See your face again Flashcards
what is an inverse agonist?
which systems do they only work on?
inverse agonist:
- acts on unoccupied receptors to produce effect opposite of agonist: negative efficacy
- shifts to inactive state
- only work on systems that are constitutively active: autonomic NS and histomine systems
what do most drugs tend to be?
what are their properties?
weak acid or weak base (incomplete dissociation in water)
- less H and negative charges (than strong acid)
- undissociated form of acid / base
- lipid soluble
explain how ion trapping works with aspirin
(pKa (pH at which drug is completely balanced between un-charged (lipid soluble) and charged (water soluble) form)) = 3. )
aspirin: R-COOH. exists in equilibrium of R-COOH (protonated) to R-COO- H+ (un protonated)
- when take aspirin orally: goes into stomach
- stomach has low pH, more free H+ ions in solution : pushes aspirin equation to R-COOH (uncharged aspirin, fat soluble, protonated form) = absorbed across stomach mucosa
- then moves to blood plasma: pH 7.
- moves to R-COO- + H+ (ionic aspirin, hydrophilic - water soluble) = trapped in blood plasma (where want to be trapped) cant return to stomach.
THEREFORE - NEED TO BE ABSORBED IN THE STOMACH BECAUSE V LITTLE WOULD BE STORED IN AN ALKALI SOLUTION
- this process = ion trapping
- Aspirin and many NSAIDs are weak organic acids that remain in the nonionized form in the strong acidic environment of the gastric lumen and can freely diffuse across the cell membrane. Once across the membrane, the high intracellular pH causes the H+ to dissociate, trapping the negatively charged organic compound in the cell.*
a protonated (less dissociated / proton still there) weak acid is more X soluble?
an un-protonated (more dissociated / proton left) strong acid is more X soluble?
a protonated (less dissociated / proton still there) weak acid is more lipid soluble (liphophilic)
an un-protonated (more dissociated / proton left) strong acid is more water soluble (hydrophilic)
what happens to a protonated drug in the kidney?
- almost all drugs are filtered by kidneys
- protonated drug in kidney: reabsorbed back into blood
what is differences in dose response curves for competitive antagonist vs non-competitve antagonists?
- *competitive antagonist:**
- add more drug to get EC50
- *non-competitive antagonist**
- never get maximal effect
- EC50 is the same
what is the difference between efficacy and potency?
efficacy: effect of drug -> larger effect = more efficaciois (aka intrinsic activity)
potency: concentration of drug needed for same effect
what is EC50?
Half maximal effective concentration (EC50) refers to the concentration of a drug, antibody or toxicant which induces a response halfway between the baseline and maximum after a specified exposure time.[1]
where do drugs with large / small VD distributed to?
Large VD: distributed to tissues (fat / bones)
Small VD: distributed to blood
what influenecs the amount of drug available to bind to target?
albumin
what is the relationship between drugs working and proteins in the blood?
- drugs are only active when unbound to proteins: unbound drugs are excreted quickly
- drug bound to protein: pharmacologically inactive. non-diffusable, non-metabolised and non excreted
what type of molecules bind to intracellular receptor proteins?
- hydrophobic signal molecules (hydrophilic drugs cant pass through cell membrane)
- work by:
a) activating nuclear receptors: can bind to DNA regions
b) regulate gene transcription
- e.g:
- *1. steriod hormones
2. thryoid hormones
3. retinoids
4. vitamin D**
how are signal pathways regulated to stop excessive activation?
- tachyphylaxis: acute tolerance from rapid and repeated admin of drugs in short intervals (the image)
- tolerance: chronic longer term admin can reduce drug effect (e.g. alchohol)
what are the mechanisms for tolerance or tachyphylaxis [3]
- receptor desensitized or loss of receptors
- receptor internalisation (degraded in lysosome)
- increased metaboloic degradation of drug
how can we use the fact that oral administation of drug undergoes liver metabolism to a beneficial way?
prodrug mechanism:
- biological inactive parent drug, when passing through liver require chemical / enzymatic transformation to release active drug
- some drugs cannot pass through physiological barriers (e.g. BBB): pro-drug can instead
- after passing through - gets cleaved into drug
- some prodrugs are active parent drug and then when metabolised, are also active: longer effect
what are the two types of metabolism?
phase 1- biotransformation: drug becomes smaller and more water soluble so the kidney can remove it
- a polar group is introduced or unmasked (this is the biotransformation) to the drug
- biotransformation occurs by: oxidation (majority), hydrolysis or reduction
- some metabolites after this: water soluble enough to be excreted straight away (via kidneys) = metabolite A
- other drugs may need additional step to make more water soluble / polar -> go to phase 2
phase 2: synthesis (stick a group onto drug to make it more soluble)
- *-** conjugation
- e.g. liverr takes big chem (e.g. glucose) adds it onto drug
- is able to be excreted
what method of biotransformation in phase 1 drug metabolism occurs the majority of the time? by which family of enzymes?
what are the other ways?
majority of time = oxdidation. undergone by cytochrome P450 family enzymes
also: hydrolysis or reduction
which of phase 1 or phase 2 reactions are:
- a) synthetic?
b) degradative reaction? - form smaller or larger molecules?
- a) phase 2 metabolism uses synthetic reactions
b) phase 1 metabolism uses degradation reactions (unmask polar group) - phase 2 makes larger molecules, phase 1 makes smaller molecules
where does phase 1 / phase 2 metabolism occur?
are phase 1 / 2 products active or inactive?
in the liver !!
(phase 1 = active (prodrug) or inactive. phase 2 = inactive
what are NANC neurons?
where found?
what are the NTs used ? (probs dont need to know exact)
- NANC = non-adrenergic non cholinergic neurons (NTs aren’t adreneric or cholinergic class)
- location: peripheral tissues - smooth muscle in GI, airways and reproductive tracts
- NTs: nitric oxide, ATP, 5HTP, neuropeptide Y
what are parasympathomimetics?
parasympathomimetics: parasympathetic agonists
- produce similar response to Ach: can activate muscarinic receptors or prevent normal Ach break down, so can have bigger effect (more endogenous NT)
how many types of muscarinic receptors are there? which ones are inhib/ excitatory? - what are second messengers for inhibit / excitatory/
5 types:
- *- M1 = excitatory**: 2nd messenger = IP3 & DAG
- *- M2 = inhibitory:** 2nd messenger = cAMP
- *- M3 = excitatory:** 2nd messenger = IP3 & DAG
- M4 and M5 in CNS (dont need to know)
most of autonomic NS pharmacology is targeted at which receptors? why?
muscarinic receptors: bc located on target organ = precise response
where is muscarininc M1 / 2/ 3 found? role?
M1:
- location: GI system
- function: gastric acid secretion
M2:
- location: heart
- function: cardiac inhibition (bradychardia)
M3:
- location: smooth muscle, vascular endothelium
- function: secretion of glands, vasodilation, smooth muscle contraction
what do sympathomimetics do?
what are two important classes?
produces a similar response as noradrenaline and adrenaline on the sympathetic NS
classes:
i) monoamines
ii) catecholamines (e.g. noradrenaline, adrenoline)
what type of protein are adrenoreceptors? what does that mean ?
GCPR - can have excitatory or inhibitory response (depending on 2nd messenger system)
what variants of adrenoreceptors are there? which are pre / post synaptic? excitatory or inhbitor?
- *alpha:**
- alpha 1: postsynaptic excitatory
- alpha 2: presynaptic. inhbits further release of noradrenaline
- *beta:**
- beta 1: postsynaptic excitatory
- beta 2: postsynaptic excitatory
- beta 3: postsynaptic excitatory
