PBL 6- an intractable problem Flashcards
How do drugs exert there effect?
They interact with molecules or proteins. Once bound they alter the function of the molecule and protein
Name the 4 types of proteins drugs usually interact with
- A receptor
- Ion channels
- An enzyme antibiotics – quinolones target bacterial topoisomerases
- Carrier molecules (loop diuretics NKCC2)
List all the drug receptor targets and there activity
Ligand gated ion channels (nicotinic acetylcholine receptors)
G-protein coupled
Receptors e.g. muscarinic acetylcholine receptors. (G prtein activation, generation of second messenger, activation of cell signalling)
Enzyme-linked
Receptors- e.g. HER2
(phosphorylation of tyrosine on key signalling molecules- activation of cell signalling
Intracellular
Receptors e.g. oestrogen receptor
(transports to nucleus, activates transcription and translation)
What is the equation for VD (volume of distribution)non-
VD=total amount of drug in the body/ drug blood plasma concentration
What does a high and a low VD mean?
High- Drug is distributed to the tissues (fat and brain)
Low- Drugs is confined to blood (too large to leave or binds preferably to albumin)
What happens to drugs which are bound to proteins in the blood?
diffusible
not metabolised
not excreted
What does polypharmacy mean?
Competition between drugs for protein binding
What effects a drugs ability to have an effect on the target?
Capillary structure
Chemical nature of the drug
Blood flow through the tissue
presence of a non active binding site
Which type of drugs are excluded from the cell membranes? Which type of drug accumulates in fat cells?
Excluded- polar drugs
Accumulate- small, apolar, lipophilic
How do ligand gated ion channels work?
Receptors are found on the cell surface
A pore that allows ions to flow in and out of the cell
Activated by ligans e.g. Ach, glutamate, ATP, GABA.
When ligand binds, channel opens into membrane.
Which ligand is used to allow Na+, Ca2+ and Cl- into the membrane? What effect does each component have in the cell?
Na+- nicotinic Ach receptor
(depolarises cell)
Ca2+- Glutamate (depolarises cell)
Cl- GABA (hyper-polarises cell)
What activates G-proteins?
ACh, serotonin, noradrenaline, hormones
Explain how G protein coupled receptors work?
At rest they are bound to G-proteins
When the ligand binds the G protein is activated (changes GDP-GTP)
This activates intracellular signalling
How is a G protein switched off?
Converting GTP-GDP
via hydrolysis
What are protein kinase’s?
enzymes that phosphorylate other proteins. An example of an enzyme linked receptor Phosphorylation cascades allow signal amplification.
Name the 2 ways enzyme linked receptors work? What are they formed by?
directly as enzymes or are
directly associate with enzymes that they activate.
Transmembrane proteins
What is the largest class of enzyme linked receptors?
tyrosine kinases
What type of molecule is a fibroblast growth factor receptor?
Enzyme-linked receptor
Name 4 intracellular receptor proteins?
steroid hormones
thyroid hormones
retinoids
vitamin D
How do intracellular receptor proteins work?
small hydrophobic signal molecules diffuse directly across the plasma membrane and bind to intracellular receptor proteins
What activates nuclear receptors?
steroids/estrogen
How do nuclear receptors work?
Once activated they travel to the nucleus, bind to specific DNA sequences and regulate transcription and translation.
What is Tachyphylaxis?
acute tolerance
rapid and repeated administration of drug in shorter intervals
What is tolerance? What causes it?
Chronic longer term administration can reduced drug effect.
- loss of receptors
- receptor internalisation
- Increased metabolic degradation of drug
- Physiological adaptation
What is an agonist? Which forms does it usually come in? When is it often used?
Binds to and activates receptors
Has affinity and efficacy at a receptor. can be full (maximal possible signal) or partial (less than maximal signal)
Usually neurotransmitters/hormones are agonists
Useful when there is not enough signal
What is an antagonist? When is it often used?
Blocks receptor activation
Has affinity but no efficacy
Blocks effects of neurotransmitters/hormones
Useful when there is too much signal
What is the difference between a competitive or Non-competitive antagonist?
Competitive- competes for binding site
Non-competitive- blocks effect through different binding site (allosteric),
What is the function of Tubocurarine? Which receptor does it target?
Function- Muscle relaxant for surgery
Receptor- Lignad gated ion channel
What is the function of Atropine? Which receptor does it target?
Function- Inhibits parasympathetic nervous system stimulation of saliva
G protein coupled receptor
What is the function of FP-1039? Which receptor does it target?
Function- Cancer therapy
Enzyme linked receptor
What is the function of Tamoxifen? Which receptor does it target?
Function- Breast cancer treatment
Nuclear receptor
What type of drug is Tegaserod? Which receptor does it activate and what kind of a receptor is this?
Selective partial agonist binds with high affinity to 5HT4 receptors (also known as serotonin type 4)- GPCR found in colon.
What is the function of Tegaserod?
Stimulates peristaltic reflex and intestinal secretion- promotes gastric emptying and reverses constipation.
What happens when Tegaserod binds to5HT4 Receptor?
It activates it causing peristalsis to increase via activating motor neurones in the colon
Which 2 neurotransmitters are involved in peristalsis?
ACh and NO
What must a drug do other than bind?
- dissolve
- survive a range of pHs (1.5 to 8.0)
- survive intestinal bacteria
- cross membranes
- survive liver metabolism
- avoid active transport to bile
- avoid excretion by kidneys
- Must effect only target organs and avoid undesired trargets
What is the difference between Pharmacokinetics and Pharmacodynamics?
Pharmacokinetics- Effect of body on drug (ADME)
Pharmacodynamics- Effect of the drug in the body
What does ADME stand for? Describe each stage What does it govern?
Absorption- from administration site to sytemic circulation
Distribution- the reversible transfer of a drug to and from the systemic circulation and tissues
Metabolism- body chemically alters drug to enable water solubility and excretion
Excretion- Transfer of drug from circulation. Sweat or urine
Governs drug disage, and drug design
What controls the mucosal and muscle layer of the stomach?
Intrinsic nerves of the enteric nervous system
and extrinsic nerves of the autonomic nervous system
How do most drugs cross the membrane? Which physical attributes of the drug determine this passage?
Most cross via passive diffusion (high to low conc)
Determine by size and lipophilicity of the drug
How are hydrophilic drugs absorbed?
They go through pors and gap junctions
How are large drugs absorbed?
Active transport using transport proteins. Requires energy
Where are most drugs absorbed and how?
Most absorbed via the enterocytes in the small intestines by the transcellular pathway
Which factors effect absorption?
- Acid stability- Stable in the acidic conditions in the stomach and neutral Ph in the small intestines at body temperature
- Solubility- Needs enough aqueous solubility to be dissolved (only dissolved can be absorbed)
- Permeability- poor permeability through gut wall = poor absorption
- Lipophilicity- Only Lipophilic drugs are absorbed passively through cell membrane (but polar enough for water solubility)
Describe the first phase of drug metabolism reactions
- Occurs when blood from the gut components passes go to the liver- hepatic circulation.
- 3 main reactions in phase 1-
oxidation, reduction, hydrolysis - As most drugs a lipophilic, they are oxidised to be more water soluble. So the most common phase 1 reaction is oxidation
- Oxidation is catalysed by hepatic cytochrome p450 enzymes.
Describe the second phase of drug metabolism reactions
-This phase makes drugs larger, more polar so more water soluble.
The drug is conjugation to another molecule:
glutathione
sulphate
glucornide
Phase 2 makes the drugs more likely to be eliminated via kidney excretion
Catalysed by transferases
Describe the renal excretion of drugs
All unbound drug in plasma is filtered in the glomerulus
Some compounds are actively secreted into urine along the proximal tubule.
Unionised drugs can be passively reabsorbed from the urine into the blood.
Drugs bound to plasma protein is unfiltered
Which patient characteristics dictate a drugs dose and frequency?
Age. weight, gender, nutritional and clinical status, are they taking other drugs?
What is the theraputic window?
The therapeutic window is the range of drug doses that produces a therapeutic effect.
List the different phases involved in bringing a drug to market
phases 0-4
phase 0- lab to human
Phase 1- Small group of healthy volunteers
Evaluate safety of new treatment
Phase 2- Larger group and in people with condition being targeted
Phase 3- larger scale
Phase 4- Adverse reactions are assessed and reported- long term safety
