Pharmacodynamics Flashcards
(134 cards)
1
Q
Adjusted body weight formula
A
adjusted body weight = ideal body weight + 0.4 x (actual body weight - ideal body weight)
2
Q
What does adjusted body weight correspond to?
A
The weight of metabolically active tissue
3
Q
Outline the 4 different mechanisms by which a drug may act?
A
- Action on receptors
A. Alteration of ionic permeability
B. GPCR
C. Receptors acting as enzymes
D. Regulation of gene transcription - Effects on enzymes
A. Inhibition either reversible or non reversible
B. Activation - Action on ion channels
- Action dependent on physicochemical properties - osmotic activity, acid-base activity, chelation, oxidation, reduction
4
Q
What 4 receptors subtypes might a drug act at?
A
- Action on receptors
A. Alteration of ionic permeability
B. GPCR
C. Receptors acting as enzymes
D. Regulation of gene transcription
5
Q
Outline using a graph how drug concentration and effect are related? What equation might be used?
A
In an idealised system the relation between drug concentration and effect is described by a hyperbolic curve according to the following equation; where only a single subject studied and used to measure efficacy (Emax)and potency (EC50)
E = Emax x C / C + EC50
Y axis a continuous variable; quantal is where it is categorical
E = effect observe at concentration C
E max = maximal response of the drug
EC50 = concentration of the drug that produces 50% of maximum effect
This describes the mass action law, which describes association between two molecules of a given affinity
6
Q
Using the law of mass action illustrate how receptor bound drug is related to drug concentration? Use an equation in addition to descrbe this?
A
7
Q
When does response data is plotted why is it linear?
A
It should be logarithmic but using logarithm of dose or concentration (X axis) allows for hyperbolic curve transformation into a sigmoid curve with a linear midpoint explaining low dose scales iof effect changing rapidly and compresses it at high doses where effect is changing slowly
8
Q
What is coupling in the context of drugs and receptors?
A
The transduction process that links drug occupancy of receptors and pharmacological response is often termed coupling
9
Q
What is the term for The transduction process that links drug occupancy of receptors and pharmacological response
A
coupling
10
Q
What two factors determining coupling efficiency in drug effect?
A
- Initial confirmation change - full agonists are more efficiently coupled to receptor occupancy than a partial agonist
- Drug effect relationship to receptor occupancy - for ion channels this may be more linear, but for enzymatic signal cascades this can be more disproportionate
11
Q
What is the concept of spare receptors?
A
where maximal biologicalresponse is achieved without maximum receptor occupancy e.g. even under conditions where 90% of Beta adrenorecpeotrs are occupied by irreversible antagonist maximal response can still be achieved i.,e. Heart has heaps of spare beta receptorsas does the NMJ
12
Q
Why do spare receptors exist
A
Provide protection against failure of transmission in the presence of toxins
13
Q
At what point does the concept of spare receptors get overridden?
A
75% receptor occupancy of the antagonsit and then maximal response is unable to occur
14
Q
What is the affinity of agonist binding denoted as
A
Kd
The Kd of the agonist receptor interaction determines what fraction of total receptors will be occupied at a given concentration of agonist regardless of receptor concentration
15
Q
How would you denote receptor occupancy fraction compared to Kd
A
B/Bmax = C / (C + Kd)
16
Q
Draw 4 curves representing the relationship between drug dose and response?
Drug A should have moderate potency, high maximal efficacy.
Drug B will have higher potency than drug A but lower maximal efficacy
Drug C will have equal maximal efficacy to Drug A but lower potency
Drug D will have equal maximal efficacy to Drug A, lower potency than drug C or A, but a steep dose response curve
A
17
Q
Describe these curves
A
Drug A should have moderate potency, high maximal efficacy.
Drug B will have higher potency than drug A but lower maximal efficacy
Drug C will have equal maximal efficacy to Drug A but lower potency
Drug D will have equal maximal efficacy to Drug A, lower potency than drug C or A, but a steep dose response curve
18
Q
How do you describe drug potency in a drug dose vs effect curve?
A
EC50 or ED50 required to produce 50% of the drugs maximum effect
◦ I.e. a drug is potent if not much of it is needed to reach maximum effect even where another drug may have a higher maximum effect in large concentrations ◦ So drug B is more POTENT than drug A —> ◦ Dependent on ‣ Kd - affinity of receptors for binding the drug ‣ EFificency in which drug receptor binding is coupled to response
19
Q
What two factors determine drug potency?
A
Kd - affinity of receptors for binding the drug
‣ EFificency in which drug receptor binding is coupled to response
20
Q
How is drug potency different to maximal efficacy?
A
Potency is related to ◦ EC50 (concentration) or ED50 (dose) of a drug required to produce 50% fo the drugs maximum effect
◦ I.e. a drug is potent if not much of it is needed to reach maximum effect even where another drug may have a higher maximum effect in large concentrations
Maximal effect is the limit of the dose response axis
i.e. Drug B is more potent than Drug A, but Drug A has a greater maximal effect
21
Q
Explain using Drugs C and D what effect a dose response cruve shape has?
A
◦ extremely steep curves may mean the probability of undesirable over-effects occur easily and may occur where cooperative interactions of different effect sites e.g. heart, brain and kidney dose effect sites contributing to very significant and rapid overall clinical effect
22
Q
Define drug efficacy?
A
a measure of the maximal response achievable by a drug once it is bound to its recpetor (often described as eMax - the drug concentration at which maximal effect is achieved)
23
Q
What is EC50
A
- Median effective concentration (EC50) - the concentration fo a drug required to induce 50% of a maximal effect
24
Q
What is ED50
A
- Median effective dose ED50 - the dose of a drug required to produce a response in 50% of the population to whom it is administered
25
Illustrate how a quantal effect plot diferse from a dose effect plot?
Why is this more useful for some drugs than other?
What characteristics of a drug do both curves represent?
How are the axes different on the graph?
What characteristics of the curves are similar between the two graphs?
(all or nothing, and population based)
* Graded response curves do not work if there is an either-or response e.g. termination of a seizure; and will not reflect the variability in drug response between people
◦ Both dose response curves show - potency and selectively
◦ Graded dose response shows maximal efficacy
◦ Quantal dose response curve indicates potential variability among individuals
Y axis instead shows cumulative frequency instead of effect potency; plotted against log (dose)
* Characteristics of the log dose-response curve
◦ Sigmoid curve
◦ X axis the logarithmic section
◦ Middle 1/3 is linear
◦ Steep curve = increased potency (i.e. slope = potency)
* Has the
◦ Median effective dose ED50 -50% of individuals get the quantal effect
◦ Median toxic dose TD50 (if this is death - LD50 - lethal dose)
26
What are cardinal characteristics of a quantal dose response cruve
* Characteristics of the log dose-response curve
◦ Sigmoid curve
◦ X axis the logarithmic section
◦ Middle 1/3 is linear
◦ Steep curve = increased potency (i.e. slope = potency)
* Has the
◦ Median effective dose ED50 -50% of individuals get the quantal effect
◦ Median toxic dose TD50 (if this is death - LD50 - lethal dose)
27
What is Ld50 vs TD50
◦ Median toxic dose TD50 (if this is death - LD50 - lethal dose)
28
What is therapeutic index? If you were to measure this what is the equation?
* A measure of a the margin of safety which can be expected to produce a certain effect
* The TI is the ratio of the TD50 to the ED50 for some therapeutically relevant effect
TI = LD50/ED50
29
Drugs that have a low therapeutic index have what relationship between Ld50 and ED50
Close in value
Narrow safety margin
30
Draw a dose response curve representing LD50 and ED50
31
What is an idiodysncratic reaction?
Unusual drug response not usually observed, may be due to genetic differences in metabolism
32
Why might variability in drug response occur - describe in terms of mechanisms by which drug effect could be altered (4)
◦ Alteration in concentration that reaches receptor
‣ Affected by: Absorption, Distribution, Clearance
‣ Age,weight,sex, disease state,liver and kidney function
‣ Genetic differences in drug processing e.g. drug metabolism enzymes OR active transport of drug from cytoplasm (MDR - multi drug resistances genes - membrane transporters upregulation increases drug resistance)
◦ Variation in concentration of endogenous receptor ligand
‣ E.g. catecholamine surges being dampened but during normal physiology heart rate unaffected by beta blockade
◦ Alterations in number of function of receptors
‣ Other hormonal action, thyroid hormones affecting number of Beta receptors and sensitivity to catecholamines
‣ Endogenous tolerance or tachyphylaxis + withdrawal overshoot of endogenous ligand response are explained by natural responses to stimulation or lack thereof \
◦ Changes in component of response distal to the receptor
33
Clinical selectivity refers to? What drugs do we commonly use that have poor clinical selectivity? What strategies do we use to try and avoid adverse effects in these circumstances? (3)
* Selectivity usually considered in beneifical/therapeutic effects versus toxic/adverse effects
* Beneficial and toxic effects mediated by the same receptor/effector system
◦ E.g.anticoagulation,insulin —> means that avoidance of other things that increase the risk of complications,increased monitoring or careful weighting of risk/benefit in weak indications is necessary
* Sometimes it is caused by single receptor type action in different tissues
◦ E.g. digoxin, glucocorticoids
◦ Strategy to use can include
‣ Minimum possible dose
‣ ADjunctive drugs
‣ Optimise drug delivery to reduce exposure to other organ systems
* Sometimes it is mediated by different types of receptors
◦ ALpha and beta selective adrenoreceptors agonists and antagonist,histamine and nicotine blocking drugs
34
Define antagonist. What two varieties of this are there? How are they different in terms of their ability to be overcome
a drug with high affinity for a receptor but no intrinsic activity, binding to active sites or allosteric sites
reversible antagonists can be overcome antagonist action whereas irreversible binding means agonist concentration becomes independent of receptor function
35
What is an allosteric agent
◦ Allosteric binding are drugs that bind to the same receptor molecule but at a differing location to agonists and affect either agonist/antagonist binding at other sites via confirmational change enhancing or inhibiting receptor affinity. Not overcome by increasing the dose of the agonist and non competitive
36
What is the effect on Emax of a competitive antagonist? Why? What does this depend on (2)
Unaltered
You can still acheive the same maximal effect with increased drug concentration
The amount of drug required to acheive this will depend on the dose of the antagonist and its receptor affinity
37
Draw a dose response curve for an agonist, agonist + competitive inhibitor, agonist + allosteric activator, and agonist + allosteric inhibitor or irreversible compeititve inhibitor
38
Describe what each of these must correlate to
39
What is the equation which describes the relationship between agonist and antagonist effect?
What two important therapeutic considerations does this equation raise
1. Degree of inhibition produced by a competitive antagonist depends on its concentration
A. Fixed doses result in wildly different concentrations amongst patients
2. Clinical response to a competitive antagonist depends on the concentration of the agonist that is competing for binding to its receptors
A. E.g. in beta blockade the beta blocker may suppress adrenergic response under normal physiological conditions but with exercise, postural change or emotional stress this may overcome competitive antagonism
40
How are potency and efficacy affected by competitive antagonists?
a drug whose antagonistic effect can be reversed by higher concentration of the agonist
* Efficacy is unaffected (Emax) while potency is reduced (ED50 is increased)
A competitive antagonists function is much the same as a less potent full agonist
41
What is a non competitive antagonist?
* Don not bind at the same site as agonist and classically are thought not to alter the binding of the agonist however this is now known to be untrue
* Their antagonism comes from preventing receptor activation through conformational distortion - cannot be overcome by increasing agonist concentration
* e.g. ketamine at NMDA receptors
42
Allosteric modulation is?
* Non competitively by binding to a site that separate to the agonist binding site modulating receptor activity without blocking agonist binding
* Actions usually reversible if they do not bind covalentely e.g. Benzo at GABA A receptors
43
What is an irreversible inhibitor? What mechanism might they act by? What effect do they have on efficacy and potency? What does this depend on? Advantages of this style of drug? Disadvantages?
* A drug whose antagonistic effect cannot be reversed by a higher concentration of the agonist
* Either via a covalent bond or binding so tightly that is receptor for all practical purposes is unavailable
* The effect on Emax for agonists will depend on the dose of the antagonist as well as the degree of spare receptors; but in general potency and efficacy are decreased (EMax and ED50 decrease)
* Advantages of this style of drug
◦ Duration of action independent of elimination , instead it is dependent on receptor turnover
◦ Effect is independent of swings in agonist concentration if the agonist is prone to this e.g. alpha blacked in pheochromocytoma
* Disadvantage
◦ Overdose - you need to counteract it without using the receptor
E.g. Clopidogrel metabolite binds irreversibly to Gi protein coupled ADP Py2Y12 receptors
44
Advantages of an irreversible antagonist? Disadvantages?
* A drug whose antagonistic effect cannot be reversed by a higher concentration of the agonist
* Either via a covalent bond or binding so tightly that is receptor for all practical purposes is unavailable
* The effect on Emax for agonists will depend on the dose of the antagonist as well as the degree of spare receptors; but in general potency and efficacy are decreased (EMax and ED50 decrease)
* Advantages of this style of drug
◦ Duration of action independent of elimination , instead it is dependent on receptor turnover
◦ Effect is independent of swings in agonist concentration if the agonist is prone to this e.g. alpha blacked in pheochromocytoma
* Disadvantage
◦ Overdose - you need to counteract it without using the receptor
E.g. Clopidogrel metabolite binds irreversibly to Gi protein coupled ADP Py2Y12 receptors
45
What are the 2 main factors in determining a drugs pharmacological effect
1. Intrinsic activity/efficacy
2. Affinity
46
Describe agonists, partial agonsits, antagonsits and inverse agonists in terms of affinity and effiacy>
* Full agonist - high affinity = full IA (IA = +1)
* Antagonist - high affinity, no IA (IA =0)
* Partial agonist - high affinity, fractional IA (O
47
What is intrinsic actitivty/efficacy?
* A measure of the ability of a drug to produce an effect once it is bound to its receptor
48
What is affinity with reference to drug to receptor binding?
How well or avidly a drug binds to the receptor - determined by Kp or Ka
49
What is Bowmans principle?
* Weaker antagonists at the NMJ have a more rapid onset of action
* This is because they are given at a higher dose for the same maximal effect so that more molecules are available to occupy receptors —> receptor occupancy required for full effect is achieved more rapidly
* Rocuronium 1/5 of the effect of vecuronium but given at 5x the dose it acts quicker
50
How do you explain Rocuronium being faster in onset than Vecuronium?
Bowmans principle
* Weaker antagonists at the NMJ have a more rapid onset of action
* This is because they are given at a higher dose for the same maximal effect so that more molecules are available to occupy receptors —> receptor occupancy required for full effect is achieved more rapidly
* Rocuronium 1/5 of the effect of vecuronium but given at 5x the dose it acts quicker
51
How does a non competitive inhibitor effect maximum effect
reduces it, reduces maximal efficacy. However fractional response remains the same, so the dose response curve is not shifted to the right
52
What is Kd
The dissociation constant, unaltered by inhibitor
A competitive inhibitor will result in a lower maximum response, but the dose at which this maximal response is unaltered. (i..e no inhibitor may have a higher maximal response but the 50% of maximal response dose is the same; even though with an inhibitor the total maximal response is lower)
53
Draw a dose response curve illustrating the effect of a partial agonist
A is a full agonist, C is a partial agonsit
Dotted line - shows dose response for A in the presence of submaximal dose of C
At low concentrations of A the combintion results in a greater effec tthan would be seen with A alone, but as the dose of A is increased the total effect is lower until very high doses than A+C = A maximal effect
Therefore in the middle concentrations C acts as a COMEPTITIVE ANTGONIST
54
What relationship does Kd have to potency?
Low Kd = high potency
50% maximal effect with low doses
ED50 often = Kd
55
Describe a full agonist
Confers maximal activation/receptor function as can be performed for receptor occupation
High affinity, high intrinsic activity
56
How is a partial agonist different to a full agonist? Provide an example
High affinity, but lower intrinsic activity/efficacy
Intrinsic activity is independent of affinity for receptor
No amount of increase in concentration will confer maximal efficacy for the receptor
Buprenorphine
57
Draw a graph representing change in receptor activity to dose for agonist, partial agonist, antagonist and inverse agonist where there is constitutive activity
58
What is an example of an inverse agonist
Benzodiazepines
59
What is the law of mass action
The rate of a recton is proportional to the concentrations of the reacting compounds
60
What is Ka? Demonstrate how it is derived from first principles?
61
How is a receptor different from binding?
* Receptors are sites at which e
◦ Endogenous molecules can bind selectively
◦ Change of function upon binding
* Those sites at which a drug binds which do not fit the above definition are called inert binding sites e.g albumin
62
Termination of drug effect at receptors occurs because of (3)
◦ Drug characteristics
‣ Effect is dependent on drug occupation of the receptor i.e. dissociation leads to cessation of effect
‣ Action persists after drug dissociation due to coupling molecule is still present in activated form
‣ Covalent bonding of drug leading to ongoing action until new receptors are formed e.g. aspirin
◦ De-sensitisation mechanisms
◦ Pharmacokinetic effects of drug elimination and metabolism especially where drug occupation of the receptor is what results in duration of action
63
5 types of drug receptor coupling
* Lipid soluble chemical signal crossing the plasma membrane and acting on intracellular receptor - enzyme or gene transcription
* Signal binds to extra cellular domain of transmesmbane protein activating an enzymatic activity of its cytoplasmic domain - intracellular enzyme activity allsoterically regulated by a ligand that binds to an extra cellular domain
* Signal binds to extra cellular domain of a tramsmemebrane protein/receptor bound to a separate protein tyrosine kinase which it activates
* Signal binds to and directly regulates the opining of an ion channel
* Signal binds to a cell surface receptor linked to an effector enzyme by a G protein
* Drug + receptor/effector complex --> drug/receptor/effector complex --> effect
* Drug + receptor --> drug/receptor complex --> effector molecule --> effect
* Drug + receptor --> drug receptor complex --> activating of coupling molecule --> effector molecule --> effect
* Inhibitoon of metabolism of endogenous activator --> increased activor action on effector molecule
◦ e.g. anticholinesterase inhibitors, because they reduce the degreation of physiologically released agonsits they can sometimes have more selective, less toxic effects than exogenous agonists
64
Enzymes cause
* Increased concentration of the substrate usually metabolised
* Reduced concentration of the product
65
What are 2 examples of physicochemical mechanisms of a drug?
Many drugs derive their mechanism of action from chemical reactions neutralising other agents that may be involved in subsequent receptor interactions or influence the absorption or action of other substances which are ligands to receptors or alter enzymatic activity. E.g.
* Antacids neutralising gastric acid
* Chelating agents used to reduce metallic ion concentration
* Di-cobalt edetate chelates cyanide
* Gamma cyclodextrin (suggamadex) chelates rocuronium and allows deeper reversal of block than could be achieved effectively with anti cholinesterases
66
The nicotinic acetylcholine receptor at the NMJ - describe its structure?
2 alphas, beta, gamma, delta - pentameric structure
2 acetylcholine binding sites on the alpha subunits
Central pore
8nm total in diametre
When Ach binds it opens the central pore temporarily allowing Na (non selective though) down its concentration gradient proudcing an excitatory post synaptic potential for <1 msec, and ions pass at 10^7 per second. Orifice negatively charged prohibiting anion passage.
Each of the subunits crosses the lipid bilayer 3 times
67
How are ion channels regulated to allow synaptic plasticity? (2)
Phosphorylation
Endocytosis
68
What is fade due to in NMJ blockers?
Pre-synaptic inhibition of opositive feedback - Ach stimulated Ach release
69
What are 2 examples of pentameric ion channels?
GABA-A
Nicotinic
5HT3 - the only seratonin channel opening receptor
70
What is GABA? How is it made?
Amino acid
Major inhibitory neurotransmitter
Glutanate is converted to GABA and CO2 by glutamate decarboxylase
71
GABA A receptor structure
Pentameric
2 alpha
2 beta
1 gamma
72
Where is the binding sites on GABA A
alpha subunits
73
GABA binding to GABA A receptor causes what?
Confirmational cahnge and opening of the chloride sensitive ion channle - small anions mostly chloride
Membrane hyperpolarisation
74
How do Benzodiazepines work?
Agonist at the alpha/gamma interface producing positive alloteric modulation
Increase affinity of GABA for GABA - A receptor
Increase frequncy of opening
Increased membrane hyperpolarisation
75
Flumazenil acts how
Anatagonist at the alpha-gamma interface
76
Propofol MOA
Agonist of the GABA A receptor at the Beta subunit proudcing positive allosteric modulation
Increased chloride channel opening time
77
Barbituate MOA
Agonist of the GABA A receptor at the Beta subunit proudcing positive allosteric modulation
Increased chloride channel opening time
78
Halogenated volatile MOA
Agonist of the GABA A receptor at the Beta subunit proudcing positive allosteric modulation
79
GABA B receptor what type of receptor? Targeted by what?
GPCR - presynpatic
Targeted by baclofen
80
GABA C receptor located where? What type of receptor?
LIgand gate chloride ion channel receptor
Retina
81
Glutamate works on what receptors type? What are the 3?
Ligand gated ion channels
NMDA
AMPA
Kainate
82
NMDA receptor structure
2 subunits, one pore forming NR1 with 3 membrane spanning helices. 2 are separated by re-entrant pore forming loop, one regulatory that binds coactivator NR2
Receptors dimerise forming a 4 unit subcomplex
Glutamate the ligand, glycine the co-agonist
Ion pore blocked by Mg, requires partial depolarisation of the cell membrane tor emove this plug
Equally permeable to Na and K, very high Ca permeability which is the most important
Secondary events - nitric oxide production, activation and production of secondary messengers, activation of enzymes
83
What 3 agents affect the NMDA receptor?
Nitrous oxide, ketamine, xenon
84
Where is the NMDA receptor
brain
dorsal horn of spinal cord
85
What opioids also act at the NMDA receptor?
Methadone
Tramadol
86
What is an example of a non GPCR transmembrane recpeotr with secondary messenger system?
Tyrosine kinase receptors
87
What ligands have tyrosine kinase binding receptors? (5)
Insulin
Epidermal growth factor
Platelet derived growth factor
ANP
Transforming growth factor beta
88
Tyrosine kinase receptor structure?
◦ Extracellilar hormone binding domain (alpha subunit)
◦ Cytoplasmic enzyme domain - transmembrane beta subunits
‣ Protein tyrosine kinase
‣ Serine kinase
‣ Gaunylyl Cyclase
◦ Two domains connected by hydrophobic segment of polypeptide that crosses the lipid bilayer of the plasma membrane
◦ When a ligand binds - conformational change —> two receptors bind to another (dimerise) —> brings together tyrosine kinases which ar then enzymatically active and phosphorylation oneanother and other downstream signalling proteins (multiple different downstream effects e.g. incorporating glucose transport proteins into cell membranes and altering gene transcripti
89
What are cytokine receptors? e.g. 3
Tyrosine kinase like however they do not have an intrinsic kinase attached. Instead a tyrosine kinase must bind to the receptor non covalently after dimerisation to cause downstream action
e.g. EPO, interferon, growth hormone
90
GPCR structure
membrane bound proteins with a serpentine structure consisting of seven helical regions traversing the membrane
◦ Most function as monomers, however there are some homodimers (complexes of 2 identical receptor polypeptides) or heterodimers (2 different isoforms)
‣ Heterotrimers have alpha, beta and gamma subunits
◦ Act by binding to G proteins which are proteins bound to guanine nucleotides (GDP and GTP_
91
What are the subclasses of G proteins and their downstream effector? 3 examples of each
◦ Gs type - stimulate adenylate cyclase
‣ E.g. all beta, dopamine 1 and 5 receptors
◦ Gi type - inhibit adenylate cyclase
‣ E.g. alpha 2, dopamine 2-4, M2, M4 and opioid receptors
◦ Gq type - activate phospholipsae C —> membrane lipid PIP2 —> IP3 (ca release from ER ), DAG (protein kinase C activation)
‣ E.g. Alpha 1, angiotensin 2, M1 + 3 + 5
92
Once a ligand has bound to a GPCR how does downstream effect occur
1. Induced confirmational change in receptor increasing likelihood of binding with G protein in cytosol
2. G protein association on cytoplasmic face, activation via addition of GTP with displacement of GDP, and alpha subunit dissociates from beta gamma dimer and activates or inhibits other proteins. Alpha subunit a GTPase and gradually inactivates itself over time
3. The GPCR if still activated can activate further G proteins 100:1 ratio of G proteins to receptor
4. Regulation of activity does involve phosphorylation of beta arrestin which is the signal for receptor protein removal from the cell membrane
93
What is cAMP
cyclic adenosine 3-5 monophosphate
94
Adenylate cyclase is activated by which secondary messenger? What does it do?
Gs
Converts ATP to cAMP
95
What are examples of Gs protein coupled receptor ligands?
Beta adrenergic amines, glucagon, histamine, seratonin
96
How is cAMP downregulated?
Degraded by cyclic nucelotide phosphodiesterases to 5-AMP
97
What are Gi protein coupled receptor ligands?
alpha 2 amines, ACh muscurinic, opiids, seratonin
98
How does Gi protein act
Reduces adenylate cyclase
Activates cardiac K channels slownig HR
99
Gq ligands include
Seratonin 5HT2
Acetylcholine at muscarinic receptors
100
How does Gq cause downstream effect
Phsophoinositide hydrolysis occurs --> Increased phospholipase C cleaving PIP2 (phospholipid) --> Increased IP3 and DAG --> Increased cytoplasmic Ca
Binding of Ca to calcium binding protein calmodulin
IP3 inactivation by dephosphorlation, DAG phosphorylated or de-acylated to AA
101
Give 3 examples of secondary messengers
1. cAMP
2. Phosphoinositides
3. cGMP
102
cGMP is
cyclic guanosine monophosphate
103
What are the ligands for cGMP production?
ANP and nitric oxide
Cause guanylyl cyclase activity producing cGMP
104
What are the actions of cGMP
Relaxes vascular smooth muscle by dephosphorylating myosin light chain
105
What causes nitric oxide release in vascular endothelium
ACh, histamine
106
What agents possess nucleic binding domains? How do they act
Steriods
Thyroid hormone
ligand gated transcription factors meaning the DNA is confirmationally held so no transcription can occur by these inhibitory receptors —> binding = confirmational change —> permits translocation to the nucleolis —> production of mRNA
* Activity at this area then indirectly alters the production fo cellular proteins
107
Types of steriods
corticosteriods
Mineralocorticoids
Sex steriods
Vitamin D
108
What naturally inhibits glucocorticoid activity
heat shock protein - HSP90
Causes DNA to rest in inactvie confirmation state, glucocorticoids bind to this nad release HSP90 from the segment allowing for access to site
109
Explain G protein coupled receptor regulation of receptor number and activity
◦ Agonist induced change in confirmation of the receptor causes binding, activation and substrate for G protein coupled receptor kinases which phosphorylate serine residues in the receptors carboxyl terminal tail—> increasing the binding affinity for Beta arrestin —> diminished ability to interact with Gs reducing the agonist response i.e. stimulation of adenylate cyclase
◦ This process is reversed by cellular phosphatases
◦ Beta arrestin also accelerates endocytosis of the receptor in many GPCRs - promotes dephosphorylation - high phosphatase concentration in endosomes
‣ Receptors then returns o the membrane
‣ In the presence of continued activation however some GPCRs traffic to lysosomes after endocytosis e.g.Beta adrenoreceptors
110
Voltage gated channels and ligand gated channels are regulated by
Endocytosis
Phosphorylatiuon
111
Mechanisms of receptor downregulation e.g.
* Desensitisaiton of receptors repeatedly exposed to an agonist
* Proposed mechanisms
◦ Decreased receptor density via endocytosis
◦ Structural changes in receptor morphology - e.g. phosphorylation
* Examples
◦ Prolonged treatment of asthma with beta adrenergic agonist dads to tachyphylaxis due to reduced receptor density
112
Receptor upregulation mechanisms? e.g.
* Increased recetor sensitivyt after chronic deprivation fo agonist either by denervation or chronic administration of antagonist
* Proposed mechanisms
◦ Increased receptor density
◦ Improved communication between receptor and enzyme
* Example
◦ Abrupt ceasing of clonidine
◦ Abrupt ceasing of beta blockers with rebound hypertension
113
Kp is what?
Kp - dissociation constant at equilibrium
* The drug concentration at which 50% of receptors are occupied
* It is a measure of affinity as the higher the Kp the lower the affinity fo the drug
114
Explain the meyer Overton hypothesis
* Meyer-Overton hypothesis
◦ States the potency of anaesthetic agents is related to their lipid solubility
◦ Anaesthetic molecules dissolve in membranes of cells within the CNS
‣ Membrane disruption
‣ General anesthesia
◦ Not all lipid soluble drugs are general anaesthetics
◦ Other factors may also disrupt cell membrane without causing general anaesthesia
‣ E.g. increases in body temperature
115
Define isomer
Isomer molecules have the same formula but different molecular structure
Structural isomers have atoms and functional groups joined in different ways
116
Stereoisomer
Stereoisomer molecules have the same bond structure but different 3D shape
117
Enantiomer
Enantiomer molecules have the same bond structure and 3D shape, but are mirror images of each other (i.e. their shapes cannot be superimposed).
118
Racaemic mixture
a Racemic mixture is a 50/50 mix of two enantiomers, heras an enantiopure mixture only contains one enantiomer.
119
Stereoselectivity
Stereoselectivity is the phenomenon whereby biologic macromolecules (eg. enzymes) show strong binding preference for one enantiomer over another
120
What are chemical properties of enantiomers
Enantiomers rotate polarized light in opposite directions, but otherwise they have identical chemical and physical properties.
They appear distinct under Xray crystallography
They may have different reaction kinetics with chiral catalysts
They are metabolised differently by stereoselective enzymes
Crystals of enantiomers are macroscopically different
121
What implications are there of enantiomers affecting pharmacodynamics
Enantiomer-receptor interactions: obviously, some drugs will be active, and others may only be partially active, inactive or antagonistic.
Enantiomer-enantiomer interactions: in most scenarios, enantiomers are sufficiently similar that they will compete for the same protein binding sites (i.e. the inactive enantiomer will displace the active drug, making it more available)- this is seen in propoxyphene
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How does enantiomerism affect pharmacokinetics
Dose decrease is possible. For instance, one only needs to take 1mg of eszopiclone, whereas before one would have had to take a whole 2mg of racemic zopiclone.
Passive absorption is unchanged. There is no difference between the lipid or aqueous solubilities of enantiomers, so passive absorption is the
Active transport mechanisms may favour one drug over another, eg. L-dopa is absorbed more rapidly than D-dopa. A more extreme example is methotrexate: the D-enantiomer has 2.5% bioavailability as compared to the L-enantiomer, because the L-enantiomer enjoys active transport and the D-enantiomer relies on sluggish passive absorption
Stereoselectivity of first pass enzymes may result in different rates of presystemic extraction; one might end up selecting out one of the enantiomers - for example, this happens to verapimil, where systemic availability of the more active L-verapimil was 2 to 3 times smaller than for D-verapimil
Stereoselectivity of clearance mechanisms: S-ibuprofen should be 160 times more potent than R-ibuprofen, but in vivo activity is only 1.4:1 because of an in-vivo racemisation
Stereoselectivity of protein binding may result in different rates of renal clearance and dialytic removal (but there is no convenient example of this in routine use). An inconvenient foregattable example is L-tryptophan, which binds albumin 100 times more avidly than D-tryptophan
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In the context of enantiomers what do R, S, D and L and +/- refer to?
Typical nomenclature of enantiomers is to prefix the chemical name with dextro (+) or levo (-), according to optical activity - or R and S for those drugs in which the absolute configuration is known, or D and L for amino acids.
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What 2 types fo isomers are there
Structural
Stereoisomer
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What types of structural isomers are there
Static
Dynamic/tautomer - moelcule exists in different moelcular structures depending on environment
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iWhat is a tautomer? What is an example?
The molecule exists in a different molecular structures depending on the environment.
e.g. Midazolam has pH dependent imidazole ring opening. When the pH is less than 4 the ring remains open, maintaining water solubility. Midazolam is supplied at pH of 3.5, and so is water soluble on injection but (due to its pKa of 6.5) becomes 89% unionised at physiological pH therefore able to cross lipid membranes.
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What types of static isomers are there
Chain isomer
The carbon skeleton varies, but position of functional groups is static.
Position isomer
The carbon skeleton is static, but the position of functional groups varies.
e.g. Isoflurane vs. enflurane
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Define structural isomer
Identical chemical formula but different arrangement of atoms. Structural isomerism is subdivided into: Static and dyanmic
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Stereoisomers are divided into
Geometric
Optical
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Define stereoisomer
Atoms are connected in the same order in each isomer, but different orientation of functional groups. Stereoisomers are not super-imposable, meaning the different isomers can't be rotated so that they look the same. Stereoisomers are divided into:
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Define geometric isomer
Have a chemical structure (e.g. a carbon-carbon double-bond) prevents free rotation of groups, so different locations of chemical groups will create an isomer. Geometric isomers are known as cis- or trans- depending on whether the subgroups are on the same or opposite sides (respectively) of the chemical structure.
e.g. Atracurium
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Define optical isomer
Optical isomers are chiral. This means they have no plane of symmetry. Optical isomers:
Were initially named based on how they rotated under polarised light:
(Note this is different from D- and L- molecules, where the D-isomer refers to the molecule synthesised from (+)glyceraldehyde).
Dextrorotatory
(d- or (+) isomers) molecules rotate clockwise under polarised light.
Levorotatory
(l- or (-) isomers) molecules rotate counter-clockwise under polarised light.
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How are optical isomers divided
Enantiomers - 1 chiral centre
Diastereoisomers - multiple chiral centres
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