Applying PD/PK theory to stimulants

Question 1

what is the preferred administration for cocaine and nicotine and why

Answer 1

inhalalational, so effects are produced more rapidly

Question 2

rank the fastest to lowest for routes of administration for peak effect in brain

Answer 2

inhalational, intra-venous, intra-nasal and oral

Question 3

why does oral take the longest time to peak effect

Answer 3

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

Question 4

why is intra-nasal slower than intra-venous

Answer 4

there is no direct route from nasal passage to brain, so drug must cross mucous membranes of nasal sinus and enter venous system

Question 5

what enzyme metabolize cocaine

Answer 5

cholinsterase

Question 6

what enzyme metabolize nicotine

Answer 6

cytochrome p450

Question 7

why does inhalational takes the fastest time

Answer 7

drug rapidly difuses across the alveoli and enters pulmonary artery that travels to left atrium and directly into left ventricle and sent to aorta.

Question 8

why does drugs become addictive

Answer 8

with faster onset of action, it being deactivated by metabolism increases drug’s addictive potential

Question 9

why does cocaine binds to at different concentration

Answer 9

catecholamine reuptake proteins - noradrenaline and dopamine at low doses, sodium channels at high dose

Question 10

why are the similarities between cocaine, noradrenaline and dopamine

Answer 10

they all possess a lipophilic ring structure, intermediate linking bond and amine group

Question 11

how does cocaine inhibits retuptake of catecholamines

Answer 11

acts as a substrate for reuptake proteins

Question 12

how does tyrosine convert to dopamine

Answer 12

tyrosine is the precursor of dopamine and is first converted to DOPA by tyrosine hydroxylase and converted to dopamine via DOPA decarboxylase

Question 13

what is the effect of cocaine to dopamine

Answer 13

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

Question 14

effect of cocaine on sodium channels

Answer 14

by becoming more ionised within in the cell, cocaine block sodium channels providing local anaesthetic effects

Question 15

how to calculate how much cocaine ionises

Answer 15

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

Question 16

function of nicotinic acetylcholine receptor

Answer 16

component of autonomic nervous system - regulates heart rate, GI function, sweating, pupil dilation and blood glucose levels

Question 17

where is nicotinic receptor found

Answer 17

found on muscle and bound to by acetylcholine that is released at the neuromuscular junction

Question 18

action of acetylcholine

Answer 18

binds to nicotinic receptor and promotes ion channel opening and movement of ions from extracellular to intracellular side

Question 19

how does drugs induce feeling of reward

Answer 19

from stimulation of dopaminergic neurons, which originate in the ventral tegmental area and project to nucleus accumbens

Question 20

how does nicotine causes euphoria

Answer 20

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

Question 21

how does cocaine cause euphoria

Answer 21

cocaine slows reuptake receptor and let dopamine accumulate in synapse prolonging euphoria

Question 22

how is euphoria lost

Answer 22

dopamine removed from the synapse via dopamine transporter

Question 23

how does cocaine and nicotine mimic the sympathetic nervous system

Answer 23

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

Question 24

compare effect of cocaine and nicotine on heart rate and potential side effects

Answer 24

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

Question 25

What danger effects does these drug posses

Answer 25

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.

Question 26

Compare the acute and chronic toxic effects between nicotine and cocaine

Answer 26

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.