Pharmacology Flashcards
1
Q
What are drug targets?
A
Drug Target - Class of cellular macromolecules that drugs can bind to and mediate chemical signalling. This can include: Receptors, Ion channels, enzymes & transport proteins.
2
Q
What is a ligand?
A
Ligand - Substance that binds to a protein
3
Q
What is the “affinity” of a ligand?
A
Affinity = Tendency of ligand to bind to receptor
4
Q
What is a drug?
A
Drug = Chemical that affects physiological function in specific way, used in treatment, prevention and diagnosis of disease
5
Q
What is the “dose”?
A
Dose = Specified quantity of drug administered once or at stated intervals
6
Q
What are receptors?
A
Receptors = Class of macromolecules concerned specifically and directly with chemical signalling. Should display stereoselectivity to ligand isomers.
7
Q
Structurally, what are the 4 receptor superfamilies?
A
4 receptor superfamilies: ligand gated ion channel receptors, G-Protein coupled receptors, Kinase-linked receptors or nuclear receptors.
8
Q
What is the pharmacodynamics?
A
Pharmacodynamics:
- What drug does to the body
- Affinity, potency, efficacy. Calculating Ki, EC50, Emax
9
Q
What is the pharmacokinetics?
A
Pharmacokinetics:
- What body does to the drug
- Absorption, Distribution, Metabolism & excretion
- Volume of distribution, elimination half life, clearance or bioavailability
10
Q
- What are ligand gated ion channels also known as?
- What do ligand gated ion channels lead to, when activated?
- How long does it take for ligand gated ion channels to initiate their cellular effects?
- What is an example of a ligand gated ion channel?
A
- Ionotropic receptors
- Hyperpolarisation or Depolarisation
- Milliseconds
- Nicotinic Ach Receptor
11
Q
- What are G-Protein Coupled Receptors also known as?
- What do G-Protein Coupled Receptors lead to, when activated?
- How long does it take for G-Protein Coupled Receptors to initiate their cellular effects?
- What is an example of a G-Protein Coupled Receptor?
A
- Metabotropic receptors
- They can either lead to a change in excitability, or the activation of second messengers
- Seconds
- Muscarinic ACh Receptor
12
Q
- What do kinase-linked receptors lead to, when activated?
- How long does it take for kinase-linked receptors to initiate their cellular effects?
- What is an example of a kinase-linked receptor?
A
- Protein Phosphorylation -> Gene transcription -> Protein synthesis
- Hours
- Cytokine Receptors
13
Q
- What do nuclear receptors lead to, when activated?
- How long does it take for nuclear receptors to initiate their cellular effects?
- What is an example of a nuclear receptor?
A
- Gene Transcription -> Protein Synthesis
- Hours
- Oestrogen Receptor
14
Q
What are G Protein’s?
A
G Protein’s:
- Peripheral membrane protein
- 3 polypeptide subunits (alpha, beta, gamma)
- G nucleotide binding site in alpha subunit, that can hold GTP or GDP
15
Q
How do G-Protein Coupled Receptors work? What steps are involved?
A
No signalling:
1. Receptor unoccupied
2. Alpha subunit binding site occupied by GDP
3. Effector is not modulated
Turning signal on:
1. Agonist activates receptor, causing a conformational change
2. G protein couples with receptor
3. Alpha subunit releases GDP and GTP binds in its place
4. Alpha subunit dissociates from receptor and beta-gamma dimer (Alpha subunit and beta-gamma dimer are both signalling units)
5. Alpha subunit combines with effector and modifies its activity
6. Agonist may dissociates from receptor but signalling can persist because G protein and receptor are now separate
16
Q
How can you turn a G-Protein signal off?
A
Turning signal off:
1. Alpha subunit acts as an enzyme - hydrolyses GTP to GDP & Pi (Signal is now off)
2. Alpha subunit recombines with beta-gamma subunit
17
Q
What does passive diffusion involve?
A
Passive diffusion:
- Directly through lipid bilayer/ aquaporins
- Drugs with high lipid solubility - high conc gradient
18
Q
- What does facilitated diffusion take place via?
- Does this require energy?
- Do the molecules move down or against the conc gradient?
- Are the drugs, which use facilitated diffusion, generally lipid or water soluble?
- What is a characteristic of facilitated diffusion?
A
- Via specialised carrier proteins
- No, energy is not required
- Movement is down the conc gradient
- Water soluble drugs are generally involved
- Can show saturation kinetics - limited amount of carriers
19
Q
- What does active transport take place via?
- Does this require energy?
- Do the molecules move down or against the conc gradient?
- Are the drugs, which use active transport, generally lipid or water soluble?
- What is a characteristic of active transport?
A
- Via specialised carrier proteins
- Yes, requires energy - ATP hydrolysis or Symport/Antiport
- Movement is against the conc gradient
- Water soluble drugs
- Can show saturation kinetics
20
Q
What are some principal sites of carrier mediated drug transport?
A
- Blood Brain Barrier
- GI Tract
- Placenta
- Renal Tubule
- Biliary Tract
21
Q
What does endocytosis involve?
A
Endocytosis:
- Invagination of a part of the membrane
- Drug is encased in a small vesicle, then ‘released’ inside the cell
- Transport of large drugs across cell membrane
22
Q
With regard to ionisation:
Only __________ forms readily diffuse across the lipid bilayer
A
Only unionised forms readily diffuse across the lipid bilayer.
23
Q
What does the degree of ionisation of a drug depend on?
A
Degree of ionisation depends on pKa of drug and local pH
24
Q
What is the pKa of a drug?
A
pKa: pH at which 50% of the drug is ionised and 50% is unionised
25
What is the Henderson-Hasselbalch equation used for?
What is the Henderson Hasselbalch equation?
What does it allow you to determine?
Henderson-Hasselbalch equation is used to determine proportions of ionised and unionised drugs in a given pH environment. The equation can be seen below:
pKa = pH + log(AH/A-)
It allows you to determine how active a drug may be in the body.
26
At what pH are acidic drugs:
- Unionised
- Ionised
For acidic drugs:
- Low pH - Unionised
- High pH - Ionised
Vice versa for bases
27
What does pH trapping involve?
Where do weak bases accumulate?
Are weak or strong acids/bases absorbed better?
pH trapping: ‘Trap’ a particular drug based on its physiochemical property in compartments that have a particular pH
Weak bases accumulate in compartments with low pH
(& reverse).
Weak acids and bases are better absorbed than strong ones.
28
Where in the GI tract are weak acids absorbed?
Where in the GI tract are weak bases absorbed?
What compartment of the GI tract does the majority of absorption take place in?
Stomach = Weak acid absorption
Intestine = Weak base absorption
Majority of absorption = intestine (cause of Large SA)
29
What are the 6 different routes of administration of a drug?
Administration:
- Oral or Rectal -> Gut
- Percutaneous -> Skin
- Intravenous -> Plasma
- Intramuscular -> Muscle
- Intrathecal -> CSF
- Inhalation -> Lungs
30
What are the 4 different routes of elimination of a drug?
Elimination:
- Urine
- Faeces
- Milk, Sweat
- Expired Air
31
What does ADME stand for?
Absorption: drug is absorbed from site of administration, entry into the plasma
Distribution: Drug leaves bloodstream and is distributed into interstitial and intracellular fluids
Metabolism: Drug transformation by metabolism - liver & other tissues
Excretion: Drug & drug metabolites excreted in urine, faeces or bile
32
What does the “apparent volume of distribution” refer to?
Apparent volume of distribution (Vd): extent to which a drug partitions between the plasma and tissue compartments
33
What does a Low Vd mean?
What does a High Vd mean?
Low Vd = drugs retained in vascular compartments (hydrophilic)
High Vd = Drugs retained in non vascular compartments - Adipose, Muscle etc (Lipophilic/ Unionised)
34
What is the equation for Vd?
Vd = dose/ [drug]plasma
35
What is albumin?
Albumin is the most abundant plasma protein, binds mainly to acidic drugs.
36
What is the effect of plasma protein binding on Vd?
Plasma protein binding affects Vd:
- Reduces the ability of the drug for diffusion to target organ
- May also reduce transport of the drug to non vascular compartments
37
What does drug metabolism refer to?
Drug metabolism: Enzymatic conversion of the drug to another chemical entity
38
What is the most important metabolic organ?
Liver = most important metabolic organ (kidney, gut mucosa, lungs and skin also contribute)
Phase I and II both take place in liver.
39
What is the effect of metabolism in the liver on orally administered drugs?
Metabolism in liver (+ gut) reduces bioavailability of drugs when administered orally.
40
What are hepatic drug metabolising enzymes embedded in?
Hepatic drug metabolising enzymes are embedded in the SER of hepatocytes.
41
What is the ‘bioavailability’ of a drug?
Bioavailability: Amount/ Proportion of drug (dose administered) that eventually reaches systemic circulation. Hence available for action on target.
42
What is the equation for bioavailability?
F (bioavailability) = AUC/ dose
AUC - Quantity of drug that reaches systemic circulation
Dose - Quantity of drug administered
43
What are the 2 main drug metabolism stages?
Drug metabolism stages:
1. ‘First pass’/ pre systemic metabolism - Occurs with oral route, drug absorbed in gut transported to liver, decreases bioavailability
2. Systemic metabolism - Phase I & II
44
What does Phase I metabolism involve?
Phase I metabolism: change in the drug by oxidation, reduction or hydrolysis.
Usually results in pharmacologically active and/or toxic metabolites.
45
What is oxidation accomplished by?
Oxidation is accomplished by cytochrome P450 enzymes in the ER.
46
1. What are cytochrome P450 enzymes?
2. What is there activity determined by?
3. Can drugs interact with P450 system?
1. Cytochrome P450 enzymes are a family of haem proteins.
2. Their activity is genetically determined:
- Some people lack activity - higher drug plasma levels
- High levels of activity = reduced drug action
3. Yes, other drugs can interact with P450 system - increase or decrease activity
47
What is involved in Phase II metabolism?
What does it usually involve?
What happens to the biological activity of the drug in this Phase?
Where can the products be readily excreted?
Phase II metabolism: involve the combination of the drug with one of several polar molecules to from a water soluble metabolite - conjugation
- Usually involves the reactive group produced by Phase I
- Usually terminates all biological activity
- Products can be readily excreted via kidney
48
What is an example of a drug which can go directly to Phase II metabolism? What is the impact of this?
Some drugs (e.g codeine) can go directly to Phase II metabolism:
- Can produce metabolites that are pharmacologically active
49
What is glucuronidation?
What enzyme is used in this process?
What co factor is used?
Glucuronidation = Phase II reaction example:
- Enzyme - Uridine diphosphate-glucoronosyltransferases
- Cofactor - Uridine diphosphate glucuronic acid
50
What are the 2 stages involved in drugs elimination?
Metabolism & excretion
51
Where is the majority of a drug eliminated?
Renal filtration (Kidney)
- Does most of drug elimination
- Water & electrolytes reabsorbed into blood in renal tubules
- Drug metabolites - excreted in urine
52
What is the “Clearance” of a drug?
Clearance (CL) = Elimination of the drug from the body/ volume of blood removed of drug per min or hour etc.
53
What is involved in total clearance?
Hepatic vs renal clearance + skin etc => Total clearance
54
How can a steady state be reached?
Steady state occurs when:
Rate of administration = Rate of elimination
55
What is the dosage rate (for SS for IV)?
What is the dosage rate (for SS)?
Dosage rate (for SS for IV) = [drug]plasma x CL
Dosage rate (for SS) = [drug]plasma
56
What order of kinetics does drug plasma conc start at, and what about when it reaches Vmax?
Drug plasma conc. starts first order kinetics, ends zero order kinetics when Vmax is reached
57
What is the elimination half life determined by?
Determined by Vd and CL
58
What is the equation for elimination half life?
T1/2 = 0.693 x Vd/CL
CL increases, T1/2 decreases vice versa
Vd increases T1/2 increases vice versa
59
What are some factors which affect Vd?
Do they cause an increase or decrease in Vd?
Therefore what is the effect of these factors on t1/2?
- Ageing - ⬇️ muscle mass ⬇️ Vd ⬇️ t1/2
- Obesity - ⬆️ adipose ⬆️ Vd ⬆️ t1/2
- Pathological fluid - ⬆️ Vd ⬆️ t1/2
60
What are some factors which affect CL?
Do they cause an increase or decrease in CL?
Therefore what is the effect of these factors on t1/2?
- Cytochrome P450 Induction - ⬆️ CL ⬇️ t1/2
- Cytochrome P450 Inhibition - ⬇️ CL ⬆️ t1/2
- Cardiac/ Hepatic/ Renal Failure - ⬇️ CL ⬆️ t1/2
61
What is the efficacy of a drug?
Efficacy = Tendency of agonist to activate receptor resulting in biological response
62
What is the “drug potency”?
Drug potency = Expression of drug activity in terms of concentration needed to produce defined effect
63
What is the drug potency dependent upon?
It is dependent on receptor (affinity, efficacy) and tissue (receptor numbers, drug accessibility).
64
What is the EC50?
EC50 - Conc of agonist that elicits half maximal effect
65
What is the “selectivity” of a drug?
Selectivity: the ability of a drug to distinguish between different molecular targets within the body
66
What is an agonist?
Agonist = Results in biological response after it (a ligand) binds. Affinity and efficacy.
67
What is a partial (vs full) agonist?
Partial (vs full) agonist - Agonist that cannot elicit as large an effect (even with 100% occupancy), as another acting on the same receptor and same tissue. Differing efficacy and potentially affinity.
68
What is The Two State Model?
The Two State Model:
1. Receptor occupancy (affinity)
2. Receptor activation - amplification etc. (efficacy)
69
What is an antagonist?
Antagonist - Reduces action of another drug. Only affinity, not efficacy
70
What are the 4 main branches of antagonism?
Antagonism:
1. Reversible competitive antagonism
2. Irreversible competitive antagonism
3. Non competitive antagonism
4. Others
71
What does reversible competitive antagonism involve?
Reversible competitive antagonism:
- Surmountable over wide range of agonist conc (agonist will eventually override antagonist)
- In antagonist presence conc response curve of agonist will shift right but not change shape
72
What does irreversible competitive antagonism involve?
Irreversible competitive antagonism:
- % maximal response reduce, insurmountable
73
What does non competitive antagonism involve?
Non competitive antagonism:
- Irreversible or reversible
- Antagonist and agonist can bind at same time
- Receptor only active when agonist alone is bound
74
What are 3 others forms of antagonism?
Other forms of antagonism:
A. Chemical antagonism - combines in solution with agonist
B. Physiological antagonism - Two agonists with opposing actions cancel each other out
C. Pharmacokinetic antagonism - Antagonist reduces active drug form
75
What is the Orthosteric site?
Orthosteric site = Active Site, vs Allosteric Site
76
What are the 3 components of the Autonomic NS?
Enteric, Sympathetic & Parasympathetic division
77
In the Motor ANS:
Do pre ganglionic fibres tend to be myelinated or unmyelinated?
Do post ganglionic fibres tend to be myelinated or unmyelinated?
Pre ganglionic neurons - Tend to be myelinated, white appearance
Post ganglionic neurons - Tend to be unmyelinated, grey appearance
78
Where are ganglia located in Sympathetic NS?
Ganglia in Sympathetic NS
- Paravertebral ganglia
- (Preganglionic neurons = short axons)
79
Where are ganglia located in the Parasympathetic NS?
Ganglia in Parasympathetic NS
- Terminal ganglia
- (Preganglionic neurons = long axons)
80
Where is sympathetic outflow from the spinal cord?
Sympathetic outflow is from Thoracic and Lumbar regions
81
Where is parasympathetic outflow from the spinal cord?
Parasympathetic outflow from cranial (3/7/9/10) and sacral regions
82
What neurotransmitter do sympathetic and parasympathetic preganglionic fibres transmit?
What receptor does this neurotransmitter act on?
Sympathetic & parasympathetic preganglionic fibres release ACh which acts on Nicotinic cholinergic receptors.
83
What neurotransmitter do sympathetic post ganglionic fibres transmit?
What receptor does this neurotransmitter act on?
They release noradrenaline which acts on alpha or beta adrenergic receptors.
84
What neurotransmitter do parasympathetic post ganglionic fibres transmit?
What receptor does this neurotransmitter act on?
They release ACh which acts on muscarinic cholinergic receptors.
85
How many subtypes of ACh muscarinic receptors are there?
5 subtypes, expressed across tissues/organs, 1-3 most important in ANS
86
How many subtypes of alpha and beta adrenergic receptors are there?
Alpha 1/2, Beta 1/2/3
87
What other neurotransmitters are involved in the parasympathetic system?
As well as ACh, there is NO & VIP
88
What other neurotransmitters are involved in the sympathetic system?
As well as NA, there is ATP & NPY
89
What type of receptor is a Nicotinic ACh receptor?
A ligand gated ion channel
90
What type of receptor is a Muscarinic ACh receptor?
A G Protein Coupled Receptor
91
What type of receptor are adrenoreceptors?
They are G protein coupled receptors.
92
What is the effect of the sympathetic system on HR?
What receptor is involved?
Increases HR (Beta 1)
93
What is the effect of the sympathetic system on force of contraction in atria & ventricles?
What receptor is involved?
Increases force of contraction in atria and ventricles (Beta 1)
94
What is the effect of the sympathetic system on bronchi?
What receptor is involved?
Relaxes bronchi (Beta 2)
95
What is the effect of the sympathetic system on mucus production?
What receptor is involved?
Decreases mucus production (Beta 2)
(Decreased airway resistance)
96
What is the effect of the sympathetic system on intestinal motility?
What receptor is involved?
Reduces intestinal motility (Alpha 1, Alpha 2, Beta 2)
97
What is the effect of the sympathetic system on sphincter muscles in the intestines?
What receptor is involved?
Constricts sphincters (Alpha 1, Alpha 2, Beta 2)
98
What is the effect of the sympathetic system on vasculature?
What receptor is involved?
Constricts vasculature in most locations (Alpha 1), but relaxes in skeletal muscle (Beta 2)
99
What is the effect of the sympathetic system on the bladder?
What receptor is involved?
Relaxes wall (detrusor) of bladder (Beta 2/ Beta 3)
100
What is the effect of the sympathetic system on internal urethral sphincter?
What receptor is involved?
Constricts internal urethral sphincter (Alpha 1)
101
What is the effect of the sympathetic system on the male reproductive system?
What receptor is involved?
Stimulates ejaculation (Alpha 1)
102
What is the effect of the parasympathetic system on HR?
What receptor is involved?
Decreases HR (M2)
103
What is the effect of the parasympathetic system on force in the atria?
What receptor is involved?
Decreases force in atria (M2)
104
What is the effect of the parasympathetic system on bronchi?
What receptor is involved?
Constricts bronchi (M3)
105
What is the effect of the parasympathetic system on mucus production?
What receptor is involved?
Stimulates mucus production (M3)
(Increased airway resistance)
106
What is the effect of the parasympathetic system on intestinal motility & secretions?
What receptor is involved?
Increases intestinal motility & secretions (M3)
107
What is the effect of the parasympathetic system on sphincters in the intestines?
What receptor is involved?
Relaxes sphincters (NO, M3)
108
What is the effect of the parasympathetic system on vasculature?
What receptor is involved?
Largely no effect, but relaxes vasculature in a few locations (e.g penis, salivary glands, pancreas (NO, M3))
109
What is the effect of the parasympathetic system on the bladder?
What receptor is involved?
Contracts wall of bladder (M3)
110
What is the effect of the parasympathetic system on internal urethral sphincter?
What receptor is involved?
Relaxes internal urethral sphincter (NO)
111
What is the effect of the parasympathetic system on the male reproductive system?
What receptor is involved?
Stimulates penile erection (NO, M3)
112
What are the steps involved in autonomic ganglia (Nicotinic ACh) Synaptic transmission?
Pre synaptic:
1. ACh synthesis
a. Mitochondria produce AcCoA
b. Choline uptake by CHTransporter
c. Enzyme choline acetyltransferase mediates reaction to produce ACh
2. ACh stored in vesicle (along with ATP & other anions)
3. Depolarisation -> Ca2+ influx -> Exocytosis
Synaptic:
4. ACh receptor activation (Nicotinic/ Muscarinic)
5. ACh degraded to acetate & choline by AChE
6. Reuptake and reuse of Choline
Post synaptic:
7. Excitatory Postsynaptic Potential (EPSP) meets threshold
8. Activation of V-gated Na Channels
9. Action Potential
113
What are 3 mechanisms by which synaptic transmission in autonomic ganglia can be blocked?
Give examples of a drug which uses each mechanism.
Mechanisms:
- Depolarisation block by high agonist conc e.g nicotine
- Competitive antagonism e.g trimetaphan
- Non competitive antagonism e.g open channel block by hexamethonium
114
With regard to the arterioles:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the arterioles?
1. Sympathetic (adrenergic)
2. Vasodilation; Increased peripheral blood flow; Hypotension
115
With regard to the veins:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the veins?
1. Sympathetic (adrenergic)
2. Vasodilation; Increasing pooling of blood; Decreased venous return; Decreased cardiac output
116
With regard to the Heart:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the Heart?
1. Parasympathetic (cholinergic)
2. Tachycardia
117
With regard to the Iris:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the Iris?
1. Parasympathetic (cholinergic)
2. Mydriasis (pupil constriction)
118
With regard to the ciliary muscle:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the ciliary muscle?
1. Parasympathetic (cholinergic)
2. Cycloplegia (focused for far vision)
119
With regard to the GI Tract:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the GI Tract?
1. Parasympathetic (cholinergic)
2. Decreased tone & motility; Constipation; Decreased secretions
120
With regard to the bladder:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the bladder?
1. Parasympathetic (cholinergic)
2. Urinary retention
121
With regard to the salivary glands:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the salivary glands?
1. Parasympathetic (cholinergic)
2. Xerostomia (dry mouth)
122
With regard to the sweat glands:
1. Does the sympathetic or parasympathetic system display a predominant tone?
2. What are the effects of autonomic ganglion blockade on the sweat glands?
1. Sympathetic (cholinergic)
2. Anhidrosis (absence of sweating)
123
What are the steps of synaptic transmission at the Parasympathetic Neuroeffector Junction (Muscarinic ACh)?
1. Synthesis & storage of ACh as previously described
2. Depolarisation by Action Potential
3. Ca2+ influx through V-activated Ca2+ channels
4. Ca2+ induced release of ACh (exocytosis)
5. Activation of muscarinic ACh receptor subtypes (M1-M3) causing cellular response (tissue dependent)
6. Degradation of ACh to choline and acetate by AChE - terminates transmission
7. Reuptake and reuse of Choline
124
1. What subtype of muscarinic receptor can be found in the stomach?
2. What effect does activation of this receptor have on acid secretion in the stomach?
3. When the receptor is activated, what 2nd messengers are involved to contribute to the change in acid secretion?
1. M1 Receptor
2. Increased Acid Secretion
3. M1 activation -> Gq protein -> Stimulation of Phospholipase C -> Increased Acid Secretion
125
1. What subtype of muscarinic receptor can be found in the Heart?
2. What effect does activation of this receptor have on Heart rate?
3. When the receptor is activated, what 2nd messengers are involved to contribute to the change in Heart Rate?
1. M2 receptor
2. Decreased Heart Rate
3. M2 activation -> Gi protein -> Inhibition of Adenylyl Cyclase; opening of K+ channels -> Decreased HR
126
1. What subtype of muscarinic receptor can be found in the bronchi & salivary glands?
2. What effect does activation of this receptor have on the bronchi & the salivary glands?
3. When the receptor is activated, what 2nd messengers are involved to contribute to the change in the bronchi & salivary glands?
1. M3 Receptor
2. Causes bronchoconstriction & increased saliva secretion
3. M3 Receptor -> Gq protein -> Stimulation of phospholipase C -> Contraction of Bronchi & increased saliva secretion
127
What are the steps of Synaptic Transmission at Sympathetic Neuroeffector Junctions (Adrenoceptor NA)?
1. Synthesis of NA (multiple steps)
2. Storage of NA by transporter (concentrates)
3. Depolarisation by Action Potential
4. Ca2+ influx through V-activated Ca2+ channels
5. Ca2+ induced release of NA
6. Activation of adrenoceptor subtypes causing cellular response (tissue dependent)
7. Reuptake of NA by transporters uptake 1 (U1) and uptake 2 (U2)
8. Metabolism of NA by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
128
What subunit do Beta 2 receptors contain?
Where can Beta 2 receptors be found?
What 2nd messengers are involved when Beta 2 receptors are activated?
What is the effect of activation of Beta 2 receptors?
Beta 2 adrenoceptors:
- Gas subunit
- In lungs
- Adenylyl cyclase activation → cAMP → Protein Kinase A → MLCK inhibition
- BRONCHODILATION
129
What subunit do Alpha 1 receptors contain?
Where can Alpha 1 receptors be found?
What 2nd messengers are involved when Alpha 1 receptors are activated?
What is the effect of activation of Alpha 1 receptors?
Alpha 1 adrenoceptors:
- Gq subunit
- In blood vessels
- Phospholipase C → DAG & IP3 formed → Calcium ion conc increases → MLCK stimulation
- VASOCONSTRICTION
130
What subunit do Alpha 2 receptors contain?
Where can Alpha 2 receptors be found?
What 2nd messengers are involved when Alpha 2 receptors are activated?
What is the effect of activation of Alpha 2 receptors?
Alpha 2 adrenoceptor:
- Gai subunit
- In GI tract
- Adenylyl cyclase inhibition → ATP not converted to cAMP
- GI TRACT RELAXATION (& Noradrenaline inhibition in CNS)
131
In what ways are Beta 1 and 3 similar/ different to Beta 2?
Beta 1 and 3 have same pathway, but different functions to Beta 2.
132
What is the main function of activation of Beta 1 receptors?
Beta 1 - Increased HR and Cardiac Contraction
133
What is the main function of activation of Beta 3 receptors?
Beta 3 - Thermogenesis in skeletal muscle, lipolysis
134
What drug is an agonist for all adrenergic receptors?
Adrenaline
135
What drug is an agonist for only Beta 1/2 adrenergic receptors?
Isoprenaline
136
What drug is an agonist for only Beta 2 adrenergic receptors?
Salbutamol
137
Why might salbutamol not be a good long term drug for treating Asthma/ COPD?
Instead, what drug could be used?
Asthma/ COPD
- Long term salbutamol = receptor down regulation
- Instead use theophylline, which prevents cAMP termination by PDE
138
What receptor is located on the axon terminals of post ganglionic parasympathetic neurons, to help modulate the release of Acetylcholine?
M2 Receptor (Agonists of the M2 receptor decrease influx of Ca2+, and therefore decrease neurotransmitter release).
139
What receptor is located on the axon terminals of post ganglionic sympathetic neurons, to help modulate the release of Noradrenaline?
Alpha 2 receptor (Agonists of Alpha 2 receptors decrease influx of Ca2+, decreasing release of Noradrenaline)
140
There are 4 drugs which impact on cholinergic transmission, these can be seen below:
- Nicotinic tubocurarine
- Botulinum
- Hemicholinium
- Neostigamine
What are the modes of action of these drugs?
Nicotinic tubocurarine - Direct agonist/ antagonist to post synaptic receptor
Botulinum - Directly affects neurotransmitter release
Hemicholinium - Directly inhibits choline uptake carriers
Neostigamine - Directly inhibit metabolising enzymes e.g AChE
141
What is the mode of action and use of Atropine?
Atropine:
- Muscarinic ACh receptor (1,2 & 3)
- Parasympathetic ANS blockade
- Reverses bradycardia following MI & in anticholinesterase poisining
142
What is the mode of action of Cocaine?
What is the physiological effects of the drug?
Cocaine:
- Blocks presynaptic neuron NA transporter uptake
- Increased adrenoceptor stimulation
- Peripheral vasoconstriction, cardiac arrhythmias…
143
What is the mode of action of Amphetamine?
What are the physiological effects of the drug?
Amphetamine:
- Inhibits MAO (responsible for NA metabolism)
- Increased adrenoceptor stimulation
- Peripheral actions
144
What is the mode of action of Prazosin?
What are its physiological effects?
Therefore what is a potential use of the drug?
Prazosin:
- Selective Alpha 1 competitive antagonist
- Vasodilator
- Antihypertensive agent
145
What is the mode of action of Atenolol?
What are its physiological effects?
Therefore what is a potential use of the drug?
Atenolol:
- Selective Beta 1 competitive antagonist
- Slows Heart Rate
- Anti-angina & anti-hypertensive
146
What is the mode of action of salbutamol?
What are its physiological effects?
Therefore what is a potential use of the drug?
Salbutamol:
- Selective Beta 2 agonist
- Bronchodilator - Asthma
147
What does MEC stand for?
What does MTC stand for?
MEC = Minimum effective concentration
MTC = Maximum tolerated concentration
148
What is the Therapeutic Ratio?
Therapeutic Ratio = MTC/MEC
The higher the TR the safer the drug
149
Glomerular filtration takes place in the proximal tubules of the kidneys.
Epithelial cells of the proximal tubule contain 2 transporter systems.
1. What do these transporter systems do?
2. What are the 2 different transporter systems?
3. What types of drugs does each transporter system handle?
1. The 2 transporter systems actively secrete drugs to lumen of nephron
2. The 2 transporter systems include:
- Organic anion transporter
- Organic cation transporter
3. The organic anion transporter:
- Handles acidic drugs
- Penicillins, uric acid, frusemide, thiazides
The organic cation transporter:
- Handles basic drugs
- Morphine
150
What factors influence the reabsorption of drugs in the proximal tubule of the kidneys?
Factors influencing reabsorption:
- Lipid solubility
- Polarity
- Urinary flow rate
- Urinary pH
- Alkaline - increases excretion of acids
- Acidic - increases excretion of bases
