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Year 3 Sem 1 COPY COPY > PA30324 2. Pharmaceutics > Flashcards

PA30324 2. Pharmaceutics Flashcards

1
Q

Describe basic mechanisms for crossing the blood-brain barrier

A

A) Passive, transcellular diffusion
- more lipophilic molecules can move through the cell membrane (Most CNS active drugs use this process)

B) Active transport (facilitated diffusion)
- substances that the brain needs such as glucose and amino acids are carried across by transport proteins

C) Receptor-mediated transport (receptor meditaed endocytosis)
- insulin

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2
Q

Describe Lipinski’s Rule of 5 and best chance of good BBB penetration

A
  • <5 hydrogen bond donors
  • <10 hydrogen bond acceptors
  • molecular weight <500
  • LogP <5

Best chance of good BBB penetration

  • Molecular weight is reduced
  • Lipophilicity is ‘high’
  • Low number of polar atoms (N and O)
  • No carboxylic acids
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3
Q

What is the proportions of basic, neutral and acidic CNS drugs?

A

~75% basic

~19% neutral

~6% acids

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4
Q

What is the general design principles for improving CNS exposure?

A

Low molecular weight
- <400 Daltons

Low polar surface area
- <90

Moderate lipophilicity
- logD between 1 and 3

Maximum of one H-bond donor

No acids

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5
Q

Define the following terms

  • Pharmacokinetics

- Pharmacodynamics

A

Pharmacokinetics
- study of bodily absorption, distribution, metabolism and excretion of drugs

Pharmacodynamics
- study of biochemical and physiological effects of drugs and the mechanisms of drug action

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6
Q

Describe codeine.

A
  • analgesic, with around one tenth the potency of morphine
  • retains most of its activity after oral administration therefore can be used in tablet form whereas morphine suffers from considerable first pass metabolism, making codeine ideal for mild/modrate pain relief and as antitusive agent
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7
Q

Describe metabolism of morphine

A

1) Morphine

2) Morphine-3-glucuronide
- major metabolite
- inactive and rapidly excreted

3) Morphine-6-glucuronide (M6G)
- lesser metabolite but more potent than morphine

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8
Q

What does replacement of the nitrogen methyl group result in analgesics?

A

In general
- analgesic activity initially decreases as the size of the N-substituent increases but then rises again, reaching a peak at C6

  • The most active compound in this series
    : N-beta-phenethylnormohpine
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9
Q

Administration of Nalorphine was shown to reverse the effects of morphine and pre-treatment with nalorphine blocks the effects of subsequently administered morphine e.g it acts as an antagonist

…but in 1950’s, it was discovered to relieve postoperative pain in humans e.g it acts as an agonist

Why is this happening?

A
  • N-allylnormorphine

Dual action is a result of action at two opioid receptors

a) antagonism at the mu opioid receptor
b) agonism at the kappa opioid receptor

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10
Q

What is Controlled Drug Delivery Systems (CDDS)?

A
  • Preparations designed in such way that the rate or location of API release is controlled
  • Often referred to as modified relesae or extended release preparations
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11
Q

Why do we use Controlled Drug Delivery Systems?

A
  1. Reduce fluctuations in drug plasma concentration
    - reduce concentration-related side effects (rapidly absorbed drugs)
    - often used for drug with a narrow therapeutic index
  2. Reduce dosing frequency
    - improve patient compliance
    - especially useful for drugs with short half-lives
  3. Control delivery site
    - releases drug at site of optimum absorption or site of action
  4. Timed release
    - Drug releases is delayed or pulsed so it occurs when there is a clinical need
    - e.g angina, asthma, etc hormones vaccines
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12
Q

Describe mechanisms for controlling drug releases for the following methods

  • Water Penetration-controlled DDS
  • Diffusion-controlled DDS
  • Chemically-controlled DDS
  • Responsive DDS
A

Water Penetration-controlled DDS

  • Swelling
  • Osmosis

Diffusion-controlled DDS

  • Reservoir device
  • Monolithic device

Chemically-controlled DDS

  • Monolithic device: surface or bulk erosion
  • Pendant systems

Responsive DDS

  • Physical
  • Chemical
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13
Q

Describe 3 phases in Water Penetration-controlled DDS

A

Phase 1
- swelling

Phase 2
- Swelling/erosion

Phase 3
- Disentanglement/dissolution

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14
Q

Regarding Water Penetration-controlled DDS, what affects the release rate?

A
  • polymer MW, concentration and chemical structure
  • Drug concentration, solubility and location
  • Geometry of tablet and modifications
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15
Q

Describe how Osmotically-controlled devices work

A
  • Drug is mixed with water-soluble ore material
  • Core surrounded by water-insoluble semi-permeable polymer membrane, in which is laser-rilled a small orifice
  • Water diffuses into core through outer membrane to form concentrated solution inside
  • Osmotic gradient established across semi-permeable membrane and drug is pushed out of hole
  • Release rate tailored by modifying excipients
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16
Q

Advantages of Osmotically driven systems?

A
  • Provide precise, controlled drug delivery for upto 24 hrs
  • Can be used with a range of compounds, including poorly soluble or highly soluble drugs
  • Can target specific areas of GI tract to improve bioavailability
  • Can be tailored for patterned delivery profiles
  • Protects the drug until release
  • Can be used to deliver high drug doses
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17
Q

What is the difference between Reservoir Diffusion-controlled DDS and Monolithic (matrix) Diffusion-controlled DDS?

A

Reservoir DDS

  • Water-insoluble polymer
  • Solid drug or concentrated soluiton
  • Membrane either non-porous or micro-porous

Monolithic (Matrix) DDS

  • Water-insoluble polymer
  • Drug dissolved in polymer solution prior to device formation

Tend to be restricted to implantable devices

Type used depends on the physicochemical properties of the drug, release rate and duration, manufacturing facilities

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18
Q

Describe Chemically-controlled DDS

A
  • Similar to a diffusion-controlled matrix device
  • Drug dissolved in polymer solution prior to device formation
  • Drug is released as the polymer matrix dissolves or degrades
  • Predominantly for long-term implantation
  • Natural or synthetic polymers

Production methods include

  • compression and melt moulding
  • solvent casting
  • extrusion
  • emulsions e.g micro&nanoparticles
  • electrospinning
  • 3D printing
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19
Q

How does polymeric devices degrade by in Chemically-controlled DDS? (2 methods)

A

1) Gradual disolution of the polymer matrix
- enteric coatings

2) Degradation of the polymer matrix via chemical or biological processes

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20
Q

Describe enteric coatings (delayed release)

A

Traditional enteric coating
- tablets coated wit ha polymer that is insoluble in the highly acidic environment of the stomach, but dissolves in the small intestine (>pH5.5)

  • can protect the drug from the stomach or the stomach from the drug
  • numerous polymers available, including cellulose derivatives and methacrylic acid co-polymers
  • release area can be tailored depending on pH/solubility profile
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21
Q

Give examples of natural polymers and synthetic polymers in Chemically-controlled DDS

A

Natural polymers

  • Collagen
  • Fibrin
  • Gelatin
  • Hyaluronan
  • Chitin/chitosan
  • Silk

Synthetic polymers

  • Poly(esters)
  • Poly(anhydrides)
  • Poly(ortho esters)
  • Poly(phosphoesters)
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22
Q

What are the factors that affect the polymer degradation rate (hence drug release rate) in chemically-controlled DDS?

A
  • chemical structure of polymer
  • polymer molecular weight
  • presence of low MW compounds e.g drug and excipients, residual solvent
  • cyrstalline vs amorphous polymers
  • size and shape
  • processing method
  • porosity
  • site of implantation
  • degradation mechanism: enzyme vs water
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23
Q

Describe Swelling-Controlled Drug delivery systems

A
  • Devices swell by absorbing water, drug diffuses through gel matrix
  • Hypromellose (HMPC) is the most common matrix polymer
  • Rate of swelling affects drug release rate
  • Polymer, drug and excipient properties affect swelling rate
  • Diffusion of drug and erosion of matrix both occur
24
Q

Describe Swelling/Burst-Controlled Drug delivery systems

A
  • Matrix swells, but is contained by a membrane which bursts when set pressure is reached within device
  • Hybrid release profiles can be achieved
25
Q

Describe Osmotically-Controlled DDS

A
  • Water ingress into the device produces an osmotic gradient, causing drug to be forced out
  • Solid or liquid drugs depending on system used
  • Can be tailored for various release profiles
26
Q

Describe Diffusion-controlled DDS

A

1) Reservoir systems
- membrane-controlled diffusion

2) Matrix systems
- drug diffuses through whole matrix

Factors affecting drug release rate
Reservoir DDS
- membrane thickness

27
Q

Describe Diffusion-controlled DDS

A

1) Reservoir systems
- membrane-controlled diffusion

2) Matrix systems
- drug diffuses through whole matrix

Factors affecting drug release rate
Reservoir DDS
- membrane thickness
- membrane porosity
- chemical nature of membrane material
- nature of drug and excipients

Matrix DDS

  • polymer properties
  • diffusivity of drug in matrix
  • nature of drug and excipients
  • geometry
28
Q

Describe Chemically-controlled DDS

A
  • Drug released by dissolution or degradation of polymer matrix
  • Predominantly for long-term release

Release rate influenced by

  1. Matrix polymer
    - Hydrophobicity
    - Molecular weight
    - Chemistry
    - Degradation mechanism & products
  2. Drug and excipients
    - Hydrophobicity
    - pH
  3. Geometry of device
29
Q

What is Responsive Drug Delivery Systems?

A
  • Devices release drug by responding to pH, enzymes etc
  • Largely for implantable or parenterally delivered dosage forms
  • Actual release mechanisms vary e.g diffusion, osmosis etc
30
Q

What are ‘implantable devices’?

A
  • Enable long-term and/or localised controlled delivery of drugs
  • Improve compliance and minimise side-effects, but require surgery and aren’t easily removed
  • Numerous mechanisms of drug release, but future directions promise the novel use of technologies for long-term release or precise release of multiple drugs from one device
31
Q

Name 6 control factors in Responsive DDS

A
  • pH
  • Chemicals (metabolites)
  • Enzymes
  • Ultrasound
  • Magnetism
  • Light

Predominantly used in implantable devices or parenterally delivered DDS

32
Q

Responsive DDS: characteristics of Mesoporous silica nanoparticles?

A
  • Inert
  • Thermally stable
  • Easy to functionalise
  • controlled particle size
  • homogeneous, tunable porosity
  • great potential for controlled delivery of traditional drugs, proteins and necleic acids
33
Q

Define ‘implantable devicies’ and its pros and cons

A

Drug delivery system designed to deliver a controlled level of drug over an extended time period

Pros

  • Convenience
  • Compliance
  • Control
  • Commercial

Cons

  • Surgery
  • Failure
  • Potency
  • Reactions/compatibility
  • Commercial
34
Q

Give examples of Localised and Long-term use of Implantable devices

A

Locailised

  • Ocular
  • Dental
  • Contraception
  • Pain
  • Vasculature

Long-term

  • Contraception
  • Pain management
  • Diabetes
  • Incontinence
  • System infection
35
Q

What are Vaginal rings?

A
  • Diffusion-controlled DDS
  • Contraception
  • Flexible, drug-containing polymer rings which are seated around the cervix
- Numerous products on the market, in trials or development for the delivery of
\: contraceptive therapy
\: HRT
- IVF Therapy
- Microbicides
36
Q

Give examples of some implantable devices for intraocular delivery

A

Medidur (pSivida)

  • injectible, erodible, or non-erodible intravitreal device for the treatment of Diabetic Macular Edema
  • Release a constant amount of drug to the back of the eye upto 36 months

Vitrasert (Bausch & Lomb)

  • Intraocular ganciclovir for AIDS-related cytomegalovirus retinitis
  • implanted in the posterior of the eye
  • lasts 5 to 8 months

Ocusert (ALZA)
- Pilocarpine-loaded device for contro lof elevated intraocular pressure in polocarpine-responsive glaucoma patients

37
Q

Describe comparison between oral delivery and topical delivery of drugs

A

Oral delivery
- absorption is rapid
: kinetics of absorption are faster than kinetics of elimination
- Cp increases quickly to a maximum then decays with a half-life corresponding to kinetics of elimination
- High Cp is achieved, but level cannot be maintained without re-dosing

Topical delivery
- absorption is slow
: kinetics of absorption are usually slower than kinetics of felimination
- Cp increases slowly to max, then decays with t1/2 longer than that seen after oral dosing
- high Cp not achieved, but sustained levels are possible, increase ‘control’ and decrease dosing frequency

38
Q

Pros of topical drug delivery of potent drugs systemic effect?

A
  • sustained concentration
  • control of delivery
  • reduced dosing frequency
  • fewer side effects are possible
39
Q

What is Nitroglycerin (GTN)?

A

Typically, sublingual tablet for treatment of angina

  • fast onset, partial avoidance of 1st pass effect
  • GTN t1/2 = 2-3 minutes, effect of 0.4mg tablet is short-lived
GTN ointment (2% w/w)
- 1-5cm to chest and occlude

Advantages

  • skin ‘control’
  • sustained effect

Disadvantages

  • larger dose
  • slower onset of action
  • potential risk of losing dose
40
Q

Why do we use transdermal drug delivery?

A
  • Avoid pre-systemic metabolism
    : lower daily dose
  • Maintain drug level within the therapeutic window for prolonged period
    : extend duration of drug action
    : reduce frequency of dosing
    : avoid toxicity
  • Reduce inter- and intra-patient variability
  • Improved patient compliance and acceptability of drug therapy
  • Drug input terminated simply by patch removal
41
Q

What are the limitations of Transdermial drug delivery?

A

Limited to potent drug molecules
- daily dose <50mg, typically much less

Physical chemistry

  • size, generally small molecules
  • lipophilic good, but solubility in oil and water required

Pharmacokinetics/pharamacodynamics
- t1/2 metabolism, dosing regimen, tolerance problems

Area of patch (<100cm2)

Drug must not be locally irriating or sensitizing

Efficiency of drug use, expense

42
Q

What are the materials used in tersdermal delivery systems?

A
  • Drugs
  • Polymers
    : pressure sensitive adhesives
    : release liners
    : backings and laminates
  • Vehicles
  • Other excipients
43
Q

Describe the characteristics of transdermal delivery

A
  • TDD depends on area of contact between patch and skin
  • TDD is less sensitive to drug loading especially when skin controls input
  • Patch design does not predetermine degree of rate control
  • Drug loading in patch anad release mechanisms are inappropriate measures for bioequivalence
  • Ideally drug loading is close to amount to be delivered
44
Q

What is Scopolamine used for?

A
  • Transdermal drug delivery system

- motion sickness

45
Q

what is Clonidine used for?

A
  • Transdermal drug delivery system
  • Potent anti-hypertensive drug
  • decrease side effects and increase patient compliance
  • problem: allergic sensitisation
46
Q

What is Estradiol used for?

A
  • Transdermal drug delivery system
  • Post-menopause hormone replacement therapy
  • Oral = very high hepatic 1st pass effect, elevated estrone/estradiol ratio
  • Transdermal = sustained plasma levels , normalised estrone/estradiol ratio
47
Q

What is oxybutynin used for?

A
  • Transdermal drug delivery system
  • treats overactive bladder
  • relaxes bladder muscle to prevent urgent, frequent, or uncontrolled urination
48
Q

Rate in = Rate out equation

A

Area (cm2) x J (microgram.cm-2.hr-1)
= Cl (cm3.hr-1) x Css(microgram.cm-3)

  • calculation of transdermal feasibility for a drug requiring a daily dose of D mg, the average, required rate in = D/24 mg.hr-1
49
Q

Defin rate-limiting step

A
  • The slowest step in a series of kinetic processes is the rate-limiting step
  • The rate-limiting step imposes the upper limit on the rate of all subsequent steps
50
Q

What is Disposition?

A

= Distribution + Elimination

Elimination = Excretion + metabolism:k
=K.exc + Kf

51
Q

Describe Drug input into the body regarding rate-limiting step

A

Drug input into the body can be

  • Dissolution (or release) rate-limited
  • Permeability rate-limited
  1. Drug with poor solubility
    - The constant rate of dissolution is less than the constant rate of absorption
    - A very slow dissolution limits in the rate of the following steps
    - When this occurs dissolution becomes the ‘rate-limiting step’
  2. Modified-release formulations
    - Sustained and extended forms which release the drug slowly over an extended period of time
    - The constant rate of release is less than the constant rate of absorption
    - The slow release process limits the rate of the following steps and becomes the ‘rate-limiting step’

How can we tell?

  • When an increase/decresae in dissoolution rate = faster/slower absorption
  • When an increase/decrease in release rate = faster/slower absorption
52
Q

What are the objectives in finding rate-limiting steps

A
  1. Recognise whether drug input (absorption) into the body is either
    a. dissolution (or release) rate-limited
    b. permeability rate-limited or
  2. Recognise whether drug elimination is either
    a. disposition (elimination) rate-limited
    b. absorption rate-limited or
  3. Describe the ‘flip-flop’ kinetics observed following administration of some disage forms
  4. Recognise whether metabolite elimination is either
    a. rate-limited by its formation
    b. rate-limited by its elimination
  5. Describe the metabolite plasma profiles expected after an IV Bolus and IV infusion of a parent drug
53
Q

Describe a case where Disposition (elimination) is the rate-limiting process

A
  1. The most frequent case
  2. When the absorption rate constant is greater than the elimination rate constant. Or in other words: the absorption half-life is shorter than the elimination half-life
  3. The absorption will proceed faster than elimination
  4. The elimination step (elimonation rate constant, k) controls the decline of the drug concentration during terminal phase
  5. Most of the drug has been absorbed and little has been eliminated when the peak is reached
54
Q

Describe a case where Absorption is the rate-limiting process (flip-flop kinetics)

A
  1. Less freuqently, the absorption process is slower than the elimination
  2. The absorption rate cosntant is smaller than the elimination rate constant. Or in other words: the absorption half-life is longer than the elimination half-life
  3. A very slow absorption will rate-limit all subsequent processes including elimination and the terminal phase of PK profile
  4. At any time, most of the drug is
    - either at the absorption site
    - has been eliminated
  5. Considerable amount of drug has not yet been absorbed when the peak is reached
55
Q

Why are we interested in Metabolite kinetics?

A

Metabolites can be

  1. Inactive waste products
    - used to measure BA of the parent compound
    - use to detect exposure to illicit drugs
  2. The active compound
    - a pro-drug is administered that depends on metabolism to be activated
  3. Pharmacologically active
    - sum to the effect of parent drug
    - have a different effect than the parent compound
    - cause toxic effects
  4. Modify the response to the parent compound
  5. Modify the disposition of the parent compound
56
Q

What do we need to know about metabolites?

A

Potential properties of the metabolite

  • Activity
  • Toxicity
  • Alter binding of the parent compound or other drugs
  • Alter response to parent drug

AND

Concentration and PK profile of the metabolite

  • Will the metabolite concentration be high enough that there is a therapeutic concern?
  • Can we use PK parameters of the metabolite to estimate exposure to parent compound?

Year 3 Sem 1 COPY COPY (7 decks)

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