BLOCK 3 PHARMACOLOGYAmazing Patrick Elder & Natalie Maltseva

DEPRESSION

Depression pharmacology• What is the monoamine theory of depression?• Decreased levels of the neurotransmitters 5HT and NA

cause depression. • So – treatment – to rise the levels of 5HT and NA• Any complication of these approach? • Overexcitement of the system.• LSD – synthetic agonists of 5HT receptors(and dopamine)

can lead to psychotic episodes, panic attacks.

What are the main classes of antiDepressants?

• Selective Serotonin Reuptake Inhibitors (SSRIs)• Tricyclic Antidepressants (TCAs)• Monoamine Oxidase Inhibitors (MAOI-A)• Atypical Antidepressant, (e.g. NASSA, NRI)

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Increases 5HT levels by inhibiting re-uptake pumpExamples:• Fluoxetine• Paroxetine• Sertraline• Citalopram• Prozac

• Side effects:• Slow onset• Nausea• Sleep disorders• Sexual dysfunction• Drug interactions may lead to ‘serotonin syndrome’ (hyperthermia,

cardiovascular problems, aggression, tremor and rigidity)• 5HT1A agonists (e.g. buspirone) have fewer side effects and no sedation or loss

of coordination

If your patient is on citalopram what dietary restrictions would you tell him about?• None.• Citalopram is SSRI and it is MAO inhibitors that we worry

about. Why?• Cheese reaction!• Ripe cheese, red wine, concentrated yeast products

contain tyramine = indirectly acting sympathomimetic amine

• Normally it is broken by MAO, but if people take MAOI – more tyramine enters systemic circulation. Leads to release of NA – results in an adrenergic response – high BP, HR, flushing, arrythmias, headache

Monoamine Oxidase Inhibitors(MAOI-A)• Increases NA/5HT levels by inhibiting enzymatic breakdown

Examples:• Phenelzine• Isocarboxazide• Moclobemide (RIMA)

• Side effects:• Similar to TCAs• Many cross drug reactions(DO NOT USE WITH SSRIs/TCAs)

• Postural hypotension• Restlessness• Convulsions• Sleep disorders• ‘cheese reaction’ – tiramine

Tricyclic Antidepressants (TCAs)TCAs have 5 main actions: • 5HT reuptake blocker• NA reuptake blocker – main • α1 adrenoreceptor antagonist

• H1 receptor antagonist

• M1 receptor antagonist

• Also used to treat neuropathic pain• Examples:• Amitriptyline• Nortriptyline• Clomipramine• Imipramine• Trimipramine• Doxepin• Cocaine (!)

Can you work out side effects of TCAs?

• Sedation – blockage of H1-receptors

• Postural hypotension and• Cardiac dysrhythmia – blockage of a-adrenergic receptors

• Confusion• Visual problems• Urinary retension – blockage of Ach-receptors

Atypical antidepressants• NRIs (aka NaRIs, atypical) work in the same way as

SSRIs – upcoming drugs• Reboxetine

• SNRI (atypical) combined 5HT and NA reuptake inhibitors• Venlafaxine

• 5HT partial agonists reduce activity to increase transmitter levels• Buspirone• Trazodone

PAIN!

Analgesia – What are the two main types of pain?

• Nociceptive: cause by physical damage and activation of nociceptors (aka physiological pain)

• Neuropathic: caused by damage/malfunction of the neural components of pain (aka chronic/persistent pain)

The WHO Pain Ladder

Adjuvants include TCAS and Benzodiazepines

NSAIDs: what is their mechanism of action?

• Normally:

• When cells are damaged, inflammation occurs and cell membrane phospholipids are converted to arachidonic acid by phospholipase

• Arachidonic acid is oxidised by cyclo-oxygenase (COX) enzymes to prostaglandins

• Prostaglandins bind to prostanoid receptors and increase depolarisation, transmitting pain signals to the brain

Learn this pathway!

M.O. at neuronal level

Vo

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αi/oβ

ProstanoidReceptor

γPLA2

+5-HPETE12-HETE

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CREB

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↓ Depolarisation

NSAID

Prostaglandin

Wouldn’t bother learning!

NSAIDs: what is their mechanism of action?• NSAIDs Block production of

prostaglandins by inhibiting COX (cyclo-oxygenase) enzymes NSAIDs

What are the 4 clinical uses of NSAIDs?

Anti-inflammation

Anti-pyretic

Analgesic

Anti-coagulant

• N.B. May delay healing, not used post operatively, post partum

NSAIDs: which ones do we use?• Aspirin (from humble origins to CV drug)

• Ibuprofen (weak action)

• Naproxen (strong, low side-effects)

• Diclofenac (similar to Naproxen)

• Indomethacin (strong, high side effects)

• COX-2 Inhibitors: Celecoxib

Etoricoxib

Parecoxib• (similar to naproxen, lower GI effects)

What are the 6 clinical uses of opioids?

• Analgesia – chronic and acute• Anaesthesia (Alfentanil, Fentanil, Remifentanil) • Antitussive (Phlocodine, Dextromethorphan)• Antidiarrhoeal (codeine, loperamide)

• Coronary Care (pre-surgical, surgical and post)• Cancer Care (Morphine, Diamorphine, Oxycodone)

What is the mechanism of action of opioids?• Act on opioid receptors:

• μ, κ, δ and ORL1 (OP1-OP4)

• They bind to G-protein coupled opioid receptors

• They work by a second messenger pathway.  They inhibit adenylate cyclase, reducing levels of cAMP.  This increases opening of K+ channels.

• Increase in K+ outflow via K-ATP and K-IR (inward rectifying) channels.  This causes hyperpolarisation, making it harder for the neuron to be excited.

• Opioids also decrease opening of voltage-dependent calcium channels and decrease calcium release from intracellular stores.

• Decrease in intracellular calcium inhibits the release by exocytosis of neurotransmitters, preventing impulses from being transmitted.

How do you reverse opioids? • Naloxone: half-life 1-2 hours - very quick, you can just

give repeated boluses as required. Use this to reverse and overdose.

• Naltrexone: 10 hours - very long-acting and helpful to give to addicted patients because it removes the association between drugs and the high - can help to end addiction.

Which four things do you give to a patient to wake them from an opioid-induced coma?

• Coma cocktail:

• Naloxone• O2

• Glucose• Thiamine

How do you treat neuropathic pain?• As a general rule of thumb, neuropathic pain rarely

responds to standard analgesics. In these cases your drugs choice is from two main groups:

• Anti-epileptics• Anti-depressants (mainly the tricyclic antidepressants

(TCA))

Which drugs do we use for neuropathic pain? In which combinations?• The most common drugs used to treat neuropathic pain

are:• Amitriptyline (TCA)• Nortriptyline (TCA)• GABApentin (AED)• Pregabalin (AED)• Carbemazepine (AED) – really good for trigeminal

neuralgia

 • You can use amitriptyline/nortriptyline (one, not both) and

GABApentin or Pregabalin in combination, but carbamazepine should never be used in combination.

BASAL GANGLIA

Parkinson’s disease (PD) = Hypokinetic disorder

• As dopamine doesn’t cross the Blood-Brain Barrier you need to remember to use

• Precursor of dopamine = Levodopa• But you want to start this as late as possible. So.. Early on

(pre-PD) – use ..• synthetic agonists of dopamine: • Early-onset PD is premature – and respond to pra-mi-

prexole• If that doesn’t work you can try roping in another to do the

job, try ro-pinirole

What would you use for drug-induced PD?

• Anticholinergics:• Orphenadrine• Pro-cyclidine • Why would you use anticholonergics?• Decrease in Ach leads to increase in DA.• What drugs could induce PD?• Long-term antipsychotics

What do you need to know when prescribe Levodopa?• It gets broken down peripherally by dopa-decarboxilase • And centrally by – catechol-o-methyl transferase and

monoamine oxidase inhibitors - B form. • SO you want to be CERtain to include:• Carbi-dopa – to inhibit dopa-decarboxylase• Enta-capone - to Inhibit COMT• Rasagiline – to inhibite MAOIBs

Hyperkinetic disorders• Huntington’s disease, choreas, athetosis and ballismus –

all respond to atypical antipsychotics. Examples?• Risperidone• Quetiapine

• What would you use for tremors?• B-blockers – propanolol – to reduce sympathetic activity

EPILEPSY

Epilepsy: what causes it? 4 different types

• Changes in neuronal excitability:

• Reduction in GABA• Increase in Ach transmission• Increase in Na+ transmission• Decrease in K+ transmission

• Mutations in channel structure often linked to genetic epilepsy

• Mutations found in K+, Na+, Ach and GABA receptors

What are the four mechanisms of anti-epileptic drugs?• Generalised Mechanisms of Action:

• Sodium Channel Blocker• Primarily targeted for voltage-dependent Na+ channels• Only block channels in inactivated state

• Calcium Channel Blocker• Voltage dependant or low-threshold (T-type) Ca2+ channel blockers

• GABA modulation• Enhance activation of GABAA mediated channels• Inhibition of GABA breakdown• Inhibition of GABA uptake

• GABA mimetics

• Most AEDs are dirty drugs and affect multiple receptors.

Epilepsy drugs

Name 3 Na+ channel blockers:

• Carbamazepine• Lamotrigine• Sodium Valproate

Name 4 calcium channel blockers

• Ethosuximide (T-type Ca2+ blocker)• Gabapentin• Lamotrigine?• Topiramate

What is the mechanism of action of benzodiazepines?• Act on GABAA receptor (γ

subunit) to increase activity• Reduces neuronal

transmission by enhancing inhibition

• Increased GABA activity increases movement of chloride ions by increasing chloride channel activity, thereby bringing about hyperpolarisation – reduction in neuronal transmission

What is the mechanism of action of barbiturates?

• Work in exactly the same manner as benzos but on the β-subunit of the GABAA receptor to increase activity

• Reduces neuronal transmission by enhancing inhibition

• Commonly used as anaesthetics/anxiolytics

BDZs

BarbituratesGABA

How do you treat…• Partial seizures and partial with secondary generalised?

• First Line:• Carbamazepine• Lamotrigine*• Oxcarbazepine• Sodium Valproate*

• Generalised - Grand-mal

• First Line:• Carbamazepine• Lamotrigine*• Sodium Valproate*

How do you treat…• Generalised - Petit mal

• First Line:

• Ethosuximide• Sodium Valproate*