5P Flashcards
Bioavailability
Fraction of the administered dose of drug that reaches the systemic circulation
Apparent volume of distribution
theoreticalvolume in which the amount of drug would need to be uniformly distributed to produce
observed plasma concentration.
Clearance
volume of plasma from which a substance is completely removed per unit time
Half-life
time required for serum plasma concentration to decrease by half
Linear Pharmacokinetics
Concentration that results from a dose is
proportional to the dose
Double the dose, double the concentration.
Rate of elimination is proportional to the concentration
NonLinear Pharmacokinetics
plasma drug concentration changes either more or less than would be expected from a change in dose rate.
Rate of elimination is constant regardless of amount of drug present.
Therefore, drugclearancedecreases with increasing
drug concentration
Affinity
measure of the propensity of a drug to bind to its receptor; the attractiveness of drug and its receptor
Efficacy
(or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect
Antagonists have affinity but not efficacy
Potency
relative position of the dose-effect curve along the dose axis
Effects of Renal Disease on Pharmacokinetics and pharmacodynamics
Pharmacokinetics:
o Decreased elimination
o Decreased protein binding (plasma proteins lost in urine)
Pharmacodynamics:
o Altered sensitivity to drug effect
o Adverse effects
Increase dosage interval
Cystic Fibrosis and pharmacokinetics/dynamics
o Increased metabolism/elimination
o Larger VD
o Thus increase dosage, decrease dosage interval
Effects of Hepatic Impairment on Pharmacokinetics and pharmacodynamics
Pharmacokinetics o Decreased First pass metabolism o Decreased Activation of prodrugs o Decreased protein binding o Decreased elimination o Same/increased VD and slower rate of enzyme metabolism o Thus decrease dosage, increase dosing interval
Pharmacodynamics
o Altered drug effect
Which drug is contraindicated in renal impairment?
Naproxen
Core features of ADHD
1) inattention and lack of persistence
2) impulsivity (verbal and physical)
3) hyperactivity
Clinical features must be:
Apparent before the child is age 7 years
Excessive for the child’s age and development
Pervasive i.e. evident in more than 1 environment e.g. at home and in school
Steps of ‘Metastatic Cascade’
1) local invasion
2) angiogenesis
3) detachment
4) intravasation
5) transport
6) lodgement/arrest
7) extravasation
8) proliferation at ectopic site
vitronectin receptor
alpha-v-beta-3 = specific integrin that promotes invasion & metastasis. Found on metastatic melanoma cells
acts as a binding site for the enzyme MMP-2 from WBC in TME (solubel proteases can bind to integrins)
How does synthetic insulin compare to endogenous insulin
Analogues - different chemical structure to insulin, in aim to achieve faster onset of effects, or delayed effects.
Long-acting and short-acting analogues can be used as a combination.
Illness Behaviour
the way in which symptoms are perceived, evaluated, and acted upon by a person who recognises some pain, discomfort or other signs of organic malfunction
e.g. consulting behaviours adherence to treatment health-promoting behaviours avoidance unhelpful coping strategies - e.g. drugs, alcohol
Sick role
a term used in medical sociology regarding sickness and the rights and obligations of the affected
being sick means that the sufferer enters a role of ‘sanctioned deviance’.
Rights:
The sick person is exempt from normal social roles
The sick person is not responsible for their condition
Obligations:
The sick person should try to get well
The sick person should seek technically competent help and cooperate with the medical professional
Transition into the sick role may have some incidental secondary gains for patients = advantage that occurs secondary to stated or real illness.
Disease vs illness
Disease: disorder of structure and/or function
Illness: the expression and experience of ill health. Psychological, social and cultural factors are crucial
Locus of control
the degree to which a person believes that control to influence events resides with themself or others
Internal locus of control vs external locus of control
Internal locus of control vs external locus of control
Internal locus of control
believe that they have agency in their behaviour and ability to influence the world about them
Tend to adjust better to illness and have better management of illness → better health outcomes
NB: downside - can lead to feelings of guilt and safe blaming
external locus of control
believe that they have little control over events and that outcomes will be determined by others or by fate
Passive
Good coping with chronic illness
optimal functioning
self management strategies - good for adjustment to illness
reduced co-morbidity - prevent/minimise mental illness as a comorbidity
helpful coping behaviours - i.e. not drugs/alcohol
Successful adjustment
successful performance of adaptive tasks absence of psychiatric disorder presence of high positive affect adequate functional status satisfaction and wellbeing in various domains (quality of life)
Effect of psychiatric comorbidity on chronic illness
Increased morbidity and mortality Reduced adherence to treatment (x3) Reduced quality of life increased smoking reduced social and occupational functioning altered (poorer) illness behaviours
Barrier to Adjustment to chronic illness
Characteristics of the illness (e.g. pain, fatigue, unpredictability)
Characteristics of the treatment (e.g. dialysis)
Societal - stigma, rejection, discrimination
Comorbid psychiatric illness
personality, locus of control
social circumstances - finances, social support
Delirium
acute neuropsychiatric syndrome that has variable presentations.
Generally characterised by:
- Impaired consciousness (fluctuating level of consciousness)
- Acute onset
- Change in cognition
- Visual hallucinations (and other psychotic symptoms)
- Sleep-wake cycle disruption
- Affect changes
- In most cases, evidence of an underlying direct cause
Deririum vs dementia
1) delirium is acute, dementia is progressive
2) delirium is secondary to an underlying cause, dementia is a primary CNS disease
3) There are hallucinations and illusions in delirium, but less so in dementia
4) delirium causes fluctuation on levels of consciousness, but consciousness is not impaired in dementia
differential diagnosis for delirium
AV DEMENTIA A - alzheimers V - vascular D - depression, drugs, dementia E - ethanol M - metabolic E - endocrine (thyroid dysfunction, diabetes) N - neurological T - toxins I - infection A - autoimmune
Dementia
syndrome with chronic, progressive (usually irreversible) cognitive impairment due to brain disease
Characterised by a set of symptoms:
- Memory loss
- Deterioration from a higher level of function
- Multiple cognitive deficits
- Consciousness is preserved however
- Chronic duration > 6 months
- Impact on social/occupational function
Cognitive Tests
Addenbrooke’s Cognitive Examination (ACE)
MMSE (Mini-Mental State Examination)
Six-item Cognitive Impairment Test (6CIT)
Abbreviated Mental Test (AMT)
MMSE (Mini-Mental State Examination)
commonly used set of questions for screening cognitive function
24/30 = cutoff for dementia
Advantages
1) Ease and speed of administration
2) standardised
3) Screening tool and good for monitoring change
4) High inter-rater reliability
Disadvantages:
1) Insensitive to early impairments e.g. mild cognitive impairment (MCI)
2) Poorly covers executive function. Weighted heavily towards memory/attention → insensitive for frontal lobe dementia
3) Influenced by age, education, socio-economic status
Which memory is affected first in AD?
anterograde memory (episodic). Gradual transition to loss of retrograde memory working memory is preserved
Clinical Features of AD
- Failing memory - episodic memory is affected.
progressive loss of ability to learn, retain and process new information. - Cognitive decline (language, writing, reading, calculation, attention/problem solving)
- personality/mood changes.
- Neurological - primitive reflexes, postural abnormalities
- Frontal executive function - impairment of organising, planning and sequencing.
- visuospatial difficulties
Pathological hallmarks of AD
Deposition of β-amyloid (Aβ) in amyloid plaques in the cortex (especially hippocampus and medial temporal lobe)
Tau containing intracellular neurofibrillary tangles.
Amyloid may also be laid down in cerebral blood vessels, leading to amyloid angiopathy
Amyloid plaque and NFT formation in AD
Cleavage of APP by beta secretase leads to formation of β-amyloid , which is insoluble. β-amyloid aggregates to form plaques in the extracellular space, interrupting neuronal signalling. Plaques also initiate inflammtory reactions. Pro-inflammatorycytokines are believed to activate intracellular kinases, leading to hyperphosphorylation of tau protein. The hyper-phosphorylated tau collapses into twisted strands, which aggregate to form neurofibrillary tangles.
Hyperphosphorylation of tau causes microtubules to dissociate, interrupting neuronal transport.
Nutrients and other essential supplies can no longer move through the cells, which eventually die.
Results in widespread neuronal death and NT deficits.
As neurons die, large scale changes start to take place in the brain: Cortical atrophy Narrowing of gyri Widening of sulci Enlargement of ventricles
Vascular Dementia
multi-infarct dementia
effectively a series of mini-strokes, causing damage to the brain and thus memory.
Patient often has hypertension - Small vessel disease - subcortical - Large vessels disease - cortical multi-infarcts. Stepwise progression Memory impairment Lack of insight
Fronto-Temporal Dementia
group of neurodegenerative disorders characterised by frontal lobe and temporal lobe atrophy
Sporadic/Inherited
Often seen in younger patients: 45-65 year olds.
Frontal lobe dysfunction
- behavioural/personality changes
- Disinhibition, aggression
- Depression
- Agitation
Temporal dysfunction
- progressive impairment of language function.
- Progressive expressive aphasia
- Cognitive and memory impairment
Dementia with Lewy Bodies (DLB)
characterised by visual hallucinations, and fluctuating consciousness.
Progressive cognitive decline
strongly associated with Parkinsonism (may evolve later and is typically mild)
The lewy bodies formed are aggregates of the protein α-synuclein.
This is due to the protein misfolding into a β-pleated sheet structure.
These then further aggregate into higher-order insoluble structures (fibrils), which are the building blocks for Lewy bodies.
Avoid antipsychotic drugs in these patients!!
Parkinson’s Disease with Dementia
Classical lewy bodies
Bradykinesia, rigidity, tremor
Autonomic dysfunction
Cognitive impairment
When dementia develops after an established motor disorder, we call the disease Parkinson’s disease with dementia (PDD).
In contrast, when dementia develops prior to or at the same time as the motor disorder, we call the disease DLB.
Behavioural & Psychological Symptoms of Dementia
non-cognitive symptoms of dementia
symptoms of disturbed perception, mood or behaviour, frequently occurring in patients with dementia.
Confusion
Delusions
Hallucinations
Agitation and aggressive behaviour
medication options for patients with dementia
Symptomatic therapies
cholinesterase inhibitors
partial NMDA antagonist
Psychotropic medications for secondary symptoms
Cholinesterase Inhibitors
Donepizil, Rivastigmine and Galantamine
increase brain acetylcholine levels by inhibiting CNS acetylcholinesterase
Used in AD/PDD/DLB = all have marked cortical deficits of acetylcholine
not useful in frontotemporal dementia/vascular dementia
- FTD has a serotonin deficit
Partial NMDA Receptors Antagonist
memantine
acts on the glutamatergic system by blocking NMDA receptors
By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, which forms the basis of neuronal excitotoxicity.
there is a buildup of glutamate in AD brains, thus Memantine is used to block NMDA receptors and stop the overactivity of the glutamatergic system.
Can be used alone or in combination with AChE inhibitors
used in moderate/severe AD or when cholinesterase inhibitors are not tolerated
Wernicke’s encephalopathy and Korsakoff’s psychosis
Wernicke’s encephalopathy is a serious acute medical illness
Korsakoff’s psychosis is a chronic mental disorder (= alcohol amnesia). amnestic syndrome with impaired recent memory and relatively intact intellectual
function
Two stages of the same disorder. Although the disorder is mainly linked with alcoholism it is due to a deficiency of thiamine.
Changes in the brain with alcohol dependence:
Cortical shrinkage and ventricular enlargement
Deeper, wider sulci in the cortex of the brain
Cerebellum is shrunken
hypofunction of parietal lobe
Approaches to Immunotherapy
1) Vaccination strategies
2) Nonspecific therapies (e.g. IL-2 therapies)
3) Antibody therapies (rituximab, bevacizumab)
4) Cell-based (e.g. HSCs for leukaemia)
Philadelphia translocation
specific genetic abnormality in chromosome 22 of leukaemia cancer cells
Chromosomes have misaligned during mitosis and repaired themselves incorrectly after a break
This chromosome is defective and unusually short because of reciprocal translocation of genetic material
between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL.
This gene is the ABL gene of chromosome 9 juxtaposed onto the BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is constitutively active, causing the cell to divide uncontrollably.
Imatinib
a drug that inhibits Abl
binds to the amino acids of the BCR/ABL tyrosine kinase ATP binding site and stabilizes the inactive, non-ATP-
binding form of BCR/ABL
This prevents tyrosine autophosphorylation and, in turn, phosphorylation of its substrates.
VHL protein
classified as a tumour suppressor gene
VHL works by binding to hypoxia inducible factor
HIF results in transcription of growth factors for angiogenesis
HIF is kept in check by VHL -> tags HIF for destruction
molecular aberration in the VHL gene is common in renal carcinoma (HIF levels increase and cause very prolific blood supply to develop to the tumour)
critozinib
ALK = Anaplastic Lymphoma Kinase inhibitor
Prognostic marker
informs about the patient’s outcome regardless treatment
May help choose which patients to treat, but not how to treat them
Irrespective of treatment = prognostic
Predictive marker
predicts which patients will respond well to a particular treatment
Helps choose which treatment to use
forms the basis of precision medicine
Treatment-dependent = predictive
Enzalutamide
hormone therapy for men with advanced prostate cancer that has stopped responding to other hormone
therapy and chemotherapy treatments
AR signalling inhibitor that directly targets three stages of the AR signalling pathway
- blocks binding
- impairs nuclear translocation
- impairs DNA transcription
Enzalutamide is normally effective but splicing mutations can occur
Affect exon 5 of the mRNA, which codes for the ligand binding domain of the AR
results in constitutive activity, which cannot be inhibited by Enzalutamide as the AR does not even require androgen binding for action
psychiatry
medical speciality concerned with diagnosis, treatment
& prevention of mental health disorders
Organic Disorder
Change in mental function secondary to a physical process rather than psychiatric illness
Psychosis
altered relationship with reality
Delusion
fixed false belief held despite evidence to contrary, outwith sociocultural norms
Hallucination
sensory perception in the absence of external stimuli
illusion
misperception of real external stimuli
DEPRESSION: Core clinical features
pervasive low mood
+/- anhedonia
+/- fatigue
symptoms must persist for at least 2 weeks
Mood
subjective feeling of sustained emotion
Affect
objective immediate conveyance of emotion
blunt, flat, labile
Biological causes of depression
Genetics (60% MZT, 40% 1o)
Medical comorbidities (thyroid, HF, MS, CVA)
Psychiatric comorbidities (schizophrenia,)
Medications (steroids)
Neurochemical (↓ 5HT, NA, DA) = ‘Monoamine hypothesis’
Neuroendocrine (↓T3, TSH, ↑ cortisol)
