Phys and pharm 1 Flashcards
1
Q
What is pharmacology?
A
The study of mechanisms by which drugs (biologically active compounds) affect the function of living systems
2
Q
Define the term receptor
A
A protein that when bound to a ligand transmits a signal which turns on or off a specific biological response
3
Q
What is an agonist?
A
A drug that binds to a receptor producing a response
4
Q
What is an antagonist?
A
A drug that binds to a receptor and prevents the agonist from binding
5
Q
What is a ligand?
A
A general term for a molecule which binds specifically to a receptor and thus has affinity. It may or may not have efficacy
6
Q
Define affinity
A
A measure of how strongly something binds to a receptor
7
Q
Define efficacy
A
A measure of the effect on some biological property
8
Q
Define occupancy
A
The proportion of receptors occupied. (Will vary with the agonist concentration)
Occupancy = (number of receptors occupied)/(total number of receptors)
9
Q
How can occupancy be measured directly?
A
Radioligand binding
10
Q
What are the five steps of radioligand binding?
A
1) Prepare cells or membranes - detergent treatment and centrifugation
2) Aliquot out membranes onto filters
3) Add radiolabel at different concentrations and equilibrate
4) When equilibrated remove unbound drug by filtration (bound drug remains attached to filter)
5) Count radioactivity of filter
11
Q
Define mass action
A
Rate of a reversible chemical reaction is proportional to the product of the concentration of the reactants
12
Q
What is the equation for the agonist concentration required to occupy 50% of the receptors?
A
Xa = Kd where Kd is the dissociation constant and Xa is the concentration when agonist X is added
13
Q
What is the Langmuir equation?
A
Pa = (Xa)/(Xa + Kd)
14
Q
What is the Langmuir equation used for?
A
To fit the experimental binding data
15
Q
How do you convert occupancy to actual values?
A
Multiply by Bmax Bound = (BmaxXa)/(Xa + Kd)
16
Q
What does Kd give an estimate of?
A
Affinity, high Kd = low affinity and vica versa
17
Q
Why may binding and response curves differ?
A
The response is often several steps downstream from the binding
18
Q
What is EC50?
A
Measure of drug potency, the lower the EC50 value, the higher the potency. Concentration of agonist evoking 50% of the response
19
Q
Define affintity
A
The probability of a drug molecule binding to a free drug receptor at any given instant
20
Q
Define efficacy
A
The ability of a drug to evoke a response by binding to a receptor
21
Q
Antagonism can be divided into 5 different classes, what are these?
A
1) Chemical 2) Pharmacokinetics 3) Physiological 4) Non-competitive 5) Competitive
22
Q
What is chemical antagonism?
A
Agonist is chemically altered by antagonist
23
Q
What is pharmacokinetic antagonism?
A
Reduction of the amount of drug absorbed by change in rate of renal excretion of agonist and/or change in drug metabolism
24
Q
What is physiological antagonism?
A
The interaction of two drugs with opposing actions in the body
25
What is non-competitive antagonism?
Blocks some steps in the process between receptor activation and response. Does not compete with agonist for the receptor site
26
What is competitive antagonism?
Act at the level of the receptor and so compete with the agonist for occupancy of the receptor
27
Competitive antagonists can be sub divided into?
Reversible and irreversible
28
How does reversible competitive antagonism affect concentration response curves?
There is a parallel shift to the right with increasing antagonist concentration, the max is not changed
29
Define dose ratio
How many more times agonist is needed in the presence of an antagonist DR = [agonist in presence of antagonist]/[agonist in presence of antagonist]
30
Define pA2
Minus vlaue of where Schild plot crosses x axis
-log10(molar concentration of antagonist that gives a dose ratio of 2)
antagonists with high pA2 are more potent than those with low pA2 values
31
Define pharmacokinetics
How drugs are processed in the body
32
What are the four ways drugs are processed?
1) absorption 2) distribution 3) excretion 4) metabolism
33
What factors affect absorption of a drug?
Site/method of administration, molecular weight - affects rate of diffusion, lipid solubility - ability to cross lipid membrane by diffusion, pH and ionisation - only uncharged species can cross lipid bilayer, carrier mediated transport - active or facilitated for polar molecules
34
What are the 3 methods of excretion?
1) renal 2) GI 3) lung
35
What are pharmacokinetic models used for?
Predict time course of drug action taking into account absorption, distribution, metabolism and elimination
36
Define the term drug
Any compound that can modify the physiological/biological function of living organisms
37
How do ion channel blockers work?
Drug sits in channel to affect permeation
38
How do ion channel modulators work?
Drug binds to the channel protein to affect gating
39
Define false substrates
Drug used by enzyme to genreate abnormal product (e.g. amphetamines)
40
Define pro-drugs
Molecule first requires modification by enzyme before being active (cocaine)
41
What are the three main classes of cell surface receptors?
1) Ligand-gated ion channels 2) GPCR 3) Enzyme linked receptors
42
What is the basic structure of a GPCR?
Single polypeptide chain, all possess 7TM domains (a helical), ligand binding - extracellular domain or buried within TM2&3, all are glycoproteins, some may function as dimers, 3rd intracellular loop responsible for G-protein interaction
43
What is the basic structure of heteromeric G-proteins?
Made up of 3 subunits, alpha, beta, gamma. Couples the GPCR to an effector protein, has intrinsic GTPase activity
44
What are the five steps of GPCRs when activated?
1) Binding of ligand induces conformational change in receptor
2) Activated receptor binds to Ga subunit (activated ligand bound receptor acts as GEF)
3) Binding induces conformational change in Ga; bound GDP dissociates and is replaced by GTP; Ga dissociates from Gbeta gamma
4) Hormone dissociates from receptor; Ga binds to effector activating it
5) Hydrolysis of GTP to GDP causes Ga to dissociate from effector and reassociate with Gbeta gamma
45
Define second messengers
Small diffusible moelcules that relay signals from an effector protein to target molecules
46
What is the basic structure of receptor tyrosine kinase?
Extracellular ligand binding domain, transmembrane domain, intracellular tyrosine kinase domain
47
What are the 3 steps in tyrosine kinase activation?
1) Ligand binding 2) Dimerisation 3) Tyrosine phosphorylation
48
What do adrenoceptors do?
Mediate the actions of adrenaline and noradrenaline
49
Distinguish between adrenaline and noradrenaline
Adrenaline is a hormone released by chromaffin cells in the adrenal medulla, noradrenaline is a neurotrnasmitter released by noradrenergic neurons in the central and autonomic nervous systems
50
What do the central noradrenergic systems participate in modulating?
Attention, memory/learning and (sexual) arousal
51
Distinguish between sympathetic activity and parasympathetic activity
Sympathetic activity increases at times of stress, parasympathetic brings things back to normal
52
What are variscosities?
Where sympatheric axons terminally branch. They are able to release noradrenaline at the post ganglionic neuroeffector junction
53
What are the key steps in adrenergic transmission?
1) synthesis: NA is synthesised from tyrosine within the nerve terminal. Tyrosine is converted into DOPA and then to dopamine in the cytoplasm. Dopamine is taken up into vesicles where it is converted to NA. Adrenal medulla chromaffin cells express phenylethanolamine N-methyltransferase which converts noradrenaline to adrenaline.
2) Storage: NA terminal vesicles possess a dopamine/NA transporter that allows accumulation of noradrenaline at high concentrations inside vesicles.
3) Release: NA release is triggered by depolarisation of the nerve terminal, calcium influx and vesicle fusion with the pre-synaptic plasma membrane
4) Signal transmission: Released NA can bind to adrenoceptors
5) Signal termination: NA is rapidly removed from the synaptic cleft
6) Metabolism
54
Define asthma
Chronic inflammatory disease associated with smooth muscle hyperresponsiveness
55
How can difficulty breathing out during an asthma attack be measured?
FEV1 (forced expiratory volume in 1 second)
56
What are the two types of modern treatment for asthmatics?
Prophylaxis - prevent/reduce inflammation using anti-inflammatory agents, symtomatic relief - rapid reversal of bronchoconstriction
57
What is the function of the vascular system?
To supply oxygenated blood and nutrients to tissues and to remove waste products
58
Blood vessels have three layers, what are these?
Connective tissue adventitia, smooth muscle layer and endothelium
59
What is the blood-brain barrier?
Endothelium of the cerebral capillaries and the choroids plexus epithelium form tight junctions, drugs cannot pass between cells so must cross membrane. This is a barrier for systematic drugs, only water, CO2 and O2 enter the brain with ease
60
What is the function of the blood-brain barrier?
Helps maintain a constant environment around neurons
61
What are lympahtics and what do they do?
They act as a filter at the lymph nodes and remove foreign particles such as basteria
62
What is an Oedma?
Block of lymph flow
63
What is the blood pressure of a normal adult at rest?
120systolic/70mmHg diastolic
64
What is cardiac output?
The volume of blood the heart pumps at a given time (Blood flow at any level of circulation)
CO = HR x SV
65
What is the equation for velocity of blood flow?
Velocity = flow rate/cross-sectional area
66
How is hypertension defined?
Diastolic arterial BP > 90mmHg
67
What are three different voltage dependent calcium channels?
N-type - on neurons involved with transmitter release, T-type - in brain and heart, transient openinf, L-type - on smooth muscle, long lasting
68
Distinguish between primary and secondary hypertension
Primary HT - no apparent cause, associated risk factors are genetic predisposition, obesity, alcohol consumption, lack of exercise, smoking
Secondary HT - renovascular disease or endocrine disease
69
Name four factors that regulate blood pressure
1) Drugs that affect the sympathetic nervous system/muscle contraction
2) Endothelium/local regulation
3) Renin-angiotensin system
4) Changes in blood volume
70
Where does the biggest drop in blood pressure occur?
Arterioles
71
What is the function of baroreceptors?
Detect blood pressure in aortic arch and carotid sinus. Increase in pressure increases baroreceptor output - increased baroreceptor output leads to decreased sympathetic activity and vica versa
72
Name 3 sites of action to block artery contraction
1) Block NA release
2) Adrenoceptor antagonist
3) Effects on calcium
73
What is Reserpine and what are its effects?
It is an adrenergic neuron blocker that affects the storage of NA. It is taken into nerve by uptake 1, binds to storage vesicles and stops them concentrating NA so less NA is available for release.
74
What is the difference between a1 adrenoceptors and a2 adrenoceptors?
a1 found in artery smooth muscle, agonists treatment for hypotension and shock, a2 found at nerve terminals, agonists act presynaptically to inhibit transmitter release
75
Describe a-adrenoceptor activation
Sympathetic nerve stimulation leads to depolarisation of smooth muscle and activation of voltage dependent calcium channels. a-adrenoceptor activation couples through Gq g proteins to stimulate PLC-B and generate IP3 which releases calcium from calcium stores
76
What are endothelins?
Family of peptides, three different types -1, 2 and 3 that cause vasoconstriction in different places. ET-1 in endothelial cells, ET-2 in kidney, ET-3 in brain, lung and adrenal gland
77
What is the function of the kidney?
Excretion of waste products such as urea, regulation of salt and electrolyte content and the volume of extracellular fluid
78
What is the renin-angiotensin system?
Decrease in NaCl in the filtrate is sensed by the macula densa cells of the distal tubule and stimulates renin release, the release is controlled by renal BP (increases in renal BP locally decreases renin release and vica versa). Human angiotensin is continuously synthesised and secreted by the liver. Circulating renin acts on circulating angiotensin to produce angiotensin 1 in the plasma. A1 is converted by plasma to A2 the active form.
79
What are the actions of angiotensin 2?
Angiotensin 2 receptors can be divided in to two subtypes.
subtype 1 - predominantly in vascular and myocardial tissue
subtype 2 - found in adrenal medulla and possibly CNS
80
What are diuretics?
Drugs that increase the rate of urine flow
81
What is the basic unit of the kidney?
Nephron
82
What makes up the nephron?
Glomerulus (filtering apparatus), tubular portion that reabsorbs filtrate
83
What is the difference between filtrate and plasma?
Same but filtrate has very little protein
84
What is the function of the cardiovascular system?
Major transport system, supplies O2, nutrients to the cells, removes CO2, waste products, regulates pH of ECF, osmotic balance and has a signalling function - hormones, immune function
85
Name four cardiovascular diseases
1) myocardial infarction 2) angina 3) heart failure 4) arrhythmias
86
What is the typical resting heart rate?
70 beats min^-1
87
What is the typical stroke volume?
70ml
88
What is the typical cardiac output?
5l min^-1
89
Where does the initiation of the heart beat come from?
Initiated and controlled by electrical signals in the cardiac muscle cells. The electrical activity is myogenic, initiated by the muscle itself normally at the sino atrial node. Nerves modulate but do not intiate the heart beat
90
What are intercalated discs?
They separate cardiac muscle cells. They have many gap junctions to allow electrical conduction thus action potentila spreads from cell to cell throughout the heart
91
Describe the spread of electrical activity in the heart
SA node to atrial AP to AV node (delay) to bundle of his (conducting system) to ventricular AP (apex to base)
92
One action potential spreading through the heart has five phases, describe these
Phase 0 - rapid depolarisation - inward Na+ current
Phase 1 - early partial repolaristaion
Phase 2 - plateau - inward Ca2+ current and outward K+ current ~ equal
Phase 3 - repolarisation - outward K+ current predominates
Phase 4 - resting potential - largely inward rectifyer K+ current, keeps potential near Ek
93
Describe how calcium triggers contraction in cardiac muscle
Calcium binds to the protein troponin C which acts through the troponin-tropomyosin complex associated with the actin filament to allow myosin head to attach to form cross bridges, followed by cross bridge cycling and contraction
94
Describe the mechanism of rise in calcium
Action potential travels over surface membrane and down T-tubules. Depolarisation activates L-type voltage dependent calcium channels causing calcium entry. The rise in calcium concentration activates ryanodine receptors (RyRs) to release further calcium from the sarcoplasmic reticulum, this is called calcium induced calcium release.
95
Describe the baroreceptor reflex
Provides negative feedback control system that regulates blood pressure. An increase in aterial pressure stimulates barorecptors increasing actvity in the afferent nerves. In response, the medullary centres decrease sympathetic activity and increase parasympathetic activity. This reduces heart rate and contractility reducing cardiac output and reduces contractile tone in blood vessels to reduce peripheral resistance
96
What effects do the sympathetic nerves have on the heart rate and contractility?
Increase in heart rate and contractility
97
What effects do the parasympathetic nerves have on heart rate and contractility?
Decrease in heart rate and contractility
98
How does sympathetic stimulation increase contractile force?
Increases activity of PKA which phosphorylates L type calcium channels to increase their activity. This leads to increase action potential plateau and calcium entry which leads to increases calcium release (CICR) and therefore increase in contractile force
99
What effects do cardiac glycosides have on the heart?
Increase in intracellular calcium and contractile force, decrease in heart rate
100
Define the term arryhthmia
Disorder of the normal cardiac rhythm
101
There are two types of arrythmias, what are these?
Increased heart rate - tachycardia
| Decreases heart rate - bradycardia
102
What are the four mechanisms of arrythmias?
1) Re-entry
2) Delay after depolarisation
3) Abnormal pacemaker activity (normally quiescent regions of the heart begin pacemaking)
4) Heart block (damage to nodal tissue causes failure to conduct AP properly through the heart)
103
Define ischaemia
Inadequate blood flow
104
Define angina
Chest pain
105
What are the three types of angina?
1) stable angina - pain on exercise, fixed coronary narrowing
2) Unstable angina - pain with increasingly less exercise than rest, formation of thrombus, high risk of MI
3) Variant angina - much rarer, spasm in coronary arteries
106
How do anti-anginal drugs work?
Decrease cardiac workload and O2 demand and improve O2 delivery by dilating coronary arteries
107
Name four anti-anginal drugs and describe their mechanisms of action
1) B - receptor antagonists - decrease force of contraction and heart rate and so cardiac workload, increase efficiency, decrease O2 demand
2) Organic nitrates - cause coronary artery vasodilation
3) Calcium channel blockers - block voltage gated L-type calcium channels
4) Potassium channel openers - Hyperpolarise coronary arterial smooth muscle which closes calcium channels reducing calcium entry and so causing relaxation and vasodilation
108
Describe the steps leading to myocardial infarction
Underlying atherosclerosis - plaques in coronary arteries, plaque rupture, platelet adhesion to exposed glycoporteins, platelet activation, aggregation to form thrombus, reinforced by fibrin, blocks coronary artery
109
Name four treatments for myocardial infarction and describe how they work
1) Nitrovasodilator - dilates collaterals to improve blood supply, reduces pain and load on heart
2) Fibrinolytic agent - dissolves clot
3) Aspirin - prevents further clot formation
4) B-adrenoceptor antagonist - reduces sympathetic drive on B-receptors, decreases cardiac work and ATP usage, decreases calcium entry, decreases likelihood of arrhythmias
110
What is the endocrine system?
Collection of glands located throughout the body
111
Define the term autocrine
Hormone signal acts back on the cell of origin or adjacent cells of the same type
112
Define the term paracrine
Hormone signal acts on adjacent cell over a short distance via interstitial fluid
113
Define the term Endocrine
Hormone signal carried to distant target cells via the bloodstream
114
Define the term Neurocrine
Hormonal signal originates in a neurone and after axonal transport to the bloodstream is carried to distant target cells
115
Hormones can be classified into two main types, what are these?
Water soluble - cannot diffuse through the plasma membrane (bind to cell surface receptors and activate second messengers which produce an effect)
Lipid soluble - can diffuse through the plasma membrane (Bind to specific intracellular raceptors that trnaslocate hormones to the nucleus where specific genes are activated)
116
Hormone levels are determined by three factors, name these
1) Rate of production
2) Rate of delivery
3) Rate of degradation
117
Where is the parathyroid gland located?
Nape of the neck
118
What is the role of the parathyroid hormone?
Increase plasma calcium levels, decrease plasma phosphate levels
119
What are the three main target organs of parathyroid hormone?
1) Bones - increases number and activity of osteoclasts
2) Kidneys - slows rate of calcium loss from blood to urine, increases loss of phosphate from blood to urine
3) GI tract - promotes formation of calcitrol which increases the rate of calcium and phosphate absorption from food in the GI tract into the blood
120
What are osteoclasts?
Cells that break down bone matrix releasing calcium and phosphate into the blood
121
What are octeoblasts?
Cells that lay down new bone
122
Fast and slow exchange of calcium between bone and plasma occur, describe the mechanisms of both
Fast exchange - calcium is moved from the labile pool in the bone fluid into the plasma by means of PTH activated calcium pumps located in the osteocytic-osteoblastic bone membrane
Slow exchange - calcium is moved from the stable pool in the mineralised bone into the plasma by means of PTH-induced dissolution of the bone
123
What is calcitonin and what does it do?
It is a peptide hormone produced by parafollicular cells of the parathyroid gland. It is secreted in response to GI hormones and decreases plasma calcium and phosphate levels
124
What are eight processes modulated by the hypothalamus and pituitary gland?
Body growth, milk secretion, reproduction, lactation, adrenal gland function, thyroid gland function, water metabolism, puberty
125
Describe the neurocrine function of the posterior pituitary
Oxytocin and antidiuretic hormone are produced by neurones in the hypothalamus and transported down nerve cell axons to the posterior pituitary where they are stored and released to general circulation to act on distant targets
126
Hormones produced by nerve cells in the hypothalamus act via two neurocrine pathways, describe these
Direct effects on distant targets via oxytocin and antidiuretic hormone from the posterior pituitary
Hormones secreted exclusively into hypothalamic blood vessels effect endocrine cells within the anterior pituitary
127
What effect do OT and ADH have on the body?
OT - milk let down and uterus contractions
| ADH - regulation of body water volume
128
Define trophic hormone
Hormone that controls the release of another hormone in a target tissue
129
What is necrosis?
Cell death by damage
130
What is atrophy?
Decrease in cell size and number
131
What is hyperplasia?
Increase in cell number
132
What is hypertrophy?
Increase in cell size
133
What is apoptosis?
Programmed cell death
134
GH secretion is regulated by long loop and short loop negative feedback mechanisms, describe these
Long loop - inhibit release of GHRH and action of GHRH in the anterior pituitary, stimulates the release of somatostatin
Short loop - mediated by GH via stimulation of somatostatin release
135
GH deficiency in children results in...
Pituitary dwarfism
136
What does GH excess in children and adults result in?
Children - gigantism
| Adults - acromegaly (large extremitites)
137
What is the basic structure of the thyroid gland and where is it?
It is made up of two lobes joined by isthmus, it is bow tie shape and location
138
What is TSH?
Thyroid stimulating hormone which is a glycoprotein hormone composed of two non-covalently bound subunits (alpha and beta)
(the alpha subunit is also present in FSH and LH) and is the trigger for thyroid hormone release
139
Define the term exocrine
Relating to a gland that secretes outwardly through a duct or ducts to the outside e.g. the gut
140
The pancreas is made up of both endocrine and exocrine cells, what are the function of these cells?
Endocrine - arranged in clusters called Islets of Langerhans and synthesise and secrete hormones into the blood via the pancreatic vein
Exocrine - secrete pancreatic juice into the pancreatic duct
141
In the Islets of Langerhans, what are the different cells and their functions?
```
a cells secrete glucagon
B cells secrete insulin
gamma cells secrete somatostatin
epsilon cells secrete ghrelin
PP cells secrete pancreatic polypeptide
```
142
What is the function of insulin?
To reduce blood-sugar levels
143
What is the function of glucagon?
To increase blodd-sugar levels
144
What are the hypoglycaemic actions of insulin in the liver?
Activates: glycogenesis, lipogenesis
Inhibits: glycogenolysis, gluconeogenesis, lipolysis
145
What are the hypoglycaemic actions of insulin in the muscle?
Activates: glucose transport, lipogenesis, glycogenesis, protein synthesis, AA transport
Inhibits: lipolysis, protein catabolism
146
What are the hypoglycaemic actions of insulin in the adipose tissue?
Activates: glucose transport, lipogenesis
Inhibits: lipolysis
147
Define diabetes
Characterised by chronically raised blood-glucose concentration due to lack of the hormone insulin and/or deficiency in insulin action
148
Distinguish between type 1 and 2 diabetes
Type 1 - presents in childhood, autoimmune disease caused by loss of beta cells (genetic, environmental)
Type 2 - presents in middle age, insulin deficiency due to beta cell dysfunction
149
How is diabetes diagnosed?
OGTT (oral glucose tolerance test) - overnight fast, following morning measure plasma glucose concentration, 75g glucose consumed, measure blood glucose after 2 hours
Diabetic - fasting level >7mmol/l
Diabetic - glucose plasma level exceeds 11.1mmol/l after 2 hours
150
How is type 1 diabetes managed?
Insulin injections, islet transplantation
151
How is type 2 diabetes measured?
Exercise, diet, oral hypoglycaemic drugs, insulin injections
152
How do oral hypoglycaemic drugs work?
Increase insulin secretion and sensitivity, decrease glucose absorption
153
What are the male sex hormones?
Androgens - testosterone, DHEA
154
What are the female sex hormones?
Estrogens - estradiol
155
What are the functions of sertoli cells?
Blood-testes barrier, provide nutrients to the developing germ cells, produces seminal fluid, produces androgen binding protein which binds to testosterone
156
The pituitary gland and hypothalamus are physically connected since the hypothalamus drops down through a structure known as the?
Infundibulum
