Applying PD/PK theory to stimulants Flashcards
what is the preferred administration for cocaine and nicotine and why
inhalalational, so effects are produced more rapidly
rank the fastest to lowest for routes of administration for peak effect in brain
inhalational, intra-venous, intra-nasal and oral
why does oral take the longest time to peak effect
drug has to enter GI stystem and after absorption in the small intestine drug willenter haptic portal venous and delivered to the liver and access the brain
why is intra-nasal slower than intra-venous
there is no direct route from nasal passage to brain, so drug must cross mucous membranes of nasal sinus and enter venous system
what enzyme metabolize cocaine
cholinsterase
what enzyme metabolize nicotine
cytochrome p450
why does inhalational takes the fastest time
drug rapidly difuses across the alveoli and enters pulmonary artery that travels to left atrium and directly into left ventricle and sent to aorta.
why does drugs become addictive
with faster onset of action, it being deactivated by metabolism increases drug’s addictive potential
why does cocaine binds to at different concentration
catecholamine reuptake proteins - noradrenaline and dopamine at low doses, sodium channels at high dose
why are the similarities between cocaine, noradrenaline and dopamine
they all possess a lipophilic ring structure, intermediate linking bond and amine group
how does cocaine inhibits retuptake of catecholamines
acts as a substrate for reuptake proteins
how does tyrosine convert to dopamine
tyrosine is the precursor of dopamine and is first converted to DOPA by tyrosine hydroxylase and converted to dopamine via DOPA decarboxylase
what is the effect of cocaine to dopamine
cocaine increases the number of dopamine receptor interaction by blocking the reuptake transporter protein. this does not change the affinity of dopamine for dopamine receptor
effect of cocaine on sodium channels
by becoming more ionised within in the cell, cocaine block sodium channels providing local anaesthetic effects
how to calculate how much cocaine ionises
10^(pka-ph)=[BH+}/[B]
cocaine with pka = 8.41 ionised:unionised ratio in the extracellular compartment (pH = 7.4) is 10 and in the intracellular compartment (pH = 7) is 25. Unionised cocaine is far more likely to cross the lipid membrane, however, ionised cocaine is more likely to interact with the binding site as it has polar side chains
function of nicotinic acetylcholine receptor
component of autonomic nervous system - regulates heart rate, GI function, sweating, pupil dilation and blood glucose levels
where is nicotinic receptor found
found on muscle and bound to by acetylcholine that is released at the neuromuscular junction
action of acetylcholine
binds to nicotinic receptor and promotes ion channel opening and movement of ions from extracellular to intracellular side
how does drugs induce feeling of reward
from stimulation of dopaminergic neurons, which originate in the ventral tegmental area and project to nucleus accumbens
how does nicotine causes euphoria
nicotine binds to receptor in ventral tegmental area and promotes influx of Na+ by depolarisation of neurone to increase dopamine release into the synapse and activates D1 receptors and causes euphoria
how does cocaine cause euphoria
cocaine slows reuptake receptor and let dopamine accumulate in synapse prolonging euphoria
how is euphoria lost
dopamine removed from the synapse via dopamine transporter
how does cocaine and nicotine mimic the sympathetic nervous system
nicotine can activate post-ganglionic neurone which releases noradrenaline at effector tissue which is kept in this region by cocaine blocking the noradrenaline uptake protein
compare effect of cocaine and nicotine on heart rate and potential side effects
both drugs increase heart rate with cocaine more powerful than nicotine by 30%. Both drugs also increase vascoconstriction of blood vessels to increase blood pressure. This increase myocardial oxygen demand and could cause endothelial injury due to increased blood vessel
What danger effects does these drug posses
Both drugs will also activate platelets which could contribute to causing atherosclerosis which narrows the vessels and could narrow the coronary vessels to further decrease oxygen supply to the heart. These effects could lead to conditions such as myocardial ischaemia, myocardial infarctions, arrhythmias or sudden death.
Compare the acute and chronic toxic effects between nicotine and cocaine
Nicotine alters the blood-lipid profile and increases very low density lipoproteins and low density lipoproteins which increase atherogenic risk. Hence, nicotine toxicity is not acute and is more chronic.
Cocaine’s toxic effects are acute as sodium channels in the heart could become blocked causing arrhythmias and inflammation which interferes with left ventricular function and exacerbates endothelial injury. Cocaine, being more powerful, is more likely to cause acute toxicity and myocardial infarction.
