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General Med 1 > Pharm - Exam 1 > Flashcards

Pharm - Exam 1 Flashcards

1
Q

What is metoprolol?

A

Metoprolol – used to treat a person experiencing chest pain (angina) due to insufficient oxygen to the heart caused by partial blockage of the coronary arteries.

Treatment of angina involves a combo of approached:

  1. lifestyle changes (i.e. weight reduction)
  2. Medications
  3. Surgery

Metoprolol will reduce the frequency of angina, but not reverse the underlying cause

It must be taken every day (prophylactically), which is typical for chronic disease. Some are only taken as needed to relieve/prevent symptoms. I.e. nitroglycerin is taken during angina or before activities that cause it.

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2
Q

What drug is taken for angina prophylactically, and what is taken as needed?

A

Prophylaxis = metoprolol

As needed: nitroglycerin. Taken during angina or before activities that cause it.

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3
Q

What is potency?

A

Dose required to produce an effect.

Differences in potency are rarely a determining factor in selecting medication, however a more potent drug is more useful when there is limited capacity to administer large amounts, i.e. transdermal patched.

On an effect/dose curve - moves curve left. I.e. need a lower dose to have same effect.

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4
Q

What is effectiveness?

A

Level of effect, I.e. maximum level of effect. A difference in effectiveness IS often a determining factor.

On an effect/dose curve - curve becomes higher, and does so more quickly (higher peak + steeper curve)

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5
Q

What determines affinity?

A

Strength of drug binding varies in relation to:

  • type of bond
  • distance
  • number of bonds

Combined forces will determine affinity.
60% of drugs bind to receptors.

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6
Q

What are the 4 major types of receptor superfamilies (based on how they transduce the signal)?

A
  1. Ion channel
  2. G-protein couples
  3. Enzyme-linked
  4. DNA linked

Tend to have similar general structures.

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7
Q

What is the target of metoprolol?

A

B1-adrenoceptor antagonist (G-protein coupled receptor = GPCR). Usually activated by adrenalin/noradrenaline and highly expressed in cardiac cells. By blocking actions of adrenaline, it decreases the chances of oxygen debt and therefore angina. It’s a beta-blocker.

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8
Q

What are some examples of agonists?

A
  • Phenylephrine (nasal decongestant)
  • salbutamol (asthma)
  • Adrenaline (epipen)
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9
Q

What is efficacy?

A

Measure of an agonists ability to activate receptor:

  • Full agonist – high efficacy, high level of receptor activation and large effect.
  • Partial – smaller effect.
  • Antagonists have NO EFFICACY.

On an effect/dose curve:
- antagonists are a flat line
- full agonists have high effect and steep curve
NOTE: ‘effect’ here = activation of receptor

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10
Q

Discuss competitive receptor antagonism

A

Drug binding is typically reversible. Also, B-clockers must compete for receptors. I.e. metoprolol competes with adrenaline. The winner will be determined by their relative affinities and doses.

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11
Q

How do drugs that have enzymes as their target work?

A
  • some inhibit enzymes (i.e. paracetamol)

- some bind and act as a false substrate so that an abnormal metabolite is produced and isn’t necessarily useful.

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12
Q

How do drugs that have ion channels as their target work?

A
  • Some block channels, i.e. anaesthetics
  • Some bind to accessory sites and modulate channel activity – they can increase or decrease opening probability. I.e. benzodiazepines
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13
Q

How do drugs that have transporters as their target work?

A
  • bind and block function, i.e. some anti-depressants (Prozac)
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14
Q

What is the dose response relationship?

A

can be used to describe the relative therapeutic potencies and effectiveness of drugs.

Potency: curves move right if less potent

Efficacy:
Top of curve moves higher if more efficacy

Effect (y) = % max, response

Drug (x) = log[drug]

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15
Q

What are the 4 main areas of pharmicokinetics?

A
  • absorption
  • distribution
  • metabolism
  • excretion
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16
Q

How does absorption occur?

A
  • filtration through pores
  • passive diffusion through membrane
  • active transport
  • phagocytosis/pinocytosis
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17
Q

How can efficiency of absorption be measures?

A

Efficiency of absorption can be followed by collecting biofluid samples at defined times after drug dosing.

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18
Q

What factors influence absorption?

A
  1. size (MW) -aim for
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19
Q

How is solubility measured?

A

Most drugs lie between hydrophilic and lipophilic.

Estimating lipid solubility:

a) LogP. Have two layers relating to water and fats, and measure ratio of drug concentrations in both phases (partition coefficient – P). LogP predicts ability of drugs to cross membranes.
b) Polar Surface Area

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20
Q

How does polarity/charge affect absorption?

A

Drugs only diffuse across lipid membranes if they are in a neautral state. Therefore acids need to be in acidic environments (gastric juices for example) and bases in more neutral pHs (i.e duodenum or urine- but they are still acid, just not as acidic).

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21
Q

How do transporters affect absorption?

A

Upper GIT is most important for drug absorption, but they sometimes get transported out. I.e. P-gp counteracts absorption of lipophilic drugs.

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22
Q

What is bioavailability?

A

A simple way of describing how well a drug is absorbed from the site of admin (usually GI tract). Reported as F (fraction) and assesses extent of drug absorption – NOT RATE.

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23
Q

What are prodrugs?

A

Hydrophilic groups can be masked by adding metabolism-sensitive, lipophilic substituents. After entering cell, the group is cleaved, releasing the drug.

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24
Q

How do membrane transporters affect distribution?

A

Regulates tissue accumulation. Can get influx or efflux into epithelial cells (i.e. GI tract). Can be good or bad.

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25
Q

Discuss volume distribution

A

Plasma levels reflect drug distribution in body. Lipid soluble drugs distribute into fat and can achieve low plasma concentrations.

Highly protein bound drugs distribute poorly into tissue and yield high plasma concentrations.

Water soluble, nonbound drugs stay mainly in ECF.

V(dist) = Doge(mg)/[plasma]

Usually, drug elimination obeys first order kinetics (proportional to time).
Drugs distributing mainly into fat therefore yield high Vdist, vs drugs that stay in plasma.

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26
Q

Why would you want a drug to have low Vdist?

A

Sometimes you want them to have a low Vdist, i.e. warfarin which you want to stay in the blood because that’s where it acts.

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27
Q

Where are drugs distributed to?

A

a) plasma proteins – highly bound drugs are confined to plasma and have low Vdist
b) Tissue proteins
c) Fat (high for very lipophilic drugs)

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28
Q

What is drug metabolism?

A

The chemical alteration of drugs and foreign chemicals by enzymes in the body.
It offsets the tendency for lipid-soluble chemicals to accumulate in the body.
Mainly occurs in smooth ER of liver cells but also kidneys.
It generally diminishes the likelihood of toxicity but also decreases biological activity of drugs.

29
Q

What are the Major drug biotransformation reactions?

A

a) oxidation
b) sulfation (conjugative reaction)
c) glucuronidation (conjugative reaction)

30
Q

What is an oxidative reaction and give an example.

A

Typically involve adding oxygen (i.e. –OH) or removing H.

CYP450. Most important isoform is CYP3A4. A lot of drug related harm occurs from multiple drugs where one acts as an inhibitor for a CYP450
that oxidises another drug so it can’t get metabolised properly.
CYP3A4 and the P-glycoprotein (P-gp) cooperatively control ‘first pass clearance’ in the GI tract and liver.

31
Q

How does your body become resistance to drugs in reference to CYP450?

A

CYP450 activity or expression can be induced by drugs or other chemicals (i.e. alcohol, smoking). Some drugs induce their own metabolism so your body becomes resistant to them very quickly. The result of CYP450 activity induction is that drugs have poor effect due to accelerated hepatic clearance

32
Q

What happens if CYP450 is inhibited?

A

CYP450 can also be inhibited, for example if 2 drugs compete for the same CYP isoform, one is effectively inhibiting the metabolism of the other. Consequences – toxicity

Example – grapefruit is an inhibitor.
Inhibitors diminish drug effect of PRODRUG as there is diminished metabolic activation.

33
Q

Discuss genetic polymorphism and CYP.

A 
Caused by gene duplication/repeats relating to CYP2D6 gene. 
Populations contain:
-	normal metabolizers
-	ultra
-	intermediate
-	poor
34
Q

What is the difference between excretion and elimination?

A

Excretion – removal of unchanged parent drug

Elimination – removal of parent drug + metabolites

35
Q

What are the routes of elimination?

A
  • urine
  • faeces
  • expired air
  • breast milke
  • hair
  • skin/sweat
36
Q

How do kidneys eliminate drugs?

A
  • Excretes relatively small, water soluble drugs and their metabolites into urine
  • Basic unit is nephron

Three processes influence levels of drugs and their metabolites in urine:

  • filtration – free (unbound) drugs filtered through pores in glomerulus.
  • Active transport – energy dependent transporters extract it from blood
  • Diffusion (back into blood) (reabsorption)
37
Q

How does the GI tracts and liver eliminate drugs?

A
  • Looks after larger drugs than kidneys
  • Converts drug into drug metabolites which are then excreted through kidneys.
  • Hepatocytes express transporter systems and bile forms in them and is then secreted to canaliculi. Drains into bile duct then into duodenum.
  • Transporters eliminate large, polar molecules into faeces.
38
Q

How do PNS nerves work?

A
  • cholinergic nerves, both pre and post ganglionic. At ganglion Ach acts on nicotinic cholinoceptor (N), and at final target it acts on muscarinic cholinoceptor (M).
  • Cranial or sacral nerves
39
Q

How do SNS nerves work?

A
  • Cholinergic nerves pre ganglionic, and then adrenergic nerves postganglionic.
  • Also has nerves that bypass ganglion and are cholinergic, acting on N cholinoceptors (NOT M).
  • Adrenergic nerves work on alpha and beta receptors, with specific ones depending on whether neurotransmitter is adrenaline or noradrenaline.
  • NOTE SWEAT EXCEPTION: adrenal medulla releases NA and A which affects the adrenoreceptor. Endocrine system.
40
Q

Why are drugs not usually made to target nicotinic receptors?

A

that would effect both PNS and SNS.

41
Q

How do post ganglionic nerves have an effect on their effector organ?

A

Post ganglionic nerves enter the effector organ, branch, and at intervals form varicosities (swellings). Varicosities contain vesicles of neurotransmitter, which are released by nerve action potential. The releases neurotransmitter activates receptors on the effector cells and induces a response.

42
Q

What are cholinergic nerves?

A
  • Synthesize, store and release Ach
  • ALL PNS post-G nerves
  • SOME SNS post-G nerves (i.e. sweat)
43
Q

What are adrenergic nerves?

A
  • Synthesize, store and release NA

- Most sympathetic post-G nerves

44
Q

what are adrenoagonists?

A

Bind to and activate adrenoceptors. Adrenaline, phenylephrine, salbutamol etc.

The direct effects of Adrenoagonists depend on:

  • receptor selectivity of the dry (adrenaline is all of them whereas phenylephrine is a1)
  • Adrenoceptor profile of the cell
  • Cellular response to receptor activation
45
Q

How does adrenaline work?

A
  • Stimulates a1, a2, b1, b2 and b3.
  • BUT inactive orally because of extensive metabolism in GIT and liver.
  • Local injection causes vasoconstriction (activation of a1 on blood vessels)
  • I.V. injection increases mean arterial blood pressure (a1 and B1)

Uses:

  • prolongs action and delays the systemic absorption of local anaesthetic because it constricts blood vessels (a1)
  • Cardiac arrest – helps restore cardiac rhythm (B1), and temperature, pulse and respiration during resuscitation (a1).
  • Acute anaphylactic reactions – dilates airways and inhibits mast cells (b2)
46
Q

what are Selective Adrenoceptor Agonists?

A
  • Selectively activate receptor subtypes to reduce side-effects
  • are not extensively metabolized in the GIT and liver – active orally
  • i.e. phenylephrine (a1) and salbutamol (B2)
47
Q

How does phenylephrine work?

A
  • Stimulates a1.
  • primary effects – vasoconstriction
  • decongests nasal passages
  • given orally or topically
48
Q

How does salbutamol work?

A
  • stimulates b2
  • primary effect – causes relaxation of smooth muscle
  • asthma – Ventolin
  • aerosol – more rabid bronchodilator response. Lower overall dose can be given so less side-effects.
49
Q

What are adrenoantagonists?

A

Only a1 and b1 antagonists are clinically useful.

  • a1 = for hypertension
  • b1 = many CV diseases

a) Prazosin – a1
b) Propranolol – b1 and b2
c) Metoprolol – b1 and b2

50
Q

How does Prazosin work?

A
  • selectively binds to a1
  • reverses a1 mediated contraction of vascular smooth muscle
  • causes vasodilation and lowers blood pressure
  • But may cause dizziness on standing – not first line response
51
Q

How does Propranolol work?

A
  • B1 inhibition causes a decrease in heart rate and contractility, so reduces cardiac output and blood pressure. (angina, hypertension, arrhythmias etc)
  • B2 inhibition may exacerbate bronchoconstriction in asthma, may impair circulation and may worsen glycaemic control in diabetic patients.
52
Q

How does Metoprolol work?

A
  • same as propranolol, BUT doesn’t block b2 at usual doses – only high doses.
53
Q

What other desirable actions can many B-blockers do?

A
  • antioxidant
  • K+ channel blockage
  • Vasodialiation
  • Partial agonist activity
  • Membrane stabilizing activity
  • MAIN – decrease heart rate and contractility, decrease cardiac output.
54
Q

Why are few cholinoreceptor agonists used clinically?

A

They show little cholinoreceptor subtype selectivity.

  • activate multiple subtypes of nicotinic and muscarinic receptors
  • produce widespread actions and side effects
55
Q

What is an agonist that activates muscarinic cholinoceptors and how does it work?

A

Pilocarpine.

  • activates M3 (constrictor of pupillage muscle, and promotor of drainage of aqueous humour and reduces intraocular pressure)
  • can be delivered topically to eye, which reduces systemic side effects
  • occasionally used to treat glaucoma (not first line)
56
Q

List 3 muscarinic cholinoceptor antagonists

A
  • atropine
  • tiotropium (local)
  • tropicamide - eye drops for retinal exam (local)
  • solifenacin - urinary incontenance - seems to have some selectivity for M3
57
Q

How does atropine work?

A

Blocks all M subtypes so:

  • dries up secretions (saliva, sweat, tears, gut and lung)
  • inhibits smooth muscle contraction (gut, lungs, eye)
  • increases heart rate (M2)

It also crosses into CNS to block M receptors = excitatory effects

Frontline therapy for poisoning with anti cholinesterase agents. Blocks the M mediated side effects.

58
Q

How does tiotropium work?

A

Aerosol for patients with COPD

  • dilated airways and reduces mucus secretion
  • is long acting (daily dosing)
  • used for maintenance therapy, rather than immediate relief of symptoms
59
Q

How do drugs that lateen neurotransmitter levels int he ANS work?

A

Some drugs can inhibit the metabolism/removal of NTs from the synaptic region.

I.e. amphetamine - blocks NA removal
Neostigmine - blocks Ach metabolism

Results in:

  • increased synaptic levels of NT
  • increased activation of NT receptors
  • increased responses in receptor cells
60
Q

How do adrenergic nerves work?

A
  1. ANs synthesise and store NA
  2. stimulated nerves release NA, which activates adrenoceptors on postsynaptic cells
  3. most release NA undergoes neuronal reuptake (by NA transporter - NAT), which halts signalling by reducing [NA] in vicinity of adrenoceptor.
  4. after re-uptake, NA is transported into vesicles by VMAT or inactivated by MAO.
  • the rapid reuptake of NA is an important regulatory process through which the CNS controls the activity of postsynaptic cells
61
Q

What are two inhibitors of NA uptake/metabolism?

A

Amphetamine

Pseudoephedrine

62
Q

How does Amphetamine work?

A
  • uses NAT to enter adrenergic nerve varicosity (terminal)
  • inhibits VMAT and MAO, therefore increased systolic [NA]
  • also induces reverse operation of NAT, so increased release of [NA]
  • increased [NA] in junction, which stimulated adrenoceptors on effector cell
  • may cause vasoconstriction and increased heart rate and contraction, but not clinically useful for these effects. Actually used for ADHD.
63
Q

How does Pseudoephedrine work?

A
  • also increases NA release from adrenergic nerves

- use as a nasal decongestant now restricted as it can be converted to meth.

64
Q

How do cholinergic nerves work?

A
  1. CNs synthesise and store Ach
  2. upon stimulation, nerves release Ach which activates cholinoceptors on postsynaptic cells
  3. released Ach is metabolised by enzyme AchE, which terminated signalling by reducing [Ach] in region of cholinoceptor
65
Q

How do inhibitors of AChE work?

A

Termed ‘anticholinesterases’

Usually, AchE catalyses degradation of Ach to choline + acetate (inactive).

Now, Ach is released from cholinergic nerves and:

  1. is not metabolised by AchE
  2. accumulated to elevated levels
  3. causes increased activation of receptors
  4. induces larger responses
66
Q

What are the consequences of anticholinesterases?

A

The effects of anticholinesterases on ANS tends to mimic stimulation of PNS - glandular secretions, smooth muscle contraction, slowing of HR.

However, AchE also inactivated Ach in the somatic and CNS, so the effects can be widespread and complex.

67
Q

What are the major groups of anticholinesterases?

A
  1. Long acting (days)
    i. e. organophosphate pesticides, i.e. dimethoate
    - organophosphate war gases, i.e. sarin

Atropine is frontline therapy for cholinergic overdose induced by exposure to anticholinesterases.

  1. Medium acting (hours)
    - neostigmine
  2. Short acting (minutes)
    - i.e. edrophonium
68
Q

How are anticholinesterases clinically useful?

A

Myasthenia gravis

- due to loss of sensitivity to Ach, therefore inhibit AchE.

General Med 1 (24 decks)

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