Fluids, Dehydration and Pharmacology Flashcards
What is the body’s fluid requirements?
2-2.5L water per day (mostly gained via ingestion) need it because all chemical reactions occur in aqueous conditions
What are insensible losses?
Evaporation from respiratory tract and diffusion from skin (~700ml/day) EXCLUDING SOLUTE LOSS
What are sensible losses?
Sweat, faeces and urine INCLUDING SOLUTE LOSS
Sweat depends on climate/exercise, only a little from faeces and urine highly variable
60 40 20 rule
60% of body is water
40% (2/3) intracellular (ICF)
20% (1/3) extracellular (ECF) plasma + interstitial
What is ECF split into?
Plasma - fluid component of blood
Interstitial Fluid - fluid surrounding cells
Transcellular space - space between cells
What is the main cation of ECF?
Na+
What is the main cation of ICF?
K+ ‘bananas in the sea’
What 2 factors are key in fluid movement between compartments?
Osmosis
Starling’s principle of fluid exchange
Why does osmosis occur?
Water (solvent) moves down its concentration gradient across a semi permeable membrane from an area of LOW SOLUTE CONCENTRATION to HIGH SOLUTE CONCENTRATION
What is osmolality?
Number of dissolved solute molecules per kg of solvent (osmol/kg)
Normal plasma osmolality = 280-290 mOsmol due to extracellular NaCl
What is osmotic pressure?
Pressure generated by flow of water down concentration gradient across semi-permeable membrane (pressure needed to prevent movement of free water down gradient)
How do we measure the strength of osmotic potential?
USE OSMOLALITY: Number of molecules dissolved per kg solvent
1 mol of NaCl dissolved in 1 Kg:
molality = 1 mol/Kg
osmolality of 2 Osmol/Kg (splits into Na+ and Cl-, 2 particles)
1 mol of Glucose dissolved in 1 Kg:
molality = 1 mol/Kg
osmolality = 1 Osmol/Kg (it doesn’t split and remains 1 particle)
Describe the structure of a lipid molecule?
Hydrophilic head attracted to water
Hydrophobic tail repelled by water
What are the properties of a solute?
Concentration gradient
Size of solute
Lipid solubility
What are the properties of the plasma membrane?
Membrane thickness/composition Aqueous pores in the membrane Carrier-mediated transport Active transport mechanisms Semi permeable- not a barrier to H2O
What is convection?
Movement down a PRESSURE GRADIENT (to move solutes and fluids over long distances) like blood flow from heart to vessels
Can be passive
What types of molecules can easily pass through membrane?
Small
Lipophilic
Hydrophobic
(eg. O2, CO2, urea, anaesthetics, glycerol)
What types of molecules cannot easily pass through membrane?
Large
Lipophobic
Hydrophilic
(eg. Electrolytes, glucose, amino acids, plasma proteins, therapeutic drugs)
What is simple diffusion?
No ATP required
Molecules move RANDOMLY from high to low concentration
Short distances
Lipid soluble substances
Why does simple diffusion only work for short distances?
Time taken (t) for one randomly moving molecule to move a net distance (x) in one specific direction increases with the distance squared
t = x2 / 2D
D = diffusion coefficient for molecule within the medium e.g. D for O2 in water vs. D for O2 in air are different
What is Fick’s Law?
Controls simple diffusion of solutes
Js = D A (delta C/x)
Js = mass per unit timr m/t, determined by 4 factors:
D= Diffusion coefficient of solute – Ease with which solute moves through solvent (e.g. through water, air, oil etc.)
A =Area (more area more solute movement)
DC / x =Concentration difference (C1-C2) across distance x termed concentration gradient(more gradient more movement)
Negative value : flowing ‘down’ a concentration gradient
What are the two types of passive transport?
Simple
Facilitated
What are the two types of active transport?
Primary PUMP MEDIATED needs direct ATP hydrolysis
Secondary CARRIER MEDIATED uses concentration gradient
What type of transport are endocytosis and exocytosis?
Active transport
Na/K ATPase and Ca ATPase are what kind of proteins? What is their function?
Carrier proteins that require energy (ATP) to transport ions Against a concentration gradient to control intracellular and extracellular electrolyte balance
How does facilitated diffusion work?
Initially primary active transport (energy use) creates concentration gradients, e.g. Na/K-ATPase
Co-transporters and Exchangers (carrier proteins) use these concentration gradients to transport solutes, e.g. glucose
Does not require energy (no ATP needed)
What 2 characteristics are associated with carrier mediated transport?
Specificity for a solute – e.g. GLUT transporter only carry glucose
Saturation of carrier limits solute transport – e.g. GLUT transporter numbers are finite and have a maximum capacity
How does glucose transport work in intestinal cells?
SECONDARY ACTIVE TRANSPORT: Carrier protein lets sodium ions move down their gradient, but simultaneously brings a glucose molecule up its gradient and into the cell (both going in same direction SYMPORT). The carrier protein uses the energy of the sodium gradient to drive the transport of glucose molecules.
What transporters are present in the intestine?
On epithelial membrane:
NA+/GLUCOSE TRANSPORTERS
CHLORIDE TRANSPORTERS
Why are Na+/glucose transporters important for fluid requirements?
Absorption of Na+/glucose facilitates water absorption across gut
Why are chloride transporters important for fluid requirements?
Secretion of chloride into gut lumen facilitates water secretion
What is the E.Coli effect?
Blocks sodium absorption and stimulates chloride secretion = diarrhoea
What is the mechanism by which glucose is transported across the intestinal epithelium?
Secondary active transport
What is molarity vs molality?
Molarity = MOLES per VOLUME (Litres) Molality = MOLES per WEIGHT (Kg)
What is osmolarity vs osmolality?
Osmolarity = OSMOLS per VOLUME (Litres) Osmolality = OSMOLS per WEIGHT (Kg)
What is tonicity?
Influence of a solution’s osmolality on cell size
Depends on membrane permeability of the solute - e.g. greater tonicity with NaCl (membrane impermeable ) vs. urea (membrane permeable)
What is Starling’s principle of fluid exchange?
Capillary blood pressure exerts HYDROSTATIC pressure (wants to squeeze fluid out)
Large molecules in blood (e.g. plasma proteins, albumin) exert an osmotic pressure across the capillary wall - ONCOTIC Pressure (wants to draw fluid back in)
LONG EXPLANATION
Capillary wall is a semi-permeable membrane
Allows low (e.g. glucose) but not high (e.g. proteins) molecular weight solutes through
Large molecules (e.g. plasma proteins, albumin) exert an osmotic pressure across the capillary wall: Termed Oncotic Pressure
Fluid movement depends on balance of hydrostatic (capillary blood pressure) andoncotic pressures across capillary wall
Generally produces filtration of fluid from capillaries to interstitial fluid, some reabsorbed due to oncotic pressure
What is an isotonic solution?
Isotonic conditions surrounding cells, same osmolality inside/outof cells e.g. iv 0.9% NaCl saline
What is a hypotonic solution?
Hypotonic conditions surrounding cells, less osmolality than inside cell eg. excessive NaCl loss, iv 0.45% NaCl saline
What is a hypertonic solution?
Hypertonic conditions surrounding cells,greater osmolality than inside of cell e.g. excess water loss, iv 3% NaCl saline
Where does water move in a hypertonic, isotonic and hypotonic solution?
Isotonic: no moevement of water between compartments
Hypertonic: water moves out of the cell ICF into ECF
Hypotonic: water moves into cell ICF
Besides filtration and reabsorption what maintains the interstitial volume?
Lymphatic system (makes sure not too much fluid in interstitial space, or lost from blood vessels)
What is lymphoedema?
Swelling in body tissues due to fluid not being taken up by lymphatic system
What solution has:
a) increased tonicity
b) decreased tonicity?
a) Hypertonic
b) Hypotonic
How do H2O and Na+ regulate fluid balance?
Changes in H2O / Na+ levels alter:
Changes in osmolality
Shift in H2O between extracellular and intracellular components
H2O and Na+ levels need to be highly regulated
What is the role of osmoreceptors in fluid balance?
in brain
sense Increase in osmolality
Release anti-diuretic hormone (ADH)
–> Increased H2O reabsorption in kidney
What is the role of filling receptors in fluid balance?
in heart
senses increase in blood volume
Release atrial natriuretic peptide (ANP)
Increased excretion of Na+/H2O from kidney
What is the function of the juxtaglomeruler apparatus?
senses decrease in perfusion pressure/NaCl load Increase release of Renin Increase RAAS Increase aldosterone Increase Na+/H2O reabsorption
Define dehydration
Lack of water or
Lack of water and salt or
Reduction of plasma volume
Define water overload
Excessive water intake or
Excessive water reabsorption in the kidney
(e.g. excessive ADH levels)
or
Excessive water filtration in capillaries (e.g. expansion of interstitial volume, oedema)
What is isonatremic dehydration?
Also called loss of isotonic fluid:
Loss of water and solutes in equal amount
(Normal levels of plasma Na and osmolality remain)
e.g. diarrhoea, vomiting
LOSS OF PLASMA VOLUME = LOWER BP
What happens to fluid compartments and plasma osmolality in:
a) isotonic fluid loss
b) hypo-osmotic fluid loss
c) hyper-osmotic fluid loss?
a) ECF DECREASE, ICF NO CHANGE, plasma osmolality NO CHANGE
b) ECF DECREASE, ICF DECREASE, plasma osmolality INCREASE
c) ECF DECREASE, ICF INCREASE, plasma osmolality DECREASE
How does the body compensante for isotonic fluid loss?
Decreased hydrostatic capillary blood pressure leads to movement of water (about 500 ml) from interstitial space into plasma via osmosis
HOWEVER Little change in plasma osmolality (lose both fluid and solutes)
No movement of fluid between intracellular and extracellular compartments
Need to replace fluid – 0.9% NaCl (isotonic) – expand extracellular volume
Why is someone with isonatremic dehydration given 0.9% NaCl?
This is an isotonic solution, so has the same osmolality and wont move into ICF but will stay in ECF and expand it, increase blood volume and reduce symptoms
What is loss of hyponatremic dehydration?
LOSS OF HYPER-OSMOTIC FLUID
More loss of NaCl relative to water (plasma hyponatremia remain) e.g. Addison’s disease – less aldosterone, excessive NaCl lossDiuretics - excessive Na loss
LOSS OF NACL AND DECREASED PLASMA OSMOLALITY
What is loss of hypernatremic dehydration?
LOSS OF HYPO-OSMOTIC FLUID
Extreme water loss relative to Na loss (plasma hypernatremia remains) e.g. decreased water intake, excess sweating, insensible loss, fever
LOSS OF PLASMA VOLUME AND INCREASED PLASMA OSMOLALITY
How does the body compensate for hyper-osmotic fluid loss?
Water moves from plasma to interstitial to intracellular, balance osmolality but – Cells Swell
Hyperosmotic agents - mannitol/hypertonic saline to shift fluid from intracellular into extracellular compartment
How does the body compensate for hypo-osmotic fluid loss?
Water moves from interstitial space to plasma, increasing interstitial osmolality which draws water from intracellular space – Cells Shrink
Need to replace fluid – 0.9% NaCl (isotonic, will equilibrate osmolality over time)
Right sided heart failure
Increased fluid retention in peripheral circulation
Build up of fluid in RS heart –> increased capillary pressure in peripheral side of body –> PERIPHERAL OEDEMA because of excess filtration that lymphatics cannot cope with
Left sided heart failure
Increased fluid retention in pulmonary circulation
Build up of fluid on LS heart –> increasd pressure in pulmonary veins –> increased capillary pressure in lungs and increased filtration –> more fluid filtered into interstitial space in lungs –> PULMONARY OEDEMA preventing efficient gas exchange, very serious
What is the impact of excessive fluid intake such as drinking or drugs like ecstasy (MDMA)?
increases ADH levels,excessive water reabsorption in kidneys, plus you drink more as you are hot
DECREASED plasma osmolality –> due to the excessive water intake and/or reabsorption by kidneys
COMPENSATION: water moves from extracellular to intracellular compartment due to osmosis – Cells Swell
Potentially very serious – enclosed cranium, cerebral oedema
How to treat excessive fluid intake?
Hyperosmotic agents - mannitol/hypertonic saline to shift fluid from intracellular into extracellular compartment
Reverse cells swelling
What are drugs?
Chemicals that produce biological effects
What type of drug is aspirin?
NSAID (non-steroidal anti-inflammatory drug)
PHARMACODYNAMICS:
analgesic (painkiller)
anti-pyretic (reduces fever)
anti-inflammatory (reduces immune response)
in low doses reduces formation of blood clots
What is the mechanism of action of aspirin?
Irreversible inhibition cyclooxygenase (COX) 1 & 2
Because COX cannot catalyse reaction producing PGs and thromboxane, aspirin prevents pain, inflammation, swelling and platelet aggregation (analgesic, anti-inflammatory, anti-pyretic, anti-platelet aggregation)
What is the action of COX enzyme?
Catalyses conversion of arachidonic acid into prostaglandins (PGs) and thromboxanes
PGs can:
sensitise nerve endings- produce pain
dilate blood vessels redness
increase blood vessel permeability - swelling
reset body temp - fever
thromboxane = platelet aggregation (clot formation)
What are the pharmacokinetics of aspirin?
ie how does drug enter body and what happens to it
Routes of administration – oral (other routes IV, IM, SC, inhalation)
Readily absorbed from stomach and intestine
Broken down in liver, some excreted unchanged- half-life of 4 hours in low doses
Excreted in urine – need kidney function
Important in deciding dose and how often administrated
What are the clinical uses of aspirin?
Analgesia, e.g. headaches, toothache, dysmenorrhoea
Reduce fevers (makes you feel ill)
Acute and chronic inflammation, rheumatoid arthritis
To reduce platelet aggregation after myocardial infarction, many patients take aspirin for life
What are the properties of the actions of drugs?
- Tissue selectivity (i.e., receptors located at specific tissues)
- Chemical selectivity (i.e., drugs have a specific structure → changes to structure = changes in action of drug).
- Amplification (i.e., small amounts of drug produces an action)
What are some adverse effects of aspirin?
Gastrointestinal irritation and bleeding, might be severe in some individuals (side effect)
Tinnitus, vertigo, nausea and vomiting – high doses (side effect
Should be avoided in asthmatics – may stimulate attack (potential contraindication)
May cause Reye’s syndrome in children which can be fatal – do not give to young children (contraindication)
What is a drug receptor?
A specific target molecule which a drug interacts with to produce a cellular response
It is not simply a binding site, it alters cell function
What is an agonist?
A drug which binds to a receptor to produce a biological cellular response
e.g. adrenaline increases heart rate
What is an antagonist?
A drug which binds to a receptor but does not produce a biological effect
Antagonists bind to receptors to prevent agonists producing effects e.g. Atenolol blocks adrenaline-mediated increases in heart rate
Atenolol is a beta-adrenoceptor blocker
Do antagonists have efficacy?
No, while both agonists and antagonists have affinity for receptors, only agonists produce a cellular response (have efficacy)
What are the reversible types of receptor binding?
Hydrogen, ionic bonding and van der waal’s forces
All relatively weak, reversible binding and dissociation of drug-receptor interactions
What type of receptor bonding is irreversable?
Covalent bonding
Stable strong bonds, irreversible binding and poor dissociation
What determines drug affinity?
Law of mass action: rate of reaction is deoendant on concentration of reactants involved
Agonist + Free Receptors –> Agnoist-Receptor complex
TOWARDS: Association rate
REVERSE: Dissociation rate
Low [A] - lots of Rfree - few AR interactions – reaction rate to right is limited
As we increase [A] - more AR interactions – reaction rate greatly increases
Reaches maximum as numbers of receptors is finite (There is a maximal number of AR interactions due to finite number of receptors)
What is KA?
When 50% of receptors are free and 50% are bound to agonist = equilibrium constant of a drug (KA)
KA is the [A] at equilibrium, e.g. KA of 50 nM means that at this agonist concentration 50% of receptors will be occupied
Each drug has it own KA value
Smaller KA (e.g. 5 nM) means agonist has a greater AFFINITYfor a receptor than a drug with a higher KA value (e.g. 50 nM)
What determines efficacy?
a) Threshold concentration
b) EC50 = effective concentration giving 50% biological response
Used to compare drug potency (determined by both affinity and efficacy)
c) Maximal concentration
These values are very important for determining drug dose
What is efficacy vs affinity?
Affinity – occupancy, binding of drug to receptor
Efficacy – biological effect, e.g. increase in heart rate
Affinity (KA) and Efficacy (EC50) of a drug are not equal- why?
Outcome - You do not need full occupancy to give a maximum response
Why? - Remember receptors amplify signals, so only a small number of drug-receptor interactions is needed to produce biological function
What is a partial agonist?
Present at receptors because it has high affinity but less efficacy means:
Reduce withdrawal effects
Whilst reducing addictive ‘highs’
Heroin-induced highs (diamorphine, full agonist) are reduced is taken in presence of partial agonist
What occurs in competitive antagonism?
Receptors bind either Agonist (A) or Antagonist (Ant) – not both at same time
A and Ant COMPETE FOR THE SAME BINDING SITE
A and Ant both bind reversibly
Reaction now dependent on two equilibrium constants, KA and Kant
If KAnt < KA, then Ant has greater affinity for Receptor than A
[A] must increase to overcome Ant binding to Receptor
What happens to the curve in competitive antagonism?
In the presence of the Ant - effect of curve is shifted to night
Shift to right is linearly related to [Ant]
Linear part of curve is parallel
Same maximal response is obtained
If you increase [A] you will ‘out-compete’ antagonist
‘Surmountable’ antagonism
Examples - beta-blockers preventing the action of adrenaline on the heartor anti-histamines to present histamine-induced symptoms of hay fever
What does non-surmountable antagonism do to the curve?
Reduce slope
Depress maximum
What is non-competitive antagonism?
Antagonist binds to a different site to that of the agonist
e.g. ketamine (anaesthetic) blocking glutamate NMDA receptor in brain
What is irreversible antagonism?
Antagonist binds irreversibly to either agonist- or non-agonist binding sites on the receptor through covalent bonds
Reduces number of receptors the agonist can bind to
e.g. aspirin – acetylates COX enzyme
The ANS is split into SNS and PNS. What are the features of the SNS?
“Fight or flight” • Increased heart rate and contractility • Increased BP • Opening of airways • Increased fuel deliver to muscles • Increased sweating • Pupil dilation
The ANS is split into SNS and PNS. What are the features of the PNS?
– “Rest and digest”
• Slowing heart rate – Rest
• Accommodation of the eye (i.e., pupil constriction) –
Rest (newspaper reading)
• Bladder : micturition – Rest (time for a pee)
• GI tract motility/secretions – Time for eating /
digestion
• Metabolism – Insulin release, glucose uptake and
storage
• Bronchoconstriction – Rest, less O2 intake required
What is an automatic ganglion?
A collection of cell bodies outside of the CNS, which are stimulated (or inhibited) by neurotransmitters
What is a neurotransmitter?
A chemical released from the end of a nerve fibre
Whats the main difference between sympathetic and parasympathetic ganglia?
Parasympathetic:
• Long pre-ganglionic fibre → release acetylcholine
(Ach)
• Short post-ganglionic fibre → mainly release Ach
Sympathetic:
• Short pre-ganglionic fibre → release Ach
• Long post-ganglionic fibre → mainly release
noradrenaline (NA)
What is the ENS?
ENTERIC nervous system controlling GI tract
How is ANS involved in the heart?
Sino-atrial node cells – Regulates heart rate
Atrial-ventricular node cells – Regulates electrical conduction through heart
Cardiac myocytes – Regulates contractility of heart
How is ANS involved in smooth muscle?
ANS contracts or relaxes smooth muscle cells which are present in in many tissues/organse.g. blood vessels, airways, intestine, bladder
How does ANS affect gland cells?
ANS cause secretions from glandular cells e.g. release of saliva, sweat, gastric acid,insulin, glucagon
How many nerons are involved in ANS conduction? What are they called?
2 efferent neurons arranged in series conducting electrical activity from CNS to peripheral tissues/organ
PRE-GANGLIONIC NERVE is neuron in CNS, goes to
POST GANGLIONIC NERVE which goes to peripheral organ
What are utonomic ganglia?
Group of neuronal cell bodies lying outside CNS
Why can pre-ganglionic nerves be controlled by higher functions?
Because they start in the CNS
Where do the pre ganglionic nerves of the sympathetic system lie?
Thoracic and lumbar regions
Where do the pre ganglionic nerves of the parasympathetic system lie?
Medulla and sacral regions
Why are the pre ganglionic fibres of the sympathetic system short?
Sympathetic ganglia lie close to spinal cord so PRE ganglia short, POST ganglia long
Why are pre ganglionic fibres in parasmpathetic system long?
Parasympathetic ganglia lie very close to the end organ so PRE ganglia long, POST ganglia short
What neurotransmitter is used by parasympathetic nerves?
Acetylcholine
What neurotransmitter is used by sympathetic nerves?
Noradrenaline
What receptors does acetylcholine act on in post gangionic fibres of parasympathetic nerves?
Nicotinic receptors
What receptors does acetylcholine at on in the peripheral end organ of parasympathetic nerves?
Muscarinic receptors
What receptors does acetylcholine act on in post gangionic fibres of sympathetic nerves?
Nicotinic receptors
What neurotransmiter is released by sympathetic post ganglionic fibres?
Noradrenaline
What receptors does noradrenaline at on in the peripheral end organ of sympathetic nerves?
Alpha or beta adrenoreceptors
What is the process of chemical transmission?
- Synthesis of neurotransmitter
- Storage of NT in vesicles
- Arrival of AP at synaptic terminal
- Terminal depolarises, activation of voltage-gated Ca2+ channels, Ca2+ influx
- Ca2+-dependent release of NT
- NT binds to receptor induces response
- Uptake/breakdown of NT
What organs are only innervated by SNS?
sweat glands, kidney, blood vessels
What organs are only innervated by parasympathetic?
pancreas, secretory cells of stomach, lungs (but airways contain beta adrenoreceptors, modulated by circulating adrenaline)
What is an organ that both SNS and PNS innervate to produce the same effect?
salivary gland = increase secretions
How does ANS respond to a decrease in blood pressure when standing up?
Drop in blood pressure –>
Change in baroreceptor activity (stretch receptors in aortic arch) –>
Change in firing of sensory afferent fibres to CNS
Sensory information processed by CNS –>
Signals are sent out via sympathetic nerves (efferent fibres) to the heart, blood vessels, kidney to increase in blood pressure
All pre ganglionic nerves (SNS and PNS) release…
which acts at what receptors?
Acetylcholine
acts at nicotinic receptors
What is the difference between SNS and PNS post ganglionic receptors?
PNS nerves release Ach which acts on muscarinic receptors
SNS nerves release NA which acts at alpha/beta adrenoreceptors
What do SNS nerves release in sweat glands?
Ach which acts at muscarinic receptors
Are post ganglionic fibres involved in innervation of adrenal glands?
No
stimulation of pre ganglionic sympathetic fibres releases 80% adrenaline and 20% noradrenaline from adrenal glands
