the rest of the stuff Flashcards
Explain PK-PD correlation
coupling between drug plasma concentration and drug effect, allows for the inference of drug action based only on plasma concentration
bioavailability (F) formula and definition
(AUC(oral)/AUC(IV))*(dose(IV)/dose(oral), definition: A measure of the drug available to the systemic circulation over time after administration
sites of first-pass metabolism
enterocytes and liver
apparent volume of distribution (Vd) definition and formula
Vd = amount administered/Cnaught, definition: a primary pharmacokinetic parameter, the apparent volume of space into which a drug can distribute after dosing
what happens in phase I drug metabolism?
drug –> derivative via addition of reactive functional group e.g. -OH
what happens during phase II drug metabolism?
derivative –> conjugate, via the conjugation of some compound, e.g. glucuronic acid, to the derivative via the reactive functional group
Example of prodrug activation
L-DOPA –> dopamine via DOPA decarboxylase
Paracetamol overdose explanation
NAPQI is a toxic derivative of paracetamol produced by CytP450. Once GSH is depleted, NAPQI accumulates leading to toxic hepatic necrosis
Clearance definition and formula
Definition: volume of blood cleared of a drug per unit time, the other primary PK parameter apart from Vd. formula = urinary [drug] * urinary volume/time /plasma[drug] OR total drug amount in plasma/area under curve
1/2life formula. About 4-5 half lives –> total elimination of the drug
T1/2 = 0.693 * Vd/CL, Ke = CL/Vd
antacids - chemical antagonists, don’t bind to a receptor to elicit an effect
aluminium/magnesium hydroxide
an inhibitor of excitatory neurotransmission
lithium
anti-coagulant
warfarin
Osmotic diuretic used to treat increased intracranial pressure
mannitol
What is affinity defined as?
A measure of the probability that the drug-receptor complex will form, via Kd dissociation constant = ([D][R]/[DR]). Affinity determines the drug concentration required for the formation of a therapeutically significant number of DR complexes
How to calculate bound drug?
bound = Bmax * [D] / [D] + Kd
Efficacy (alpha) and some examples
Efficacy is the ability of a drug to initiate downstream signalling. Agonists have efficacy of 1, antagonists have efficacy of 0, partial agonists have efficacy between 1 and 0. Inverse agonists (e.g. antihistamines) have negative efficacy because they reduce the activity of a constitutively active receptor
Potency
Dose required to produce a given degree of response (EC50)
How to calculate the effect of a drug
Effect = Emax * [D] / [D] + EC50
Chemical antagonism
2 drugs combining in solution and the effect of the active drug is lost prior to receptor involvement
Physiological antagonism
2 drugs causing opposing effects via distinct mechanisms
Pharmacological antagonism
2 drugs that have the same receptor, may be competitive or non-competitive (irreversible i.e. covalent)
A nasal decongestant, alpha1 receptor agonist –> Gaq signalling
phenylephrine
Photon-activated GPCR
rhodopsin, functions via transducin Gat, activates cGMP-specific phosphodiesterases leading to a decrease in cGMP levels and closure of Na+/Ca2+ channels –> neuronal hyperpolarisation
Homologous GPCR desensitisation
Phosphorylation of the G protein carboxy terminal by GRK –> internalisation in endosomes. When ligand levels are low, G protein may be phosphorylated and re-activated
Heterologous GPCR desensitisation
Affects multiple GPCR systems, e.g. if some second messenger/enzymes that is shared becomes uncoupled. PKA/PKC-mediated
local anaesthetic, MOA is sodium channel blocking
lidocaine
these Ca2+ ion channels participate in skeletal muscle contraction
dihydropyridine receptor (voltage-gated) and ryanodine receptor (ligand-gated)
L-type Ca2+ channel blocker, for use in the treatment of angina/tachyarrythmias
verapamil
bind to alosteric sites on GABA receptors, potentiate the inhibitory effect of GABA, anti-anxiety/epileptic, sedative, hypnotic, anaesthetic
benzodiazepines. uses: anti-epileptic, anti-anxiety, sedatives
Selective antagonist to nicotinic acetylcholine receptors
alpha-bungarotoxin –> paralysis
ACE inhibitors
catopril, enalopril
angiotensin receptor antagonists
losartan, valsartan
renin inhibitors
aliskeren
treatment for bedwetting/diabetes insipidus via vasopressin V2 receptor agonism –> anti-diuretic
desmopressin
selective V2 vasopressin receptor antagonist, leads to increase in urine volume, used to treat hyponatremia
conivaptan
cGMP analogue PDE5 inhibitor (original)
sildenafil citrate, promotes erection by maintaining high cGMP levels. Side effect = blue-tinted vision due to ocular PDE6 antagonism. Also leads to bleeding due to high cGMP inhibiting clotting in platelets
cGMP analogue PDE5 inhibitor (long-lasting)
tadalafil, promotes erection by maintaining high cGMP levels
treatment for hypertensive crisis
nitroprusside, raises NO levels –> vasodilation
treatment for angina pectoris
nitroglycerine, raises NO levels –> vasodilation. Contraindicated by sildenafil citrate use due to potentially lethal drop in blood pressure
PDE4 inhibitor, used in the treatment of COPD
roflumilast
sustained erection in the absence of stimulation
priapism, indicative of clotting
Higher pA2 value –> more potent competitive antagonist
formula: look at the schild plot. Antagonist concentration needed to give a dose ratio of 2. Dose ratio = EC50 in the presence of antagonist/EC50 in the absence of antagonist.
