PMP202 CNS week 2

Barriers in drug transport

1. Blood-Brain Barrier (BBB) - Capillaries to brain

2. Blood-CSF Barrier (BCB) - Capillaries to CSF

3. Arachnoid Barrier - Outer protective layers of brain (CSF & Blood)

CSF = Cerebrospinal Fluid

Modes of transport across the BBB

1. Carrier-mediated Transport

2. Receptor-mediated Transport

3. Adsorptive-mediated Transport

Passive Diffusion Features

1. Passive

2. Lipid-soluble molecules (logD)

3. Low polar surface area

4. Low molecular weight

• 98% of small molecules do not cross BBB, only 5% of >7000 drugs in CMC database treat CNS

Active Efflux & Influx

• Active (ATP required)

Carrier-Mediated Transport

• Cross-membrane protein channels

• Preferential distribution across both sides of BBB confers polarized behavior of BBB

Cell Diapedesis

Manipulating cells to transport drugs across the BBB

Most common example = Neutrophils (WBC) that provide defence against invading microorganisms so must be able to cross the endothelial BBB

Lipinski’s Rule of 5

• 5 or fewer Hydrogen Bond Donors (HBD)

• 10 or fewer Hydrogen Bond Acceptors (HBA)

• Molecular weight under 500g/mol

• LogP less than 5 (Actually: 0-3 for CNS)

• 10 or fewer rotatable bonds

• Oral Bioavailability <140 Ų (Angstroms) (<90 to cross CNS)

Used to determine what drugs should be modified for transport across the BBB

Methods of modifying drug chemical structures

1. Lipophilic Analogues

2. Prodrugs

3. Chemical Delivery Systems

4. Molecular Packaging

Lipophilic Analogues

Making drug molecules more lipophilic by adding lipid groups to polar ends of the drug molecules

Lipophilic Analogues - Cons

• Can lead to poor tissue distribution

• Can be detrimental to oxidative metabolism by CYP-450 and other enzymes

• Lowers PSA so can change bioavailability (especially oral drugs)

Prodrugs

Compounds that, on administration, must undergo chemical conversion by a metabolic process before becoming an active pharmacological agent

Chemical Delivery Systems (CDS)

Inactive chemical precursors of a drug, activated by one or more chemical modifications

3 Classes of CDS:

• Enzymatic Physiochemical CDS

• Site-specific Enzyme-activated CDS

• Receptor-based CDS

Targetor: Responsible for targeting, site-specific & lock-in

Modifier: Lipophilizers, protect certain functions, prevent unwanted or premature metabolic conversions

Molecular Packaging

Primarily used for peptides

Peptide unit forms part of a bulky molecule, dominated by groups that prevent recognition by peptidases & allow for direct passage through BBB

3 Goals of Molecular Packaging

1. Increased lipophilicity (Enhance passive transport)

2. Prevention of premature degradation (By enzymes especially)

3. Exploits lock-in mechanism to make targeting possible

Causes of Nausea & Labyrinth

• Motion sickness (Hyoscine Hydrobromide)

• GI and biliary disease (Metoclopramide)

• Underlying conditions (Antihistamines)

• Chemotherapy (Dopamine antagonist - Prochlorperazine)

• Palliative care (Antipsychotic - Haloperidol)

• Post-op (Ondansetron)

• Post-op caused by opioids (Cyclizine)

Common treatments for N&L

• Metoclopramide - Acts directly on gastric smooth muscle stimulating gastric emptying. Can cause dystonia (Involuntary muscle spasms) in young females

• Domperidone - Acts at the chemoreceptor trigger zone (Acts peripherally), less likely to cause central effects, such as sedation and dystonic reactions

• Phenothiazines - Acts centrally by blocking the chemoreceptor trigger zone (Risk of dystonic reactions) e.g chlorpromazine, prochlorperazine

N&L in pregnancy

• Common in 1st trimester

• Resolves within weeks 16-20

• 1. Self care advice (Rest, hydration, diet changes)

• 2. Available support (Self-help information, support groups)

• 3. Antiemetics (e.g Cyclizine, chlorpromazine)

Metoclopramide - Dose

10mg up to TDS, 500micorgrams/kg max dose

Domperidone - Dose

Not for children <12 OR anyone <35kg

Side effects - Arrhythmia

ADHD - Definition

Characterised by a persistent pattern of inattention and/or hyperactivity-impulsivity, with onset during developmental period, typically early to mid-childhood

ADHD - Basis for treatment

Both Dopamine (DA) and Noradrenaline (NA) are involved in the treatment response (Paradoxical effect to stimulants: Calming effect)

ADHD - Treatment Targets

• Educate about the disorder and its management

• Support the individual (± Family members)

• Improve the core symptoms

• Address the associated impairments (Depression, anxiety)

• Treat the psychiatric co-morbidity

• Monitor physical health

ADHD - Pre-medication checks

1. Confirm the diagnosis (By a specialist)

2. Review of mental health comorbidities

3. Risk assessment for substance misuse and drug diversion

4. Review physical health

5. - BP and pulse (Recorded at baseline and before every dose change)

6. - Weight (“ “)

Review at least once a year

ADHD - First line treatment

Lisdexamfetamine OR methylphenidate

Switch those who have not derived enough to benefit from the first trial to the other after a 6 week trial of the other

Atomoxetine is 2nd line if poor response or tolerance to first line

ADHD - Treatment mechanisms of action

1. Psychostimulants - Dopamine transporters (DAT) and noradrenaline transporters (NAT)

2. Non stimulants -

   1. Atomoxetine - NARI selective noradrenaline reuptake inhibitor

   2. Clonidine and Guanfacine - NA agonists

   3. Bupropion - DAT & NAT inhibitor & nicotine receptor antagonist

ADHD - Common side effects of medication

• Appetite loss

• Weight loss

• Increased heart rate and BP

• Tics and Tourette’s syndrome

• Growth restriction in children

Parkinson’s Disease - Common Symptoms

• Bradykinesia (Slow moving)

  • Hypomimia (Loss of facial movement)

• Plus one of:

  • Tremor

  • Rigidity

• Micrographia (Small writing)

• Altered posture

• Shuffling gait

Parkinson’s - Possible symptoms

• Sensory phenomena (Pain, dysesthesia(Pain due to light touch))

• Sleep disturbances

• Autonomic nervous system dysfunction

  • Constipation

  • Sexual dysfunction

  • Urinary problems

  • Sweating

• Motor symptoms

• Mental changes

  • Dementia

  • Hallucinations

  • Depression

  • Apathy

Parkinson’s - Pathology

PD brains have <10% of normal dopamine (DA) levels in the Substantia Nigra and the Corpus Striatum

This results in neuronal loss (Death) of the dopaminergic nigrostriatal pathway

Lewy bodies - Present in CNS and PNS, cytoplasmic protein inclusions that mostly contained alpha-synuclein

PD - The role of dopamine (DA)

DA is a neurotransmitter produced in neurons of the substantia Nigra (Part of the basal ganglia)

The nigro-striatal pathway is the main pathway damaged in PD (Due to Low DA levels)

Nuclei in basal ganglia crucial for the control/initiation of movement

PD - The Basal Ganglia

Initiate movement:

• A group of 5 bilateral nuclei later to the thalamus

  • Caudate

  • Putamen

  • Globus pallidus (interna and externa)

  • Subthalamic nucleus

  • Substantia nigra (SN)

Substantia Nigra: Provides dopaminergic modulation of motor pathways

Movement is initiated in the motor cortex. The basal ganglia modulate and fine-tune that movement. Dopamine from the substantia nigra modulates basal ganglia activity. The thalamus relays back to the cortex. Cortex → spinal cord → muscles

Parkinson’s - Treatment

1. Levodopa - to people in early stages of Parkinson’s disease whose motor symptoms impact on their quality of life

2. Consider a dopamine agonist

Versions of dementia/alzheimer’s

Most common to Least Common

• Alzheimer’s

• Vascular Dementia

• Mixed Dementia

• Dementia with Lewy’s Body

• Frontotemporal Dementia

Dementia - Definition

Umbrella term

The loss of mental processing ability, communication, abstract thinking, judgement and physical abilities, such that interferes with daily living.

Alzheimer’s - Background

Physical abilities may be effected in late stage

3-20 years duration (7-10 more common)

Likelihood of developing dementia increases with age:

• Age 65 - 1/14 have dementia

• Age 80 - 1/6 have dementia

• Female > Male

Alzheimer’s - Symptoms

• Memory lapses of increasing frequency

• Language deficits - word finding - comprehension - paraphasia (Unwanted words)

• Disturbed/repetitive behaviour

• Visuo-spatial deficits

• Impaired judgement and executive functions

• Effects on social function

  • Confusion, disorientation

  • Lack of memory affects organisational skills

  • Mood swings - Depression, anger, paranoia

  • Loss of confidence, withdrawal

  • Loss of life skills and independance

Alzheimer’s - Gross pathology

Nerve cells die - Brain appears to shrink

Mainly effects frontal cortex and temporal lobe

Alzheimers - “Typical“ progression

• Mild cognitive impairment

• Early phase: Forgetfulness, anxiety/agitation, paranoia, disorientation

• Middle phase: Withdrawal, loss of insight, speech difficulty

• Late phase: Aphasia, affected comprehension. Disorientation in time and space, wandering, sleep disturbances. Need for care for all daily activities

Alzheimer - Causes (Genetic)

Apolipoprotein E (ApoE₄)

• Modifies age of onset

• Molecular mechanism uncertain

• May contribute to tau and Ab pathology

• ApoE4 = Risk factor, not deterministic

Other gene susceptibility:

• TREM2 (Immune microglia cells)

• Genes of small effect

Alzheimer - Causes (Environmental)

• Age

• Hearing loss

• Head injury

• Hypertension

• Alcohol consumption

• Smoking

• Depression

• Social isolation

• Physical inactivity

• Air pollutions

• Diabetes

• Untreated vision loss

• High LDL cholesterol

Alzheimer’s - Treatments

• UK clinical practice routine treatments are all symptomatic

  • Treatments do not affect underlying disease process

• Treat cognitive symptoms

  • Acetyl cholinesterase inhibitors

  • NMDA receptor antagonists

• Non-cognitive symptoms

  • Behavioural and psychological symptoms of dementia (BPSD)

Withdrawal - Addiction:

Psychological - Craving, compulsion, loss of control, ‘Addiction‘

Physiological - When stopping a drug causes a withdrawal syndrome

Dopamine Function

In a healthy person, the reward system reinforces natural reward systems for food, sex and social interaction (e.g eating food, listening to music and others)

Dopamine in addiction

Addictive drugs (E.g cocaine, amphetamines) inhibit DA uptake, resulting in an increase in DA in the synaptic cleft

Relationship between Acetylcholine and Dopamine

High acetylcholine = Low Dopamine

And vice-versa

High dopamine = Psychosis

High acetylcholine = Parkinson’s

Parkinson’s Disease - Risk Factors

• Increasing age

• Male gender

• Head trauma

• Common genetic mutations (e.g LRRK2, GBA, SNCA)

• Environmental toxin

PD - Stages

1. Mild symptoms that don’t interfere with everyday life (e.g one sided tremors, posture, facial expressions)

2. Symptoms worsen and daily tasks become difficult and time-consuming

3. Mid stage - Loss of balance and slowness of movement. Resulting in increased falls, but still independent

4. Severe symptoms - Movement may require a walker, needs help with daily activity and is unable to live alone

5. Stiffness in the legs makes standing impossible. Patient is either bedridden or requires a wheelchair and around the clock care. Patient may experience hallucinations and delusions.

PD - Management

1. Administration of DA precursor (Levodopa preparations such as co-careldopa)

2. Activation of DA receptors using DA agonists (e.g ropinirole)

3. Enzyme inhibition to prevent the breakdown of DA

Definition - Refractory

Body is not responding to medication

Tiers of Misuse Treatment

Tier 1: Non-Drug Treatment Specific Services (E.g school nurse)

Tier 2: Open Access Services and Harm Reduction Services

Tier 3: Structured Community Based Services - Specialists and GP

Tier 4: Rehab

Drug Classes

Class C (E.g GHB, tranquilisers etc.)

Class B (E.g Cannabis, ketamine, codeine)

Class A (E.g Ecstasy, LSD, Heroin, Cocaine)

Edwards and Gross Criteria

• Narrowing of the behavioural repertoire (Narrowing to using 1 drug)

• Salience of drinking and drug use (Prioritising use)

• Subjective awareness of compulsion

• Increased Tolerance

• Repeated withdrawal symptoms

• Relief from or avoidance of withdrawal symptoms

• Post abstinence re-instatement

Addiction - Stages of Change

1. Pre-contemplation (Denial)

2. Contemplation

3. Preparation

4. Action

5. Maintenance

6. Relapse

Heroin Withdrawal Symptoms

Stage 1 (Up to 8 hours after last dose):

Drug cravings, moodiness

Stage 2 (8-24 hours after last dose)

Stomach cramps, upper body secretions, restlessness

Stage 3 (Up to 3 days after last dose)

Diarrhoea, Fever/Chills, Muscle spasms, Nausea/Vomiting, Cardiovascular Problems

What is disulfiram and what does it do? EXAM QUESTION

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Dementia - Definition

Progressive clinical syndrome characterised by a range of cognitive and behavioural symptoms that can include memory loss, problems with reasoning and communication, a change in personality, and a reduced ability to carry our daily activities such as washing or dressing.

Dementia - Cognitive Symptoms

• Memory Loss

• Lack of Concentration

• Disorientated

• Difficulty with Speech

Dementia - Non-Cognitive Symptoms

• Agitation

• Aggression

• Distress

• Psychosis

Dementia - Diagnosis

• Alzheimer’s Dementia

  • Develops after 60

  • Memory loss with varying changes in planning, reasoning, speech and orientation

• Vascular Dementia

  • Cognitive impairment

  • Patients should be screened for depression and for signs of psychomotor retardation

• Lewy Body Dementia

  • Involved visual hallucinations and Parkinson-like symptoms

  • Problems multitasking and performing complex cognitive actions

  • Sleep disorders and fluctuations in cognitive ability

• Frontotemporal Dementia

  • Develops in <65s

  • Behavioural (Decline in interpersonal skills, changes in food preferences)

  • Semantic (Not recognising words, familiar faces)

  • Non-fluent (Speech apraxia = Poor articulation)

Dementia - Alzheimer’s Disease - First Line Treatment

• Donepezil

  • Caution: Cardiac conduction disorder, neuroleptic malignant syndrome NMS, extrapyramidal symptoms, asthma, COPD

• Galantamine (Alternative 1st line)

  • Avoid in GI obstruction, urinary outflow obstruction

  • Severe cutaneous adverse reactions (SCARs) - signs of serious skin reactions

• Rivastigmine (Alternative 1st line)

  • Stop if patient becomes dehydrated from prolonged vomiting or diarrhoea

  • Less side-effects with transdermal administration

  • Monitor body-weight (Patients <50Kg more prone to ADRs)

Dementia - Non-Alzheimer’s - 1st Line Treatment

• Donepezil or Rivastigmine

  • For mild-to-moderate dementia with Lewy Bodies

• Donepezil or Memantine

  • For patients with vascular dementia if they have suspected co-morbid Alzheimer’s disease, Parkinson’s disease or Dementia with Lewy Bodies