help estimate the safety of a drug
Through the therapeutic index
122
Example of chemical antagonists
dimercaprol and mercuric ion.
123
What is pharmacological antagonism
caused by action of the agonist and antagonist at the same site.
124
I’m what type of antagonism is competitive and non-competitive used.
Pharmacological antagonism
125
What’s the effect of a competitive antagonist on the D/R curve
It shifts the curve to the right
E max is still attained BUT with an increase in dose of the agonist
126
What’s the effect of a non competitive antagonist on a D/R curve
It flattens or shifts the curve downward
E max can never be attained no matter how much you increase the dose
127
What’s an antagonist of epinephrine
Dibenamine
128
What do agonists possess that antagonists don’t
Agonist have both affinity and efficacy (due to intrinsic activity) but antagonists only have affinity but no efficacy
129
What words are pharmacodynamics gotten from
•Pharmakon =drug
•Dynamikos =force or power
130
What does pharmcodynamics entail
•It involves receptor binding (including receptor sensitivity), post-receptor effects and chemical interactions
131
What determines how quickly the drug initiates the effect and how long the effect lasts.
The strength and length of the interaction
132
Give an example of a bacterial enzyme penicillin binds to to prevent cross links in the bacteria
Transpeptidase
133
Describe the pharmacodynamics of penicillin
When penicillin binds to transpeptidase to stop cross links, if the penicillin is enough cross linking (to create strong cell walls) stops completely, but if the penicillin is too little, the enzyme resumes cross linking
‼️HENCE ; The bacterial killing activity of penicillin changes with the levels in the body.
134
What physiological changes can affect the pharmacodynamics of a drug
physiologic changes due to disorders which can change receptor binding, alter the level of binding proteins or decrease receptor sensitivity
135
Examples of physiological changes that affect drugs pharmacodynamic
genetic mutations,
malnutrition,
thyrotoxicosis.
136
What are the principles of drug action
Drugs (except those gene based)
-Do NOT impart new functions on any system, organ or cell.
-Only alter the PACE of ongoing activity.
137
What are the basic types of drug action
Stimulation
Depression
Irritation
Replacement
Cytotoxic action
138
What is drug stimulation
selective enhancement of the level of activity of specialized cells,.
139
Examples of stimulation by drugs
adrenaline on the heart,
pilocarpine on salivary glands
Picrotoxin on CNS (high dosage)
140
What is drug depression
selective diminution of activity of specialized cells,
141
Examples of depressions done by drugs
barbiturates on the CNS,
quinidine on the heart,
omeprazole on gastric secretion.
Ach on SA nodes
142
Examples of depressions done by drugs
barbiturates on the CNS,
quinidine on the heart,
omeprazole on gastric secretion
Ach on SA nodes of the heart
143
What is drug irritation
particularly applied to -nonspecialized cells (epithelium, connective tissue), a non-selective and often noxious effect.
144
What does strong irritation lead to
Strong irritation results in inflammation,
corrosion,
necrosis, and
consequently, loss of function.
145
Examples of irritation caused by drug
bitters on salivary and gastric secretions.
146
What is drug replacement
use of natural metabolites, hormones or their congeners in deficiency states
147
Examples of drug replacement
levodopa in Parkinson’s disease,
insulin in diabetes mellitus.
Iron In anemia
148
What is drug cytotoxic action
selective cytotoxic action on cancer cells or invading organisms, attenuating them without significantly affecting the host cells
149
Examples of drugs with cytotoxic action
cyclophosphamide,
zidovudine,
penicillin.
Chloroquine
150
What are the mechanisms of drug action
Physical and chemical mechanics
151
Example of physical mechanisms in drugs
-Activated charcoal binds with poisons in the stomach.
-Mannitol as an osmotic diuretic, freely filtered but not reabsorbed.
-Bulk laxatives e.g. ispaghula.
152
Examples of chemical mechanisms in drugs
-NaHCO3 as an antacid.
-Dimercaprol, penicillamine, desferrioxamine as chelating agents.
-Pralidoxime as a choline esterase reactivator.
-Cholestyramine for sequestration of bile acids and cholesterol in the gut.
153
Most drugs produce their effects by interacting with a discrete target biomolecule - usually a protein such as what
Carrier molecules
Ion channels
Receptor
Enzymes
154
Drug-enzyme interactions may take place as what and what
Enzyme activator and enzyme inhibitors
155
Give 3 examples of competitive enzyme inhibition
1.Angiotensin converting enzyme inhibitors e.g. captopril
2.Reversible anticholinesterases e.g. neostigmine, physostigmine
3.Allopurinol used in gout since it inhibits xanthine oxidase,
Atropine
Scopolamine. (Both inhibit muscarinic receptor)
156
Give 4 examples of non competitive inhibitors
1.Irreversible anticholinesterases e.g. organophosphorus compounds (insectisides and war gases).
2.Aspirin inhibits cyclooxygenase enzyme and therefore prostaglandin synthesis.
3.Monoamine oxidase inhibitors used to treat depression e.g.
4.Proton pump inhibitors: e.g. omeprazole inhibit the H+/K+ ATPase in parietal cells of stomach.
157
Examples of sodium channel drugs
Quinidine
Procainamide
Lidocaine
Carbamazepine
158
How do sodium channel drugs work
local anaesthetics block the channels, (inhibit sodium influx) thus depolarization does not take place and there is no nerve conduction in that localized area. They are used respectively in cardiac arrhythmias and as local anaesthetic.
159
How do sodium channel drugs work
local anaesthetics block the channels, thus depolarization does not take place and there is no nerve conduction in that localized area. They are used respectively in cardiac arrhythmias and as local anaesthetic.
160
How do calcium channel drugs work
Block the voltage gated calcium channels; (prevent ca influx) useful in hypertension and arrhythmias
161
Example of calcium channel drugs
nifedipine,
verapamil,
diltiazem
Amlodipine
Nicardipine
162
How do potassium channel drugs work
blockade of the channels leads to a prolonged refractory period. (Prolongs duration of action potential)
163
Examples of potassium channel drugs
amiodarone,
sulfonylureas (treats diabetes)
Dalframpidine
Dofetilide
164
How do chloride channel drugs work
upon activation, the GABA A receptor selectively conducts Cl- through its pore, resulting in hyperpolarization of the neuron, which causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring
165
Example of chloride channel drug
Benzodiazepines (lorazepam)
166
Give 5 examples of drugs that inhibit carrier molecules
-Inhibition of choline carrier by hemicholinium.
-Inhibition of noradrenaline vesicular uptake by reserpine.
-Inhibition of neuronal reuptake of noradrenaline by desipramine.
-Inhibition of neuronal reuptake of serotonin by fluoxetine.
-Inhibition of weak acid (e.g. uric acid) carrier by drugs (e.g. probenecid, which prevents uric acid tubular reabsorption, thus enhancing its excretion).
167
Which agents have no effect on receptors on its own
Antagonists
168
Examples of agonists
acetylcholine,
adrenaline,
noradrenaline
169
Examples of antagonists
atropine, (competitive muscarinic inhibitor)
scopolamine, (competitive muscarinic inhibitor)
phenoxybenzamine. (Alpha blocker)
170
Example of an inverse agonist
Beta carbolines
171
Explain agonist, antagonist, partial and inverse agonist in terms of affinity and intrinsic activity mathematically
Agonist : Affinity + IA= 1
Antagonist : Affinity + IA= -1
Partial agonists: Affinity + IA = Between 0 and 1
Inverse agonist : Affinity + IA = Between 0 and -1
172
How are the functions of a receptor determined
determined by the interaction of lipophillic or hydrophillic domains of the peptide chain within the drug molecule.
173
What induces conformational changes (alter distribution of charges and transmitted to coupling domain to be transmitted to effector domain.)
Binding of polar drugs in ligand binding domain
174
What are the subtypes of Ach receptors
Muscarinic M1, M2, M3
Nicotininic Nn,Nm
175
What are the criteria used in classifying receptors
Pharmacological criteria
Tissue distribution
Transducer pathway
Molecular cloning
176
What is pharmacological criteria of receptors with examples
it is the classical and oldest approach, based on potencies of selective agonist and antagonists – ***Muscarinic, nicotinic, alpha and beta adrenergic etc***
177
Explain the *tissue distribution* receptors
the relative organ or tissue distribution is the basis for designating the subtype e.g. ***the cardiac beta adrenergic receptor as beta 1 and bronchial as beta 2.***
178
Explain the ligand binding types of receptors
Measurement of specific binding of high affinity radio-labelled ligand to cellular fragments (usually membranes) in vitro and its selective displacement by various selective agonists/antagonists is used to delineate receptor subtype. E.g. ***multiple 5-HT receptors were distinguished by this approach.***
179
Explain the transducer pathway types of receptors
receptor subtype may be distinguished by the mechanism through which their activation is linked to the response, e.g. ***M cholinergic receptor acts through G-proteins, while N cholinergic receptor gates influx of Na+ ions.***
180
Explain the molecular cloning types of receptor
the receptor protein is cloned and its detailed amino acid sequence as well as three dimensional structure is worked out. This approach has resulted in a flood of receptor subtypes and several isoforms, even in receptors without known ligands (orphan receptors).
181
What are silent receptors
These are sites which bind specific drugs but no pharmacological response is elicited. They are better called Drug acceptors or Sites of loss ***e.g. plasma proteins.***
182
What are spare receptors
A drug can produce the maximal response when even less than 1% of the receptors is occupied. The remaining unoccupied receptors are just serving as receptor reserve and are called spare receptors.
183
What is receptor up regulation
increase in the number of receptors with subsequent increase in receptor sensitivity
184
Give 2 examples of receptor up regulation
Depletion of noradrenaline : treatment with adrenergic antagonist (absence makes the heart fonder) - leads to super sensitivity to nore adrenaline and increase in receptor number
Administration of beta blockers increase adrenergic receptors
185
What is receptor down regulation
reduction in the number of receptors available for activation
Reduced affinity & reduced No of receptors
186
Explain what causes down regulation
Due to continued exposure to a drug/ agonist: It results in blunted response: desensitisation/ refractoriness/ tolerance
187
Example of receptor down regulation
Repeated administration of adrenergic agonist leading to down regulation of beta receptors
188
What are the two types of mechanisms of receptor related diseases
• Autoantibodies directed against receptor proteins
•Mutations in genes encoding receptors and proteins involved in signal transduction.
189
Give 2 examples of receptor related diseases caused by antibodies attacking receptor proteins
•***Myasthenia gravis*** , - autoantibodies that inactivate nicotinic acetylcholine receptors.
•Autoantibodies can also mimic the effects of agonists, as in many cases of ***thyroid hypersecretion***, caused by activation of thyrotropin receptors
190
Give 4 examples of receptor related diseases
•Myasthenia Gravis:
–Antibodies against the cholinergic nicotinic receptors at motor end plate.
•Insulin Resistant Diabetes
•Testicular feminisation
•Familial hypercholesterolemia
191
What are the 4 main categories of transducer metabolism
1.GPCR
2.Receptors with intrinsic ion channel
3.Enzyme linked receptor
4.transcription factors (receptors for gene expression
192
Which receptors are called seven-transmembrane domain receptors.
GPCR
193
Which receptors Mediate the majority of cellular responses to external stimuli
GPCR
194
Which receptors common pattern of structural organization
All GPCR
195
How do GPCR span the cell
The molecule has 7 α-helical membrane spanning hydrophobic amino acid segments – 3 extra and 3 intracellular loops
196
What ligands bing GPCR
light-sensitive compounds,
odours,
hormones,
neurotransmitters,
***and they vary in size from small molecules to peptides to large proteins.***
197
What is intracellular receptor
Found in the cell
Receptor enters the nucleus and changes gene transcription
Coupling is indirect
198
Examples of intracellular receptors
Steroids
Estrogen
199
What’s the effector of a GCPR
Ion or enzyme
200
What kind of coupling or transduction do each types of receptors have
Ion channel-Direct transduction
Enzyme linked-Direct transduction
GCPR-Indirect (via G proteins)
Intracellular-Indirect
201
Examples of enzyme linked receptors
Insulin
Cytokines
202
Types of drug receptor relationship
Drug receptor binding
Drug receptor interaction
Drug receptor outcome
Drug receptor regulation
203
What are the 2 types of drug receptor binding
Reversible and irreversible
204
What type of bonds do reversible ligand binding have
Hydrogen bond
Usually competitive
205
What type of bond do irreversible ligand binding have
Covalent bond
Mostly non competitive
206
What are the types of drug receptor interactions
Ligand - Drug must be a ligand
Affinity- Drug must have affinity
Intrinsic activity- Not compulsory for drug to have
Specificity- Not compulsory for drug to have
207
What are voltage gated receptors
the rate and direction of ion movement through the pore is governed by the electrochemical gradient (as measured by its concentration on either side of the membrane as well as the membrane potential) for each ion.
208
How does Ligand-binding and channel opening occur
on a millisecond timescale, so they are confined to excitable tissues-CNS, NMJ, autonomic ganglia.
209
What receptor does Benzodiazepene work on
enhance stimulation of gamma-aminobutyric acid (GABA), resulting in increased chloride influx and hyperpolarization of the respective cell.
210
What’s another name for enzyme linked receptor
Receptor tyrosine kinase
211
Which receptors are metabotrophic
G protein
212
Function of G12/13
regulate actin cytoskeletal remodeling in cells during during movement and migration, including cancer cell metastasis.
213
Examples of ligands for GCPR
: adenosine,
bradykinin,
endothelin,
opioid peptides,
dopamine,
serotonin,
acetylcholine (muscarinic effects), histamine,
chemokines,
eicosanoids,
adrenaline, noradrenaline etc.
214
What are the three second messenger systems
•Cyclic AMP
•Cyclic GMP
•Calcium and phosphoinositol second messenger system
215
When are G proteins active and inactive
rendered inactive when reversibly bound to Guanosine diphosphate (GDP), but active when bound to Guanosine triphosphate (GTP).
216
How does the inactive G protein function
•The inactive G protein is bound to the receptor in its inactive state.
•Once the receptor is recognized, the receptor changes in its conformation and therefore, mechanically activates the G protein, which detaches from the receptor.
•The receptor can now activate another G protein or switch back to its inactive state.
217
What happens to a G protein that’s been activated by binding to an inactive receptor
Upon activation, the subunits of the G protein dissociate from the receptor, as well as from each other to yield Gα-GTP monomer and a tightly interacting Gβϒ dimer, which are now free to modulate the activity of other intracellular proteins.
218
What’s the function of Go
Reduces Ca
219
What’s the effector for Gs
Beta-receptors,
H2, D1
(Opens Ca channel)
220
What’s the substrate for the Gi
Muscarinic M2
D2, alpha-2, 5HT1, GABA B
(Opens K channel)
221
What’s the substrate for Gq
Alph-1, H1, M1,M3, 5HT2
222
What’s the substrate for Go
K+ channel in
heart, sm
M2, D2, Alpha2, 5HT1, GABA B
223
What ion channels are targets for G protein
Ca and K
224
How is cAMP produced
G-alpha binds to andenyl cyclase to produce cAMP
225
What’s the function of cAMP
regulates many aspects of cellular functions such as: ***cell division and cell differentiation, ion channels, ion transport etc***. These different activities are via a common pathway i.e. ***activation of protein kinases by cAMP***.
226
What terminates cAMP activity
terminated by phophodiestarases, which hydrolyse it to 5-AMP.
227
What forms resting G protein
The GTP is hydrolysed to GDP by GTPase activity of the α-subunit, therefore, there is reassociation with Gβϒ dimer to form the “resting” G-protein.
228
Functions carried out by enzyme linked receptors and examples
metabolism, growth and differentiation
Insulin and cytokine
229
Where are ligand gated receptors found
confined to excitable tissues-CNS, NMJ, autonomic ganglia.
230
Functions of ligand gated receptors
And example
neurotransmission, cardiac conduction and muscle contraction
example, stimulation of nicotinic receptor by ACh results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle.
231
Targets of G protein
Adenylate cycle
Phospholipase C
Ca and K ion channel
232
Function of intracellular receptors
primary targets are transcription factors, which cause the transcription of DNA into RNA and translation of RNA into an array of proteins.
233
What are the three major pathways of GPCR
•Adenylyl cyclase: cAMP pathway
•Phospholipase C: IP3-DAG pathway
•Channel regulation
234
What is cAMP dependent protein kinase
Protein kinase A
235
What is phosphate lipase C dependent protein kinase
Protein kinase C
236
Examples of hormones that need cAMP second messenger to pass info into cells because they can’t pass through the membrane
Glucagon
Adrenaline
237
Which is hydrophilic and lipophilic (IP3 and DAG)
IP3 is hydrophilic
DAG is lipophilic
238
Can G proteins open or close up ion channels without second messengers
Yes
239
What are the natural ligands for intrinsic ion channels
The natural ligands include acetylcholine, serotonin, aminobutyric acid (GABA), and the excitatory amino acids (eg, glycine, aspartate, and glutamate)
240
What are the drug receptor binding forces
•Covalent bond: Strong and in many cases not reversible under biological conditions.
•Ionic bond: Weaker than covalent, but stronger than the others
•Hydrogen bond: Stronger than Van-der-Waals
•Van-der-Waals
241
What are the receptor theories
1. Occupancy theory
2. Rate theory
3. Stephenson’s theory
4. Ariens’ theory
5. The induced-fit theory
6. Macromolecular Perturbation theory
242
State the occupancy theory
response is proportional to the fraction of occupied receptors; maximal response occurs when all the receptors are occupied.
243
State the receptor Rate theory
response is proportional to the rate of Drug-Receptor complex dissociation. Here, duration of receptor dissociation determines whether a molecule is agonist, partial agonist or antagonist.
244
State the receptor Stephensons theory
response is proportional to the fraction of occupied receptor and the intrinsic activity.
245
State the receptor Ariens theory
response is a function of affinity; maximum response can be produced without 100 % receptor occupation.
246
State the receptor Induced fit theory
binding site is not necessarily complementary with the ligand conformation. Rather binding produces a plastic molding of both the ligand and the receptor as a dynamic process (thus nullifying the obsolete “key and lock” concept)
247
State the receptor Macromolecular perturbation theory
when a drug-receptor interaction occurs, one of two general types of macromolecular pertubation is possible. Either a specific conformational pertubation (by agonist), which leads to a biological response Or a non-specific conformational pertubation (antagonist), leads to no biologic response.
248
What are the types of drug effect
Desired effect
Side effect
Adverse effect
249
What is side effect with example
Undesired, Dose dependent, predictable
Aspirin; excess bleeding
Septein; dark urine
250
What is adverse effect with examples
Undesired, unpredictable, dose independent
Aspirin; Reye sydrome
Septrin; Steven Johnson syndrome
251
Types of adverse effects
Type A - Augmented
Type B - Bizarre
Type C - Chronic
Type D - Delay
Type E - Ending of use
Type F - Failure of use
252
Which of the types of adverse effects are dose related
Type A and Type C
