Pharmacology Flashcards
Bioavailability/f is
the proportion of administered drug that reaches systemic circulation
Give 4 of the Lipinski rules
- molecular weight <500
- Less than 5 H-bond donors
- Less than 10 H-bond acceptors
- log p<5
How do drugs that obey 1st order kinetics behave?
- a constant FRACTION of drug is removed
- the time to remove the drug is independent of dose
- has a constant half life
How do drugs that obey 0 order kinetics behave?
- a constant AMOUNT of drug is removed
- the bigger the dose, the longer time taken to remove it
- as dose decreases, and mechanism is no longer saturated, process returns to 1st order
Volume of Distribution (Vd) =
Total amount of drug ÷ plasma drug concentration
Plasma Clearance (CL) =
Rate of elimination ÷ plasma drug concentration
Dosing Rate x F =
CL x Target Conc
Multiple dosing leads to steady state to balance rate of absorption with elimination, the time taken to reach steady state is
4-5 times the drugs half life
Name a drug that may be given to treat postural hypotension?
fludrocortisone - acts on mineralocorticoid receptors to increase Na+ receptors
Local anaesthetics are more non-ionised/permeable in what pH?
Why?
LAs are weak bases. They are more permeable in alkaline conditions.
What happens if LAs enter the CNS?
-initially stimulation, then depression
What happens if LAs enter the CVS?
- blocked Na+ channels so less Ca2+ influx and decreased force of contraction
- vasodilation due to symp. inhibition so BP drop
Give 4 routes of LA administration?
- surface
- nerve block
- spinal
- epidural
Give 3 reasons LA may be administered with Adrenaline.
- keeps it localised
- inhibits absorption from ECF->blood (less toxicity)
- prevents bleeding
- prolongs its action
Give a disAdv of administering LAs with Adrenaline.
- can get local hypoxia esp. in extremities
- absorption of adrenaline can cause arrhythmias
Where does drug metabolism mainly occur, what is its purpose?
- in liver, makes drug more water soluble
- less drug reabsorbed
What happens in the following drug metabolism:
- Phase I
- Phase II
I-adds chemically reactive groups by oxidation making them more polar and reactive
II-increases water solubility by conjugation
Renal Clearance (ml/min) = -units?
-urine drug conc/plasma drug conc
drug/min drug/ml
What 4 things influence ADME?
- Age (neonates, elderly)
- Genetics
- Drug metabolising enzymes (g.f. juice, alcohol)
- Disease (liver/kidney)
Give 3 Advs of monitoring drug conc.
- confirm patient adherance/individualise doseage
- determine toxicity/presence of other drugs
- useful in postmarket surveillance
What characterises a type A ADR?
-predictable, dose dependent, not lethal
How can a hypersensitivity reaction occur to a large molecular weight drug (often as bound to plasma proteins)?
They are a ‘hapten’ (identified by immune system), upon encountering again you have primed mast cells -> histamine release, anaphalaxis
3 forms of pharmacoviligince:
- Yellow Card (no denumerator)
- Black Triangle (new drug-take caution)
- Green Form (anyone on new drug, everything recorded, numerator&denumerator)
Where is there sympathetic activity induced via Ach acting on Musc receptors?
- sudomotor nerves to eccrine sweat glands
- pilloerrector muscles
Where do opiods act? By which mechanism? To do what?
- act at Gai receptors, mainly mu
- at periphery, in dorsal horn & periaq. grey
- to decreases pain by decreasing synapic transmission
Opiods mechanism of action:
Presynaptically…
Postsynaptically…
Pre…opiod binds to mu, decreased VGCC so less NT release. Also stimulates K+ channels->hyperpolarisation
Post…opens K+ channels –> hyperpolarisation
How do opiods decrease pain in the periaq. grey?
They switch on neuronal areas involved in analgesia by disinhibiting the inhibitory interneurone (more stimulation)
How do opiods lead to feelings of euphoria?
- opiods disinhibit GABAergic interneurones in reward areas
- more DA release and DAergic transmission
Why are opiods often given with metoclopramide?
Opiods cause vomiting by activating the CTZ, this prevents it.
If orally, where would opiods be mainly absorbed and why? Why are opiods given IV?
- they are weak bases, pka-8, would be in intestines
- have a high 1st pass metabolism/low f
What opiod partial agonist with long half life is given for heroin withdrawal?
Buprenorphine
At which receptors do the following act?
- alcohol
- phencyclidine hallucinogens
- alcohol at GABAa receptors
- phencyclidine hallucinogens- NMDA antagonist
How do amphetamines like methylphenidate act?
Effect?
- Displace DA from bouton
- increased alertness, euphoria, confidence, BP, less appetite
How do psychotomimetics like ecstacy act? Effect?
- inhibit M.Amine Transporters, more 5HT&DA release
- more DA causes euphoria but depletion -> irritable mood after
How do central stimulants like cocaine act? Effect?
- block catecholamine uptake so more DA, NA and 5HT
- activates HPA axis so increases cortisol
- euphoria, locomotor stimulation
How does alcohol lead to good/reward feelings?
What is alcholism treated with?
- the potentiated GABA-mediated inhibition disinhibits the mesolimbic DAergic neurones and releases endogenous opiod peptides
- Disulfiram (acetaldehyde accumulates so alcohol is iyk)
How and where does Nicotine act? Effect? Treatment?
- on nic Ach a4B2 receptors (lots in VTA&hippocampus) so more NT, opiod peptides, alertness, addictive
- treat via nicotine patches/buprion/varenicline
To maintain homeostasis upon excessive drug use, how does your body desensitise the continually activated receptors?
- arrestin binds and de-activates the receptors effect
- hyperpolarises it via K+ efflux
What is Lofexidine’s mechanism of action? (given to supress withdrawal effects of opiod abuse, or clondine for alcohol abuse)
central a2 agonist, inhibits excessive NT release
What pharmacological agents are used for treating motion sickness? How are they given? -remember more = more side effects
-Musc. Ach R Antagonists e.g. scopolamine
-Histamine 1 Antagonists e.g. dyphynhydramine
(separately if mild, mixed if bad, both +DA antagonists)
What are the most common GABAa subunits?
Where does GABA bind to the receptor?
What does activation of GABAa receptors cause?
2a, 2B, gamma
GABA binds between a and B subunits
Hyperpolarisation by opening Cl- Channels
Where on the GABAa receptor do the anxiolytic drugs: barbituates bind? What about benzodiazepines?
Barbituates bind at allosteric sites on a/B subunits
Bezodiazepines bind between a and gamma subunits at a regulatory site, stabilising GABAa R as open
Barbituates are GABAa agonists, why are they no longer used for anxiety? Now used for?
- “dirty”/many SEs, also glycine agonist, blocks ca2+ NT release… v powerful at increasing inhibition
- epilepsy, general anaesthetic, capital punishment
Flumenazil is a competitive GABAa antagonist used for overdose of which anxiolytic drug class?
Benzodiazepines
What are 3 S.E.s of the anxioltytic drug class, Benzodiazepines?
- drowsy
- confusion
- forgetfullness
- resp depression
Midazolam, zolpidem and lorazepam are types of which drug? What are they used for? How do you choose which to give?
Benzodiazepines used for: anxiolytic, anticonvulsant, muscle relaxant, sedative, amnesic
Choice based on duration of action
What are Z drugs? What are they used for?
GABAa modulators, bind between a and gamma subunits (like benzodiazepines)
-Hypnotics
What is the mechanism of action of 5HT-1 R agonists like buspirone which treats general anxiety disorder?
- activate pre 5HT1 autoreceptors, these inhibit 5HT release so less activity of NAergic neurones/less arousal
- overtime due to less 5HT you have neuroadaptation to increase it (uptake inhibited, less pre-autoreceptors)
- Seratonin levels overall increase. Takes time.
What is fluoxetine (Prozac) used to treat?
What is the mechanism of action?
- for social phobias, panic, nausea, sexual dysfunction
- its s 5HT re-uptake inhibtior
How are B-blockers used in the treatment of anxiety?
They reduce peripheral manifestations
What are 2 uses of Histamine 1 R Antagonists?
- treat allergenic/inflammatory disease
- have hypnotic/sedative effects
- act centrally to treat insomnia (maybe result of anxiety)
MAO inhibitors rapidly increase monoamines. Early non-selective irreversible drugs caused a big NA rise after eating cheese/wine, why? Effect?
Indirect sympathomimetic amines such as amphetamine and TYRAMINE increase release of monoamines.
Effect=headache, severe HT, intracranial haemorrhage..
Moclobemide is a reversible inhibitor of MAOa (RIMA), so in case of excess NA, RIMA is displaced and excess is broken down. They still have some SEs, name 3
- postural hypo
- increased appetite, weight gain
- Antimusc effects (blurred vision, constipation..)
- excessive central stimulation (tremors, insomnia…)
How do TCAs act? e.g. amitriptyline, imipramine, lofepramine…
- inhibit NA/5HT reuptake so increased conc in cleft
- chronically, down regulates B1, a1, 5HT2, 5HT1a/1d
2 side effects of TCA?
- anticholinergic/antimuscarinic (dry mouth, blurred vision)
- antihistaminergic (weight gain, sedation)
- a-antagonistic (low BP, postural hypo, tachycardia)
Give 3 reasons TCAs have a narrow therapeutic index/are undesirable?
- antipsychotic drugs, steroids..inhibit TCA metabolism
- TCAs potentiate effects of alcohol & anaesthetics
- Overdose is toxic (heart attack, convulsions..)
- TCA cant be used in elderly/dementia (confusion) or heart disease (block K+ channels->dysrhythmia)
How do SSRIs (e.g. fluoxetine; sertraline; paroxetine, cetalopram) act?
Block reuptake and increase 5HT in cleft …
- cause downregulation of the 5HT1A autoreceptors which disinhibits 5HT neurone so more 5HT is released
- the increased 5HT ‘normalises’ the post synaptic receptors (thought to be upregulated in depressed as low 5HT activity)
3 Advs of SSRIs
- safer, better tolerated
- no anticholinergic/antimuscarinic SE so better compliance
- shorter t 1/2, less severe withdrawal effects
- 5HT2A R -> antidepressant, anti OCD effect
3 disAdv of SSRIs
- take longer to act
- 5HT2A R -> insomnia, sexual dysfunction
- 5HT3 R -> nausea, GI disturbances, headaches
What is buproprion mechanism of action? Its used to treat….
- inhibits NA/DA uptake (not 5HT)
- treats nicotine dependence
