Define partial agonist
A drug that fails to produce maximal effects even when all receptors are bound by the drug
Define potency
Potency is the amount of drug required to produce 50% of the maximal response the drug is capable of inducing
Define pharmacokinetics
What the body does to the drug
What type of receptor is the nicotinic cholinergic receptor?
Ligand-gated ion channel
Define efficacy
- Efficacy is the probability of a drug activating a receptor once bound
- Aka the degree to which a drug is able to produce maximal effects
Define pharmacodynamics
What the drug does to the body
Define affinity and how it is measured
- Affinity is the probability or strength of a drug binding to its receptors
- Measured with equilibrium dissociation constant
KA = drug concentration required for 50% occupancy of receptors
Describe the journey a PO medication must take to reach systemic circulation
GIT -> liver -> R) heart -> lung -> L) heart -> systemic circulation
Define each of ADME
Absorption - how drug gets into circulation
Distribution - how drug spreads through body
Metabolism - chemical changes to the drug
Excretion - physical expulsion of the drug
What are the 6 steps in pharmacokinetics?
Administration, absorption, distribution, elimination, metabolism, excretion
Describe the 3 steps in ACh synthesis
1 Choline taken up into cell by choline carrier
2 Choline + acetyl-CoA → acetylcholine + CoA via choline acetyltransferase
3 ACh put into vesicle
What is a clinical use for nicotinic receptor antagonists?
Pre-surgical muscle relaxant
Name 3 clinical uses of ACh esterase inhibitors
Dx of myasthenia gravis
Rx of myasthenia gravis
Rx of Alzheimer’s disease
What is a clinical use for nicotinic receptor agonists?
Smoking cessation
What is the mechanism of action of atropine?
What are 4 clinical uses of atropine?
Muscarinic antagonist.
Bronchodilation and decrease respiratory mucous in anaesthesia
To increase heart rate.
Pupil dilation for eye examination.
AChE-inhibitor poisoning (organophosphates)
What is the mechanism of action of botulimin toxin
Name 3 conditions it may be used for
Botulimin toxin inhibits presynaptic ACh release by inhibiting vesicular exocytosis by acting as a protease on SNARE proteins.
Used to treat dystonia, migraine or underarm sweating
What are H2 antagonists used to treat and what is their mechanism of action?
Used to treat peptic ulcers.
Inhibit acid secretion by parietal cells in stomach by disrupting proton pump.
H1 antagonists:
What class of drugs are these?
Name 5 things they are used to treat.
Name 2 new generation drugs
Antihistamines
Used to treat hayfever, itchiness, motion sickness, anaphylaxis, bites/stings
New generation = cetirizine, loratidine
Describe the 4 steps in NA synthesis
1 Tyrosine taken up into cell
2 Tyrosine → L-Dopa (catalysed by tyrosin hydroxylase)
3 L-DOPA → Dopamine (catalysed by dopa decarboxylase)
4 Dopamine taken up into vesicle and converted into NA (catalysed by dopamine beta hydroxylase)
What are 7 clinical consequences of adrenaline administration?
Vasoconstriction
GI muscle relaxation
Salivation
Hepatic glycogenolysis
Increased heart rate
Increased cardiac contractility
Bronchodilation
What is the mode of action of aminoglycosides?
Aminoglycosides bind to specific proteins in 30s ribosome subunit and inhibit binding of formylmethionyl-tRNA (fmet-tRNA) to ribosome, thus inhibit protein synthesis,
Also cause misreading of mRNA codons
How do beta lactams exert antimicrobial effects?
Beta lactams inhibit synthesis of cell wall by binding to PBPs (penicillin-binding proteins)
List 3 enzymes that beta lactams may inhibit
Transpeptidase
Transglycosylase
Carboxypeptidase
What is the mechanism of action of loop diuretics?
Inhibit Na/K/2Cl carrier in ascending loop of Henle
What is the mechanism of action of potassium-sparing diuretics?
Block Na transporter in collecting tubules and ducts
Plus or minus:
Inhibit synthesis of Na/K cotransporter in collecting tubules and ducts
What is the mechanism of action of thiazide diuretics?
Inhibit Na/Cl transporter in distal tubule
What are 7 clinical consequences of adrenaline administration?
Vasoconstriction
GI muscle relaxation
Salivation
Hepatic glycogenolysis
Increased heart rate
Increased cardiac contractility
Bronchodilation
How does penicillin exert its antimicrobial effect?
Penicillin stops formation of pentapeptide bridge by blocking transpeptidase
List 3 enzymes that beta lactams may inhibit
Transpeptidase
Transglycosylase
Carboxypeptidase
What are 6 clinical effects of muscarinic antagonists (aka anticholinergics)?
Dry eyes
Dry mouth
Urinary retention
Constipation
Tachycardia
Confusion
What type of receptor is the muscarinic cholinergic receptor?
G-protein coupled receptor
The transcription of which cytokines is inhibited through transrepression by GCSs?
IL-1,4,5,8
GM-CSF
TNFalpha
What are 6 effects of histamine on H1 receptors?
Pain and itch
Bronchospasm
Mucus secretion
Vasodilation
Increased vascular leak
Increased wakefullness
The transcription of which genes is activated through transactivation by GCSs? And what are their effects?
Beta 2 adrenoceptor –> bronchodilation
Annexin-1 –> inhibits PLA2
SERPINA3 –> codes for alpha 1 antichymotrypsin –> inhibits neutrophil elastase
The transcription of which inflammatory enzymes are inhibited through transrepression by GCSs?
PLA2
COX-2
iNOS
Describe 6 steps in GCS transactivation
GCS cross plasma membrane and enters cell
–> binds to cytosolic glucocorticoid receptor
–> dimerises
–> enters nucleus
–> binds to glucocorticoid response element (GRE) in the promoter region of the target genes
–> gene transcription
What are the effects of histamine acting on H2 receptors?
Positive inotropic effects on heart
Positive chronotropic effects on the heart
Gastric acid secretion
The transcription of which adhesion molecules is inhibited through transrepression by GCSs?
ICAM
E-selectin
Name 3 classes of molecule that GCS inactivates through transrepression
Cytokines
Adhesion molecules
Inflammatory enzymes
In which organelles are P450s located?
Endoplasmic reticulum and mitochondria
Which cytochrome P450 is involved in the metabolism of 25% of all prescription drugs?
CYP2D6
Name two D2 antagonists used to treat nausea
Metoclopramide (maxolon)
Prochlorperazine (stemetil)
CYP 2A6
What does the 2 refer to? What does the A refer to? What does the 6 refer to?
Family. Subfamily. Form
The cytochrome P450 oxidises all foreign chemical with a molecular weight greater than what?
5,000
When is the P450 cycle of reactions initiated?
When a substrate binds to the P450
When is P450 found in microsomes?
In vitro only
What does it mean to say that a specific cytochrome P450 is inducible?
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Chronic drug/toxin exposure will result in higher levels of that P450 being expressed <!--EndFragment-->
What is the point of CYP450 enzymes?
Add -OH and sugar group onto small hydrophobic molecules to make them water soluble so they may be excreted by the kidneys
What is anakinra?
IL-1 antagonist
According to first order kinetics, what determines rate of clearance of a drug?
Drug concentration in the body (and a constant for the drug)
If a drug is given regularly every half life, what will the trough concentration be relative to peak concentration?
Half
How long will it take for an IV infused drug to reach 99% of its steady state concentration?
7 half lives
Which cytokines do glucocorticosteroids suppress the synthesis of?
IL-1,4,5,8, TNF alpha and GM-CSF
How do glucocorticoids suppress prostaglandin synthesis?
Transactivate annexin 1, which inhibits PLA-2, thus preventing formation of prostaglandins
Which cytochrome P450 metabolises steroids?
CYP3A4
Which three classes of proteins do glucocorticosteroids suppress the synthesis of?
Cytokines. Inflammatory enzymes. Adhesion molecules
What are the 3 actions/indications of NSAIDs?
Anti-inflammatory, analgesic, antipyretic
Which NSAID is generally best as an antipyretic?
Paracetamol
How do NSAIDs cause analgesia?
NSAIDs decrease production of PGs. PGs sensitise sensory nerve endings
What are the 4 main adverse effects of NSAIDs?
Gastric ulcers. Increased bleeding time. Renal impairment. Bronchoconstriction
Name 2 enzymes that glucocorticoids increase the transcription of? How do these decrease inflammation?
SERPIN A3 => codes for anti-chymotrypsin, which inhibits neutrophil proteases ANNEXIN 1 => inhibits PLA2
What is the main target of NSAIDs?
COX-2
How do NSAIDs cause gastric ulcers?
NSAIDs inhibit mucosal synthesis of PGE2. PGE2 normally protects mucosa by increasing mucous secretion, reducing acid secretion, promoting blood flow and promoting angiogenesis
Describe the 4 steps in NA synthesis
1 Tyrosine taken up into cell
2 Tyrosine → L-Dopa (catalysed by tyrosin hydroxylase)
3 L-DOPA → Dopamine (catalysed by dopa decarboxylase)
4 Dopamine taken up into vesicle and converted into NA (catalysed by dopamine beta hydroxylase)
