pharmacology 4 Flashcards
What receptors do anticholinergic drugs act on?
Muscarinic receptors
e.g atropine, glycopyrolate
Effect:
-tachycardia (blocking M2 receptors on the heart reduces vagal (parasympathetic) tone which would normally slow the heart
-Brocholdilation (M3 receptors in smooth muscle of airways)
-mydriasis (dilation)- M3 receptors in iris sphincter
-urinary retention- blocking M3 receptors in detrusor muscle.
-GI: reduced gut motility, dry mouth, constopation. block M1 receptors in stomach reduces acid production.
-CNS- drugs that cross BBB eg atropine, scoploamine can cause drowsiness, confusion, hallucinations & delirium.
reduced sweating! risk of hyperthermia in extreme cases.
-> hot as a hare, dry as a bone, blind as a bat, red as a beet (flushed skin due to vasodilation), mad as a hatter
Therapeutic uses of muscarinic antagonist (anticholinergics):
-COPD: ipratropium, tiotropium
-brady: atropine
- overactive bladder: oxybutynin
- -ophthal: tropicamide to dilate pupil for examination
- motion sickness: scopalamine
- reduce IB cramps: hyoscine butylbromide
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Acetylcholine is an agonist for these receptors.
Name three examples of anticholinergic drugs.
- Atropine
- Glycopyrrolate
- Hyoscine
What physiological effect do anticholinergic drugs have on the respiratory system?
bronchodilation
by blocking M3 muscarinic receptors (preventing ACh from attaching)
Which two anticholinergic drugs are tertiary amines?
- Atropine
- Hyoscine
What is a significant property of tertiary amines like atropine and hyoscine?
They can cross the placenta and blood-brain barrier (BBB).
What central effect can hyoscine produce?
Amnesia.
What type of amine is glycopyrrolate?
Quaternary amine
As is ipratropium. The charge prevents them from crossing the BBB (unlike teriary amines (atropine, hyocine which produce CNS effects)
Can glycopyrrolate cross the placenta and blood-brain barrier?
No, it cannot because of its charge being a quarternary amine. (same with ipratropium bromide)
What effect can anticholinergic agents have on the lower oesophageal sphincter?
They may decrease the tone.
What are enflurane and isoflurane in relation to each other?
Structural isomers
They have the same molecular formula but different structural formulae.
1.what does the law of mass action state
- what happens at equilibium between substrate and enzyme?
- What is KD?
- What is KA?
1.the law of mass action states the rate of a chemical reaction is proportional to the concentrations of the reacting components.
2At equilibrium
K1[D] [R] =K2 [DR]
with K1 being a constant that define the rate of the forward reaction (association reaction)
K2 is the constant that defines the rate of backwards reaction (dissociation reaction)
- KD is the dissociation constant (where half of the receptors are occupied (r=0.5) and allows comparison for different drug receptor combinations.
- KA is the affinity constant, and is the reciprocal of KD ( KA=1/KD). This described the affinity of a drug to its receptor (the potency)
1.what is the equation for fractional occupancy (r)?
- what is Kd
- how is affinity represented graphically?
fractional occupancy (r) is the proportion of the drug attached to the receptor.
r= [DR]/[Rt]
Rt is the total number of receptors (bound and free)
KD (dissociation constant) describes the drug concentration at which half of the receptors are occupied (r=0.5) This is important because the fractional occupancy determines the response of a drug.
Low Kd=high affinity
high Kd=low affinity
r=[D]/ Kd + [D]
- graphically this equation is hyperbolic. It is converted to a sigmoid shaped semi-logarithmic plot to give ED50=KD (where r=0.5) to allow easier interpretation)
r=[D]/ kd + [D]
drug receptor relationships
1. What is E?
2. what will the value of E be for partial and full agonist?
3. what is the equation relating E to drug and dissociation constant
- E = observed response
r=fractional occupancy
e=intrinsic activity (or efficacy)
E=er
Full agonists: provide maximum response (E=1)
Partial agonist: E between 0 and 1
if r=D/ Kd +D
E= e[D]/ Kd + [D]
Where Kd (dissociation constant is the conc of full agonist producing half-maximal response
- what is Km ?
- What is the Michaelis-Menten equation?
- How can enzyme activity be altered
- ?
1.Km is the michaelis constant, which is the concentration of substrate at which the velocity of the reaction is 1/2 the Vmax.
- Michaelis-Menton equation:
V=Vmax [S]/ (Km + [S])
3.Enzyme activity can be altered by changing substrate or enzyme concentration, or by changing the Vmax, or Km
What 3 ways can drugs increase enzyme activity?
What 3 ways can drugs increase enzyme activity?
- Direct positive allosteric modulation
(increases Vmax or Km) i.e insulin of tyrosine kinase. Insulin attaches to the two extracellular subunits on the insulin receptor which brings about conformational change to the two transmembrane beta subunits which activate tyrosine kinase activity. - indirect increase- via intermediate messengers i.e G-protein coupled receptor agonists coupled with adenylate cyclase i.e H2, D1 & b receptors
- increase in enzyme concentration (enzyme induction)
which drugs are enzyme inducers
BS CRAP GPS
barbiturates
St johns wart
Carbamazepine
Rifampicin
Alcohol (chronic)
Phenytoin
Grisefulvin
phenobarbital
sulfonylureas e.g gliclazide (avoid in acute porphyria, severe renal or hepatic impairment, risk of hypoglycaemia in elderly)
These make other drugs metabolise faster so effect is less pronounced or wears off more quickly
e.g Phenytoin or carbamazapine with vecuronium will cause a reduced duration of block.
rifampicin or carbamazapine with warfarin will reduce the efficacy of the warfarin
barbiturates reduce efficacy or corticosteroids
rifampicin reduces efficacy of ciclosporin
which enzymes are inhibitors
- how do drugs reduce enzyme activity
- direct inhibitio of enzyme via reduction in Km or Vmax.
OR indirect decrease in enzyme activity via intermediary messengers.
Tell me about reversible inhibition aka competitive antagonism.
Give examples
with comppetitive antagonism, the degree of enzyme inhibition depends upon plasma concentration of inhibitor compared to the natural agonist.
e.g
-neostigmine (ACh inhibitor)
-Ramipril (ACE inhibitor)
-Milrinone- phosphodiesterase inhibitor
-NSAIDs- COX inhibitor
1 Tell me about Acetylcholinesterase
- name 3 different examples of AChE inhibitors
- which are reversible inhibitors?
- which are irreversible inhibitors?
- AChE is responsible for ester hydrolysis of ACh at the NMJ
-Anionic site- negatively charged, attracting a positive quarternary ammonium ion
-Esteric site- involved in ester hydrolysis to form choline and acetic acid
- a .neostigmine & pyridostigmin: these are substrates that bind to both sites of AChE
b. Edrophonium: binds to anionic site only
c. Organophosphates: irreversible inhibitors of AChE.
3.These are further divided into two categories:
a. Enzyme carbamylators (neostigmine, pyridostigmine, physostigmine) - these reduced the rate of breakdown, allowing ACh to build up in the cleft
b. Anionic site competitive inhibitors e.g Edrophonium. this is a short acting competitive inhibitor used for diagnostic purposes.
**note those with Myasthenia gravis will be taking pyridostigmine and will be relatively insensitive to succinylcholine but very sensitive to non-depolarising NMBs
- IRREVERSIBE INHIBITORS of AChE:
-organophosphates e.g parathion, interact with the esteratic site to phosphorylate AChE. The drug-enzyme complex becaomes ‘aged’ with time a d inhibition becomes irreversible.
- The phosphorylated AChE reacts slowly with water allowing ACh concs to rise in all sites centrally & peripherally. This is characterised by a cholinergic crisis involving salivation, abdo pain, weakness & bradycardia.
- Pralidoxime can be used before ‘ageing’ occurs (within 36-48 hours) to reverse to complex more rapidly by displacing phosphate from the esteratic site and remains bound for a time until the poison can be eliminated. Oximes are then given to allow the enzyme to recover.
- what are phosphodiesterses (PDE)
- give an example of non-selective PDE inhibitors
- give an example of selective PDE inhibitors
PDEs are responsible for degradation of the phosphodiester bond in second messenger molecules cGMP and cAMP rendering them inactive. (PDE breakdown cAMP)
- non selective PDE inhibitors: Aminophylline & Theophylline.-> mainly inhibit PDE in bronchial smooth muscle but can also cause vasodilation, inhibition of platelet aggregation, positive inotropy.
- Selective PDE-i:
Enoximone and milrinone selectively inhibit PDE-III & are structurally similar to cAMP. PDE-III is predominantly located in the heart. with less PDE III there will be increased calcium available for myocytes, enhancing contractility (inotropy).& relaxation of vascular smooth muscle.
Dipyridamole & sildenafil both inhibit PDE-V which inhibits platelet aggregation & treats pulmonary HTN & ED respectively.
how does warfarin work?
-warfarin is a racemic mixture
-factors II, VII, IX and X require vitamin K as a co-factor
-Vit K is recycled through the actions of VKOR (vitamin K epoxide reductase). Warfarin inhibits VKOR to prevent regeneration of active vitamin K
-S-enantiomer is more potent at VKOR inhibition
-CYP2C9 is responsible for Swarfarin metabolism which is subject to genetic variation.
VKOR genetic variants also exist.
Give examples of irreversible inhibitors
irreversible inhibitors have a long duration of action as they re-quire the re-synthesis of an enzyme before normal activity can be retained e.g
-organophosphates.
-Aspirin acetylation of COX in platelets (plt lifespan 5-10days)
-non-selective MAO inhibitors (phenelzine, tranylcypromine)
List the inhibitors
Enzyme inhibitors will prolong the action of the drugs
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sodium valproate
isoniazid
cimetadine
ketoconazole
alcohol (acute?)
Chloramphenicol
Erythromycin
Sulfonamides
Ciprofloxacin
Omeprazole
Metronidazole
+
grapefruit juice
Amiodarone
name the fibrinolytics
how do they work
streptokinase, urokinase, alteplase.
these convert plasminogen to plasmin with degrades fibrin
Tell me about drug side-effects
Divided into:
1. reactions that can occur in anyone: OD, SE, drug interaction
- reactions that occur in susceptible individuals:
-intolerance- low threshold to the normal pharmacological action of a drug
-drug idiosyncrasy- genetically determined, qualitatively abnormal reaction to a drug related to a metabolic or enzyme def e.g sux apnoea, CYP2D6 deficiency, G6PD deficiency - reactions due to allergies
