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PHYSIOLOGY AND PHARMACOLOGY > PHYSIOLOGY AND PHARMACOLOGY > Flashcards

PHYSIOLOGY AND PHARMACOLOGY Flashcards

1
Q

What type of transporter has the largest turnover?

A

Channels > Carriers (e.g. Na+/Glucose) > Pumps (e.g. Na/K ATPase)

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2
Q

How can you regulate channels?

A

I = N.Po.g.(Vm-Ei)

Alter N (number of channels) by altering trafficking 
Alter Po (open probability- how long channels are open for) by phosphorylation, presence of Ca2+, G proteins, membrane potential 
Alter Vm by activation or inhibition of channels
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3
Q

Describe crystal structure of bacterial K+ channel

A

Formed by four identical subunits, each subunit containing two alpha helices connected by a loop into the pore region
Selectivity filter

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4
Q

State the extracellular and intracellular concentrations as well as the relative permeability of K+,Na+ and A-

A

EC(mM) IC(mM) Relative permeability
Na+ 150 15 1
K+ 5 150 50-75
A- 0 65 0

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5
Q

Describe action of Na+ - amino acid (Phenylalanine) cotransporter

A

Drives Nerhst potential towards ENa
After depolarisation occurs, K+ channels open to maintain activity of Na+
Repolarisation time is longer due to action of Na - amino acid cotransporter

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6
Q

How is pH measured?

A
  • Microelectrodes
    Electrodes calibrated with pH standards and then voltage is measured. This allows for calibration
  • Fluorescent Indicators
    Cells loaded with lipid soluble inactive form of indicator
    Inside the cells, it is converted to the active form
    Indicator excited with light of a specific wavelength and the amount of emitted fluorescence light at a second wavelength in measured
    Fluorescence is proportional to intracellular pH
    Membrane permeabilised with a proton ionophore and pH of bath solution changed
    In presence of proton ionophore: bath pH = intracellular pH
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7
Q

What is the action of Na/H+ exchanger?

A

Acid extrusion - Na+ transported intracellularly, H+ extracellularly
Active at low pH, inactive at high pH
Proton binding to allosteric site further increases activity

*NHE1, found on basolateral domain, inhibited by low concentrations of amiloride and EIPA

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8
Q

What is the action of Cl-/HCO3- (anion) exchanger?

A

Acid loading - HCO3- transported extracellularly, Cl- intracellularly
HCO3- unable to buffer H+ –> causes acidification
Active at high pH, inactive at low pH

  • AEs are inhibited by DIDs
  • AE1 found in red blood cells
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9
Q

Explain the importance of maintaining low intracellular [Na+] to cell function

A

Activity of NKCC2 in thick ascending limb depends on inwards Na gradient
If [Na]I increased, then NaCl reabsorption inhibited and diuresis occurs/increased NaCl in urine

If [Na]i increased in excitable cell, decrease in inward chemical gradient, decreasing ENa. Therefore

  • it will take longer for potential to develop
  • problems with the propagation of the action potential
  • slower conduction of the action potential
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10
Q

What decreases rate of transport of Na/K ATPase?

A

Saturated by increased levels of Na+/K+
The rate of transport is saturable by [ATP] so action depends on metabolic state of cell
The pump is inhibited by cardiac glycosides - ouabain and digoxin

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11
Q

Intracellular Ca2+ is kept low by…

A

-Na/Ca exchanger exchange 3 extracellular Na+ for 1 intracellular Ca2+
Effect of x10 Na+ gradient cubed to equal Ca2+ gradient
10^3.10=10000
Members of SLC8 family - NCX1

-Ca2+ ATPases
PMCA (Plasma Membrane)
SERCA (Sarcoplasmic Reticulum and ER)
SPCA (Golgi Apparatus)

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12
Q

Describe action of STIM

A

Depletion of Ca2+ from ER causes STIM to accumulate at the ER-plasma membrane (PM) junctions where it traps and activates Orai (SOCC) channels. As they are close proximity, Ca2+ can diffuse into the cell

*Cell membrane receptor activated using PLC to cleave PIP2 into DAG and IP3. IP3 binds to receptor causing calcium depletion

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13
Q

Drugs target proteins such as channels, receptors, enzymes and transporters. Drugs used to treat other protein targets include:

A
  • COLCHCINE - used in treating gout by disruption tubulin and downregulating inflammatory responses caused by uric acid crystals in joints
  • PACLITAXEL - used in cancer treatment by stabilising and overproducing microtubules promoting mitotic halt ad cell death
  • DRUGS can be used to prevent function of pro-inflammatory proteins in blood
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14
Q

Give examples of immunotherapy - the form of cancer treatment that uses the immune system to attack cancer cells

A
  • Inhibitory Checkpoint Inhibitors
  • CAR T cell therapy
  • Cancer vaccines
  • Iplimumab blocks CTL4 activating T-cell potentiation
  • Keytruda is an antibody that blocks PD-L1 allowing immune system activity
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15
Q

What is the difference between small molecules and large molecules/biologics?

A

Small molecules

  • Often orally-available
  • Synthesised in lab - exact chemical structure determined
  • Easy to manufacture
  • Typically stable at room temperature
  • Short t1/2
  • PK/PD correlation
  • Run into more toxicology issues

Large molecules or biologics

  • Usually injectable
  • Proteins synthesized by living cells
  • Challenging to manufacture
  • Often unstable at room temperature - require refrigeration
  • Long t1/2
  • No PK/PD correlation
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16
Q

What are the pros and cons of radiolabels in drug-binding experiments?

A

3H
High specific activities
Long half life
Specialised labs required so expensive and difficult

125I
Iodination is easy and cheap
Can be incorporated at high specific activities
More readily degraded
Activity of ligand may be interfered with
Short half life

17
Q

What are the limitations experienced when performing a drug-binding experiment?

A
  • NON-SPECIFIC BINDING
    Measure radioactivity when binding of radioactive ligand to receptor is inhibited by excess non-radioactive ligand. Measure non-specific binding and minus from total specific binding
  • CHOICE OF RADIO-LABELS
  • TISSUE & INCUBATION CONDITIONS
    Add free-radial scavenger (e.g. ethanol), store at low temperatures, avoid light, add protease inhibitors and antioxidants
  • SEPERATING BOUND FROM FREE
    If bound ligand has a large KD/ low affinity, it will not stay bound for long, so need faster/more efficient removal of unbound supernatant
18
Q

What are the different classes of antagonism?

A
  • CHEMICAL - substances combine in solution so that the effects of the active drug is lost
    e. g. chelating agent (e.g. dimercaprol) inactivating toxic heavy metal or monoclonal antibodies inactivating pro-inflammatory mediators
  • PHARMACOKINETIC - reduction in amount of drug absorbed, metabolised or excreted by another
    e. g. opiates reduce absorption by oral route, antibodies stimulate metabolism of warfarin (anticoagulant), or action of diuretics
  • PHYSIOLOGICAL - interaction of two drugs with opposing actions in the body
    e. g. noradrenaline raises arterial blood pressure whereas histamine lowers blood pressure
  • NON-COMPETITIVE

-COMPETITIVE
Occupancy of receptor by agonist is reduced
Can be reversible = overcome by increasing agonist conc. or irreversible = maximum response is reduced in the continued presence of the antagonist and this cannot be reversed by increasing agonist conc.

19
Q

Antagonists with a high pA2 are …

A

More potent

20
Q

What causes desensitisation or tachyphylaxis?

*This is when the effect of a drug may decline over time when given continuously or repeatedly

A
  • Loss of receptors from the cell surface. Internalisation by endocytosis
  • Change in receptor itself e.g. phosphorylation
  • Exhaustion of mediators
  • Increased metabolic degradation or extrusion of the drug
  • Physiological adaptation
21
Q

What is the action of COX enzymes?

A

Phospholipase A2 acts on phospholipids in plasma membrane producing arachidonate. Arachidonate os lipophilic so enters ER and enters ER membrane anchored dimer protein COX cyclo-oxygenase site to form prostaglandins and thromboxane
Peroxidase site contains a haem group for the reaction

*In COX2, cyclooxygenase site channel is wider - containing a valine (iso-lycine in COX1)

*COX-1 is found ubiquitously in all cells and constitutively active. Involved in homeostasis
COX-2 is found in inflammatory cells and induced to become active (e.g. by TNFa)
COX-3 is a splice variant of COX-1 restricted to CNS

22
Q

What is the action of NSAIDs and COXIBs?

A

Drugs block the cyclooxygenase site in COX enzymes
Aspirin (acetyl salicylic acid) and ibuprofen are COX-1 selective
Actions are:
Anti-inflammatory
- decrease vasodilation and oedema
-*ineffective against cytokines and chemokines and chronic inflammatory conditions

Analgesic - reduce pain
- decrease production of PGs, which sensitize nociceptors, in damaged and inflamed tissues

Antipyretic - lower fever (high temp)
- thermostat in hypothalamus activated via IL-1 induced COX2 production in PGE

COXIBs are highly selective to COX-2 selective

Paracetamol - targets CNS, perhaps COX-3

23
Q

What is the role of prostaglandins?

A 
Mediate:
constriction of smooth muscle 
bronchoconstriction 
vasodilation 
platelet aggregation 
uterus contraction
increase sensitivity of nociceptors
24
Q

What are the side effects of NSAIDs and COXIBs?

A

Side effects of NSAIDs

  • GUT = prostaglandins usually inhibit acid secretion and stimulate mucus secretion to protect gut - mediated by COX-1 *co-administration of misoprostol (PG analogue may be protective
  • Renal function = prostaglandins produced by COX-2 maintain renal blood flow
  • Liver damage = paracetamol catabolism produces toxic intermediate
  • Bronchospasm asthma attacks
  • Skin rashes

COXIBs (such as Vioxx) can have severe cardiovascular problems in patients with heart issues
- could be due to vasodilation decrease (if patient has hypertension)

25
Q

Rheumatoid arthritis is known as the swelling of the joints and associated pain
What are the drugs being used to treat rheumatoid arthritis?

A

DMARDs - Disease Modifying Anti-Rheumatoid Drugs

Small molecules

  • Methotrexate is a folic acid antagonist but works by inhibiting Th1 cell, which activates macrophages, osteoclasts and fibroblasts leading to erosion of cartilage and bone
  • Sulfasalazine scavenges free radicals
  • Ciclosporin & glucocorticoids inhibit transcription of pro-inflammatory cytokines e.g. IL-2

Biologicals
mab’s - humanized monoclonal antibodies
Specifically target pro-inflammatory cytokines

26
Q

Ciclosporin inhibits cyclophilin and other immunophilins

What is the usual action of immunophilins?

A

Bind to calcineurin, a Ca2+ activated phosphatase which dephosphorylates NFkB –> conformation change so can enter nucleus and allow transcription of pro-inflammatory cytokines

27
Q

Asthma is the chronic inflammation of the airways and bronchial hyperreactivity
Allergic rhinitis (hay fever) affects upper airways
Allergic asthma affects lower airway

How does the over reactivity of Th2 cells lead to asthma?

A

Th2 cells activate B cells which produce IgE antibodies
IgE antibodies are produced against an antigen
They bind tightly to Fc receptors on mast cells (e.g. basophils in blood or eosinophils)
Upon activate by an allergen they cause mast cells to degranulate releasing histamines
Histamines increase
- smooth muscle contraction
- vascular permeability
- mucous secretion
- stimulation of nerve endings
- recruitment and activation of eosinophils

28
Q

Inflammation of airways causes change in structure. What changes?

A

Mucous plug
Infiltration of inflammatory cells (quicker reaction)
Damage to epithelium
Hypertrophied smooth muscle (stronger bronchospasm)

29
Q

What are treatments for asthma?

A

Glucocorticoids inhibit Th2
*unwanted side effects of chronic steroid use

B2 agonists (salbutamol) are bronchodilators
*polymorphisms in B2-adrenoceptors associated with reduced efficacy

Humanized antibodies to IgE (e.g. omalizumab)

Prostaglandin antagonists

30
Q

What is the distribution of anions in intracellular and extracellular fluid?

A

HCO3- low IC high EC (in blood)
Cl- low IC high EC (in blood)
Po42- high IC (in ATP) low EC
Protein high IC low EC

31
Q

What are the phases of drug development?

A

Basic Research/Target Selection

  • Drug candidates chosen on their pharmacological properties and tested using automated screens
  • Lead optimization is used to optimize potency of compound

Preclinical Research
- ensure drug can be tested in humans

Clinical Research

  • Phase 0 - tested in 10-15 healthy volunteers - make sure drug works in humans
  • Phase 1 - tested in 20-80 healthy volunteers - aims to detect potential side effects
  • Phase 2 - groups of patients - used to detect dose and pharmcodynamic properties
  • Phase 3 - double blind trials - is it better than drugs out their already?
  • Phase 4 - using post marketing surveillance

PHYSIOLOGY AND PHARMACOLOGY (1 decks)

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