Introduction to Pharmacology

Question 1

What is pharmacodynamics?

Answer 1

• How a drug works – mechanism drug exploits to achieve its intended therapeutic effects
• Fundamental mechanisms of drug action:
  o Autonomic nervous system – controls breathing & digestion
  o Antibacterial activity
  o Antiviral activity
  o Anti-inflammatory drugs

Question 2

Describe the autonomic nervous system and drugs?

Answer 2

• Controls basic yet essential functions e.g. heart rate, breathing, digestion
• Overall activity of this system controlled by balance of sympathetic & parasympathetic branch
• Sympathetic:
  o Fight & flight response - increases heart rate and dilates airways to make breathing easier
• Parasympathetic:
  o Chill & relax – reduces BP & kicks in digestion
• Both theses systems work similarly – controlled by group of chemicals (neurotransmitter – chemical messenger that sends signals within body)
  o Key difference between the 2 systems is the type of neurotransmitter involved
   Sympathetic – noradrenaline is neurotransmitter (then bio-transformed into adrenaline)
• Adrenergic drug works on sympathetic branch
   Parasympathetic – acetylcholine is neurotransmitter
• Cholinergic drug works on parasympathetic branch

Question 3

Describe neurotransmitter, their location and what happens when neurotransmitter acts on receptor?

Answer 3

Neurotransmitter housed in pre-synaptic membrane (junction/terminal through which neurotransmitter can leave)
Gap called synapse
Then post-synaptic membrane where receptors are embedded
It is the action of the neurotransmitter on these receptors that gives rise to physiological changes like increase in heart rate or dilation of pupils seen as a result of autonomic nervous system function
Once neurotransmitter has crossed synapse, reached receptor & activated it – we see expected response

Question 4

What aer receptors in sympathetic system called? What are receptors in parasympathetic system called?

Answer 4

Receptors associated with sympathetic system are referred to as alpha & beta receptors and receptors associated with parasympathetic are referred to as muscarinic receptors

Question 5

Describe aqueous humour production?

Answer 5

• Controlled by sympathetic branch of autonomic nervous system
• Controlled by activation of alpha and beta receptors by noradrenaline
  o When alpha receptor activated – reduction/inhibition of aqueous humour production
  o When beta receptor activated – increase in production of aqueous humour production
• All glaucoma drugs have same primary course of action: reduce IOP – either by:
  o Increasing aqueous humour drainage via trab meshwork & uveal scleral outflow (‘widening plug hole’)
  o ‘Turn off tap’ – reduce rate of aqueous humour production

Question 6

Describe agonists? Adrenergic agonist? Cholinergic agonist?

Answer 6

• Activate post-synaptic membrane receptors
• Mimic action of body’s own (endogenous) neurotransmitters (Mimetics is another name for agonists)
• Stimulate post-synaptic receptors (Stimulants is another name for agonists)
• Agonists can be full agonist or partial agonist
  o Full agonist:
   Produces maximal activation
   Fits in to receptor
  o Partial agonist:
   Most of drugs in optometry/ophthalmology
   Fits in to receptor but does not produce maximal activation
• Adrenergic agonist:
  o AKA Sympathomimetic – mimetic (agonist), sympatho (works on sympathetic branch of ANS)
  o Agonist – drug copies activity of body’s neurotransmitter at the receptors
  o Adrenergic – working on sympathetic branch of ANS
  o Examples:
   Brimonidine (alphagan)
   Apraclonidine (Iopidine)
• Alpha-2-agonists – both Glaucoma medications
• Cholinergic agonist:
  o AKA Parasympathomimetic – mimetic (agonist), parasympatho (parasympathetic branch of ANS)
  o Agonist – activates receptors
  o Cholinergic – works on parasympathetic branch of ANS – works on muscarinic receptors
  o Examples:
   Pilocarpine – pupillary mioses by mimicking action of acetylcholine on iris sphincter muscle

Question 7

Describe antagonists? Adrenergic agonist? Cholinergic agonist?

Answer 7

• Blocks or occupy post-synaptic membrane receptors
• Reduce activity of endogenous neurotransmitters (lytic)
• Antagonist slots into receptor but does not activate it (it blocks it) – when neurotransmitter arrives and tries to bind to receptor, it is blocked so don’t see expected physiological response
• Adrenergic antagonist:
  o AKA sympatholytic – sympatho (works on sympathetic branch), lytic (interrupting, stopping or breaking down process)
  o Example:
   Timolol – glaucoma medication – beta blocker – block beta receptors
• Cholinergic antagonist:
  o AKA parasympatholytic
  o Example:
   Tropicamide – dilates pupil – blocks activity of acetylcholine on iris sphincter muscle receptors – iris dilater muscle is relatively unopposed and so dilates pupil

Question 8

Describe receptor selectivity?

Answer 8

• Drugs which operate by interacting with receptors on post-synaptic membrane need to be selective for different types of receptors
• Example of timolol:
  o Glaucoma med
  o Beta-blocker – lowers IOP by inhibiting synthesis of aqueous humour
   By acting as antagonist at beta receptors – offsets expected increase in production of aqueous humour when that receptor would normally be activated by noradrenaline
• Drug which shows selectivity for certain receptor types is able to identify which receptor it should be interacting with
• 2 sub-types of alpha & beta receptor:
  o Alpha-2-agonist (glaucoma meds):
   Brimonidine, Apraclonidine
   These drugs show receptor selectivity for alpha-2 receptor
  o Beta blocker:
   Timolol – generic beta-blocker – will act on either beta-1 or beta-2 receptor

Question 9

Describe pharmacokinetics, the timeline and modes of administration?

Answer 9

• Time-based description of drug activity through body
• Timeline:
  o 1. Administration – e.g. tablet or eye drop
  o 2. Absorption into body
  o 3. Distribution
  o 4. Metabolism (processed)
  o 5. Excretion (get rid of drug once used)
• Modes of Administration:
  o 1. Oral – tablet/lozenge/syrup (important to optoms)
  o 2. Ocular – eyedrops (important to optoms)
  o 3. Nasal – spray
  o 4. Sublingual/Buccal – gel on inside of mouth, drug absorbed along gum line or under tongue
  o 5. Epidermal
  o 6. Rectal
  o 7. Vaginal
  o 8. Parenteral (injection directly into px, infusion, implant) (important to optoms)
   Enteral = to/through epithelium of GI tract
   Par = not so drug not being administered through GI tract
• These injection swill be given either by ophthalmologist, registered nurse practitioner or an optometrist who have undergone appropriate training
  o E.g. anti-VEGF drugs through intra-vitreal injections for wet AMD
  o All 1-7 modes rely on GI tract at some point, 8 does not

Question 10

Describe oral administration?

Answer 10

• Example: painful eye so advise paracetamol or ibuprofen or allergic conjunctivitis and advise oral anti-histamine
• Px swallows tablet, drug acted upon by acids in stomach  once tablet been broken down, drug absorbed by blood vessels of digestive tract
• Drug carried via circulation to liver (acts like giant filter)
  o Liver decides amount of drug that ends up in pxs systemic circulation (blood stream)
• Drug must pass through liver before accessing general circulation
  o Takes it to heart, lungs, eye
• First pass metabolism reduces proportion of active drug available at target site
  o Liver acts as safety device

Question 11

Describe blepharitis and tx?

Answer 11

• Eyelid telangiectasia – BVs are dilated & a little irregular - shows eyelid margin inflammation has been present for long time (Chronic)
• Non-pharmacological: lid hygiene measures, twice daily. Hot compresses
• Artificial tears for associated dry eye (evaporative DE) – use 4x a day
• Review px in 6-8 weeks
  o At this they report no improvement of sxs, next step:
   Antibacterial ointment: chloramphenicol (broad spectrum anti-bacterial) 2x daily
   Still no improvement: IP: oral tetracycline: doxycycline (100mg), once daily
• No option in UK for topical anti-biotic at moment, just oral if IP qualified

Question 12

Describe oral vs topical (ocular) administration?

Answer 12

• E.g. corneal abrasion
  o Artificial tears: Clinitas gel (carbomer (long chain polymer that increases viscosity of artificial tears)), every 3 hours – choose artificial tear that has doesn’t drain too quickly from eye
  o Lubricant: Hylo-Night (liquid paraffin (waxy, thick substance)), once at night – to prevent recurrent corneal erosion syndrome
  o Prophylactic antibacterial?  chloramphenicol (1%) ointment TDS (3x a day)
• Antimicrobial Stewardship:
  o Use ONLY when clinically indicated
  o Don’t give every px with corneal abrasion an antimicrobial – consider each px individually – is px immunocompromised? Consider depth of abrasion – deeper, more risk of infection? What caused the abrasion – risk of contaminated material coming into contact with eye (e.g. gardening injury)?
• For painful eyes:
  o Corticosteroids – powerful anti-inflammatory drugs – impair immune response (so contra-indicated in this case)  could increase risk for opportunistic bacteria to invade abrasion
  o Non-Steroidal Anti-Inflammatory Drug (NSAID):
   Oral: ibuprofen – 400mg, 3 times a day in adult (same as for headache)
   IP ONLY: Topical: diclofenac sodium (0.1%) (Voltarol Ophtha) QDS

Question 13

What are the advantages of using topical NSAID administration?

Answer 13

• Direct delivery to target site (Eye) – if used oral then px has to swallow it, be processed by stomach acid, into digestive tract, passed through liver, into systemic circulation then be past to eye
• Increase availability at target receptor sites – less distribution
• Improved therapeutic effect at lower doses
• Rapidity of therapeutic effect
• Significantly reduced risk of Adverse Drug Reactions (ADRs)
  o ADRs associated with oral NSAIDs: gastric ulceration, peptic bleeding – less risk of these with topical NSAIDs

Question 14

Describe pharmacokinetic of topical (ocular) administration?

Answer 14

• Initial rapid wash-out – how much is lost
  o Tearfilm: 7-10µl
  o Eyedrop: 30-40µl
   Not enough room for eyedrop in tearfilm so it:
• Spills over lid margin & peri-ocular skin
• Drains through punctum (like plug-hole) – drug draining down here is rapidly lost
  o Drug that remains on eye & is not lost during wash-out is absorbed across corneal epithelium & conjunctival epithelium (then available for absorption by network of conjunctival BVs)
• Once eyedrop passed through punctum:
  o Drains into canaliculi (superior puncta towards nose & inferior puncta towards nose
  o Superior & inferior canaliculi meet and become common canaliculus
  o After passing out of common canaliculus, eyedrop drains into lacrimal sac
  o Then moves down into nasolacrimal duct due to gravity
  o Eyedrop then passes through Valve of Hassner, into nasal cavity (large space at back of nose). Nasal cavity lined by nasal mucous epithelium (nasal-mucosa  contains network of small, fine BVs – drug is available to be absorbed across BV walls of that network of small fine BVs
  o Once drug been absorbed across BVs, it has entered body’s systemic circulation & then can be carried elsewhere in body

Question 15

Describe systemic absorption of topically applied drugs?

Answer 15

• Every time drug is applied to ocular surface, unintended absorption (via nasal mucosa) into systemic circulation is inevitable
• No first pass metabolism; drug passes directly into systemic circulation
• Increased risk of significant ADRs – can be carried throughout body by circulation system – no liver to filter it
• Topical Beta Blockers:
  o Sympathetic ANS: increase heart rate – if beta blocker reaches heart it will decrease heart rate & could cause Bradycardia (<60BPM)
   In some pxs who have used beta-blockers to treat glaucoma have had clinically significant reduction in heart rate
  o Sympathetic ANS: dilation of airways (Bronchial dilation) – breathe more air into lungs – if beta blocker reaches here may see constriction/ narrowing of airways  obstructive airway disease/asthma
• Effect of topical phenylephrine on systemic blood pressure:
  o Mimics action of noradrenaline (sympathetic) at iris dilator receptors stimulating muscle to contract  pupil dilation
  o Increases blood pressure
   Time-dependent response – rise in blood pressure seen in time of effect of phenylephrine
   Dose-dependent effect
• Both graphs show that administering phenylephrine as eye drop has significant effect on pxs blood pressure (increase)

Question 16

Describe seasonal allergic conjunctivitis?

Answer 16

• Type 1 hypersensitivity
• Controlled by mast cells – mast cell contains chemical messengers (histamine & prostaglandins)
• On 1st exposure to allergen (e.g. grass pollen), body makes antibodies (immunoglobulins specifically IgE) that are specific for that allergen. IgE – Y shaped molecule
• On subsequent exposures – allergen becomes attached to IgE which signals mast cells to degranulate  mast cells releases histamines & prostaglandins into blood stream
  o Px then feels itchiness, red eyes, lacrimation, mild eyelid oedema etc
• Tx:
  o Mast cell stabiliser: sodium cromoglicate or lodoxamide, QDS (7 days before effect)
   Can wait 1-2weeks until see improvement in sxs
  o Antihistamine:
   For histamine to produce its main action (itching), histamine needs to move towards receptor & activate it  if block receptor with antagonist drug (antihistamine drug) then can inhibit sxs
   Oral antihistamine: cetirizine (10mg), once daily
   IP OPTOM ONLY: topical antihistamine: olopatadine, twice daily

Question 17

Describe topical antihistamine administration?

Answer 17

• Advantage of topical drug administration still stand (see above)
• Specific to antihistamine:
  o No ‘drowsiness’ found with older, sedating antihistamines (chlorphenamine)
   Cetirizine is a good non-drowsy oral antihistamine
  o Olopatadine also shows mast cell stabilising activity (2for1 deal)
• Without IP?:
  o Topical antihistamine: antazoline (Otrivine-Antistin)
   Other active ingredient: xylometazoline (sympathomimetic) (relative of phenylephrine)
   Warnings in using these products in pxs with common systemic conditions such as cardiovascular disease, hypertension, arrhythmia
   Pupil dilation also – if optom provides px with this, check anterior chamber angle, with van herricks – don’t want angle to close
• Olopatadine (oral) does not carry same risks

Question 18

Describe pharmacodynamics?

Answer 18

• Fundamental mechanisms of drug action
• Dose response curve:
  o Threshold describes minimum level of drug required to produce a ‘just detectable’ effect
   E.g. in bacterial conjunctivitis using chloramphenicol – antibacterial drugs are used at close to their threshold (minimum conc required to inhibit bacterial growth)
  o Saturation point – once this has been reached, any further increase in conc of drug will not produce an increase in drug effect (maxed out)
   When drugs are used at safe conc, they have therapeutic benefit for px (with ADRs/side-effects)
   As increase drug conc, relative risk of ADRs/side-effects increases considerably
   At some point increasign drug’s conc, can enable drug to turn & instead of becoming therapeutic it becomes toxic to px
   Use drugs at minimum conc/dose that enables the therapeutic effect to be achieved
  o Effective Dose 50 (ED50) – describes conc of drug required to produce 50% of drugs maximal effect (mid-way point of dose response curve)
   ED50 on own for one drug doesn’t tell much
   ED50 between two drugs tells more
• Atropine: antagonist (blocker) working on parasympathetic branch
  o Blocks activity of acetylcholine on muscarinic receptors of iris sphincter muscle – prevent contraction of this so pupilarry dilation
  o Also blocks activity of acetylcholine on receptors of ciliary muscle  leads to relaxing ciliary muscle and results in px having almost no accommodation (cycloplegic)
• Cyclopentolate: dose response curve looks similar to atropine but shifted to right
  o ED50 is considerably lower of atropine compared to cyclopentolate
• Cyclopentolate has higher ED50 than atropine
  o Low conc for ED50  high affinity for receptor
   Affinity of atropine is higher than cyclopentolate
   Drugs with high affinity = potent drugs
   Atropine more potent than cyclopentolate

Question 19

What would be the tx of anterior uveitis as an IP Optom?

Answer 19

• Atropine is significantly more potent than cyclopentolate
• May get posterior synechiae – back surface of iris stuck to front of lens
  o Significant as may prevent aqueous humour draining away via anterior chamber angle
   IOP can rise  secondary open angle glaucoma
  o Risk of secondary closed angle glaucoma is condition becomes more acute
• Use mydriatic drug to break synechiae – break adhesion by dilating pupil
• Management – IP ONLY:
  o Prednisolone acetate (1%) q1h (topical corticosteroid) – powerful anti-inflammatory that will control pxs signs & sxs overtime – used every hour or two hours
  o Cyclopentolate (1%) tds (mydriatic) – to relax ciliary muscle (ant. Uveitis may get ciliary spasm which causes pain) – also to dilate pupil to break posterior synechiae or prevent one from happening
• Atropine may be indicated in some cases of ant. uveitis to treat ciliary spasm or posterior synechiae as it is more potent than cyclopentolate
  o More severe a pxs condition, the more potent the drug we may consider to use
  o More potent durg comes with increased risk of ADRs
• Cyclopentolate & atropine both have similar side-effect profile:
  o Both cause increase in heart rate which can turn into palpitations, may cause dry mouth and may cause condition of CNS where px becomes confused & disorientated
   Rare ADRs but more common with atropine than cyclopentolate
• General rule: do not want to expose pxs to increased risk of these serious side-effects when there is no need to do so
  o Need to strike balance between potency that we require whilst not inducing ADRs

Question 20

What are the clinical implications of pharmacokinetics?

Answer 20

1. Advise px’s to leave 5 mins between eye drops
   a. Relates to volume – may loose eye drop through over-spill, absorption through ocular skin or through rapid drainage down puncta
   b. Increases effectiveness of drops if leave gap between instillation
2. Advocate lid closure following instillation
   a. Minimise how much of eye drop is drained away via route
   i. Maximises volume of eye drop retained on ocular surface and is therefore available for absorption by corneal epithelium & conjunctival epithelium
   ii. Less of drop that drains via nasal-lacrimal drainage route, the less of the drug is available for absorption into systemic circulation – may help reduce risk of systemic ADRs e.g. raised BP with phenylephrine
   b. 67% reduction in systemic absorption by nasal-lacrimal occlusion – advise px to use finger and apply a bit of pressure in area of puncta to try and create a seal to reduce amount of eye drop that drains
   c. 65% reduction in systemic absorption with eyelid closure – seals upper and lower puncta together and reduces drainage of fluid via nasal-lacrimal drainage route
   i. Can recommend either method as evidence shows both effective – px find it easier to close eye for few mins rather than apply pressure
3. Consider viscosity of eyedrop
   a. Retention period – want this to be long
   b. Duration of contact – want this to be long
   i. Can do this by providing eye drops that contain long chain polymers e.g. sodium hyloranate (makes eyedrop more gloopy & viscous). Another e.g. is polyvinyl alcohol
   c. May choose to prescribe chloramphenicol as an ointment rather than eyedrop, ointment is considerable more viscous and lasts longer on ocular surface
   i. Other antibacterial drugs that may consider prescribing to px are already available as a gel e.g. fusidic acid (alternative to chloramphenicol). Herpes simplex keratitis can be treated by IP OPTOM using ganciclovir (gel form)
4. Consider ocular health
   a. Corneal epithelium
   i. If this is compromised (e.g. dryness or SPK(loss of corneal epithelium cells) – means cornea open to absorb more of drug via corneal epithelium than would be expected in a px with a healthy intact corneal epithelium
5. Compromised corneal epithelium increase proportion of drug absorbed across corneal barrier
   b. Pseudophakia (cataract op) – these pxs more at risk of ADRs than pxs with intact crystalline lens
   i. Route has been created for more of drug to diffuse past crystalline lens and reach into posterior chamber (vitreous humour where it can then come into contact with retina) – relatively rare
6. Prostaglandin analogue for glaucoma – e.g. of px with swelling around fovea caused by this drug – Cystoid macular oedema
   a. Relatively rare side effect

Question 21

Describe pharmacokinetics: drug elimination?

Answer 21

• Once a drug has done it’s job, the final stage in pharmacokinetic journey is to be eliminated or excreted
• Elimination requires functioning kidneys and liver
  o Kidney elongated majority of drug via urine
  o Liver transforms drug into metabolite (making it easier to excrete from body)
• Impaired elimination increases risk of ADRs
  o E.g. if px has kidney or liver disease
• E.g. of Bleph:
  o First try hot compress and lid hygiene but no improvement
  o Add in topical antibacterial like chloramphenicol but still no improvement
  o Then if IP OPTOM can prescribe oral tetracycline antibiotic e.g. doxycycline, tetracycline, minocycline, oxytetracycline
   “Should be avoided or used with caution in patients with hepatic impairment” (liver disease)
   “May exacerbate renal failure and should not be given to pxs with renal impairment” (kidney disease)
• Good practice when prescribing to always consult a professional guideline or piece of evidence before handing out an Rx
• Consult BNF to flag these important points – risk in these pxs that they won’t be able to eliminate drug so more risk of ADR
• Drugs are also excreted via breast milk
  o “Should not be given to women who are breast-feeding”
   Some drugs not safe to be administered to very young children and cause risk of very serious side effects
• Oral tetracycline antibiotics are good example of this
   Always check BNF or other guidance to check if med prescribing is safe for use in woman who is pregnant or breast-feeding

Question 22

Describe drug interactions?

Answer 22

• Drugs can work together to produce unexpected side effects
• Every med carries long-list of possible drug interactions
• Before prescribing, look at BNF and look at possible drug interactions for med intent to prescribe
  o Check this list against list of meds px is on and see if can identify any possible drug interactions
  o If spot drug interaction, consider other med instead
• Impaired drug absorption:
  o Ability of 2nd drug to be absorbed by body is reduced by action of 1st drug
   Tetracycline: reduced absorption by presence of milk, calcium, magnesium, zinc, antacids
• Effect amplification:
  o 2nd drug may enhance or amplify action of 1st drug
   NSAIDs significantly increase action of warfarin (used as blood thinner, used to reduce coagulation within the blood, reducing risk of strokes): risk is that NSAID can make wardarin work too effectively (enhanced anticoagulant effect) – blood too thin and px at risk of bleeding substantially from simple cut or graze
• Cross hypersensitivity:
  o Allergy to aspirin: may extend to ibuprofen and naproxen
   Drugs chemically so similar that there is good chance that if px is allergic to one they may be allergic to another

Question 23

What are the main sources of info to look at when needed?

Answer 23

• BNF – indications, dosing, drug interactions & contra-indications
• College of Optometrists – Optometrist’s Formulary – specifically for eye so more detail
• College of Optometrists – Clinical Management Guidelines
• Community Eye Care – specific to Scotland
  o https//communityeyecare.scot.nhs.uk/
• Eye Rounds.org – more images of eye disease