What is a poison?
The poison becomes an instrument which dissociates and analyses the most delicate phenomena of the living machine and by careful study of the mechanism of death in different poisonings, he can gain knowledge, indirectly, of the physiological mechanism of life
What are the two axioms central to the effects of toxicants?
What are the purpose of toxicology studies?
What adverse effects can a drug produce
What are the parameters of toxicity(dose,route of exposure,susceptibility factors)
What can be done to monitor toxicities(drug level,biomarkers,clinical signs)
What is the review process in toxicology studies
What is the typical situation when setting doses?
Ascending dose levels
Establish maximum tolerated dose and pharmacokinetics
Normal healthy(or asymptomatic) volunteers
What are the main features in the concept of 'Dose'?
Amount of toxicant that reaches the target tissue over a defined time span
In an occupational environment, the estimated exposure or cumulative exposure is frequently used to estimate "dose"
Dose is a function of exposure concentration,duration,frequency
Individual and environmental characteristics can affect dose
What are the factors of standards and exposure limits?
Permissible exposure limits(PEL's)
based on time weighted average(TWA)
Short-term exposure limits(STEL or ceiling)
Recommended Exposure Limit(REL)
No Observed Adverse Effect Level(NOAEL)
How does one measure exposure in the environment?
Volumetrically - ppm
Gravimetrically - mg/m³
Energy units (example : dBA, mSv)
How does one measure exposure in the biological sample
Urine ( 24 hour or ug/gram creatinine)
Hair or nails
How is effect measured?
Medical Tests for screening or surveillance
Medical Tests to measure clinical effect or level of impairment
What are the medical tests to measure clinical effect or level of impairment?
Blood tests for liver,kidney,blood
Pulmonary function testing
What are the control measures when measuring effect?
How is the maximum recommended starting dose determined?
Dose affect relationship on population group
Can be acute or chronic
Medicines - prescribed or over the counter administered in 90% of incidents
Predominant cause of admission for children under 5 years with domestic chemicals e.g. bleach,detergents
What are the priniciples of treatment in poisoning?
Successful treatment depends on speed and common sense
80% of hospital admission needs only general observation and general supportive measures to metabolise and treat poisons
15% need a specific antidote
ITU needed in only 5%
What are the poison specific measures taken in treatment of poisoning?
Prevention of further absorption
Acceleration of elimination
What are the general measures taken in treatment of poisoning?
Initial assessment and resuscitation
Psychiatric and social assessment
What are the poison specific measures of identification?
Dose and time taken
Any prescription,suicide notes
Rapid drug screens of plasma or urine important
Any tablets found in vicinity
Important to decide if patient needs antidotes
Whether urine alkalisation, acidification or haemodialysis needed
Response to a specific antidote might give indications
What are examples of response to specific antidotes?
Dilation of constricted pupils after naloxone administration - opioid poisoning
Arousal after I.V flumenazil - benzodiazepine poisoning
How is further absorption prevented from the environment?
When poison has been inhaled or absorbed through skin,contaminated clothing removed and skin cleansed
How is further absorption from the gut prevented?
Emesis in conscious patients
Induced by ipecacuanha emetic mixture
Both contraindicated in corrosive poisons due to risk of gut perforation and for petrol derivatives
How is further absorption from oral adsorbents prevented?
Fullers earth and betonite
What is the mechanism of action of activated charcoal?
Very fine black powder activated by an oxidising gas flow to create a network of fine pores, binds several compounds in gut
What is the mechanism of action of fullers earth and betonite?
Bind and inactivate herbicides and paraquat
By what mechanisms do specific antidotes work?
Receptors - which may be stimulated,blocked or bypassed
Enzymes - may be inhibited or reactivated
Displacement - from tissue binding sites
Replenishment of an essential substance
Binding to a poison - chelating agents
What is an example of an antidote receptor?
Atropine - used to treat organophosphate pesticides by blocking muscarinic receptors
What is an example of an antidote enzyme
Ethanol for methanol poisoning competitively inhibits alcohol dehydrogenase preventing formation of toxic metabolites
What is an example of an antidote which works by displacement?
Oxygen used for CO poisoning since it competitively displaces CO from Haemoglobin binding sites
What is an antidote which works by replenishment of an essential substance?
Methionine is used for paracetamol overdoses where it replenishes depleted glutathione stores
What is an antidote which works by binding to a poison?
Penecillamine chelates metal ions e.g copper,gold,mercury
Dimercaprol for arsenic poisoning, supplying - SH groups instead of essential enzyme
EDTA - used for lead an calcium poisoning, and the resultant chelates excreted in urine
Desferroxamine is used to treat iron overdose in thalessemic patients
What are the methods of acceleration of elimination?
Alteration of urine pH which can be done via haemodialysis and haemoperfusion together or haemoperfusion alone
What is the role of alteration of urine pH and diuresis?
Changing glomerular filtrate pH, poison ionises, less lipid soluble, remaining in renal tubular fluid and then eliminating in urine.
What is the role of haemodialysis and haemoperfusion in acceleration of elimination?
Semipermeable membrane seperate blood from dialysis fluid thus poison passes from high concentration (blood) to low concentration (fluid)
When is haemodialysis and haemoperfusion used in the acceleration of elimination?
For salicylates, isopropanol found in aftershave lotion, window cleaning solutions
What is the mechanism of action of haemoperfusion
Blood flows over activated charcoal or ion exchange resin
What is haemoperfusion useful for?
Useful for drug excreted in bile - phenobarbitone, carbamezapine
What are the general measures taken in treating poisoning?
Initial assessment and resuscitation
Supportive measures(most patients recover if they are adequately ventilated, hydrated and perfused with own body mechanisms taking over)
Psychiatric and social assessment should be adressed
What are the main features of methanol poison?
Used as a solvent in paints and antifreezes, 10ml may cause blindness , 30ml can kill
Methanol metabolised to toxic formaldehyde and formic acid
What are the clinical features of methanol poisoning?
What are the main features of ethylene glycol poison?
Antifreeze in car radiators
Used to give body and sweetness to white table wines
Metabolised to glycolate and oxalate - acidosis and renal damage, pulmonary oedema and cardiac failure; renal pain as sodium oxalate deposited in urine
What are the main examples of volatile substance abuse?
Glue sniffing - adhesives,
What are the clinical features of volatile substance abuse?
Euphoric and excitatory effects, followed by confusion,hallucinations,delusions
What is the main damage done by volatile substance abuse?
Damage to lung,kidneys and hearts
Death caused by cardiac dysrhythmias cause by sensitization of myocardium to cathecolamines and by vagal inhibition when aerosol propellants are sprayed in throat
What are the main features of organophosphorus compounds and organic carbamates?
Used as pesticides,inhibiting anticholinesterase almost irreversibly
Mostly accidental cases e.g. agricultural industry, used in war
Absorbed through skin, inhalation and GI tract
What are the typical features of poisoning by organophosphorus compounds and organic carbamates?
G.I tract - salivation,vomiting,abdominal cramps,diarrhoea,bronchoconstriction,diarrhoea
What is the mainstay of treatment in organophosphorus compounds and organic carbamates poisoning?
2mg I.M or I.V asap - until dryness of mouth
antagonises parasympathomimetic effects of drug
What are the typical features of poisoning by dinitrocompound?
dinitro-othocresol and nitrobutylphenol used as selective weed killers and insecticides
Absorbed through skin - hair and face stained yellow, high metabolic rate, copious sweating and thirst
How is poisoning by dinitrocompounds treated?
cool patient and treat fluid and electrolyte imbalance
Why is it important to differentiate dinitrocompounds from organophosphorus?
Since if atropine is given, stop sweating and cause hyperthermia in an organophosphorus poisoning
What other dinitrocompounds cause poisoning?
What are the main features of paraquat poisoning?
Extremely toxic herbicide, ulceration of oral and oesophageal mucosa, followed by renal tubular necrosis, pulmonary oedema and necrosis
How is paraquat poisoning treated?
Treat urgently with gastric lavage, activated charcoal,aluminium salicylate
What other compounds are involved in poisoning?
amphetamine - ecstasy
what are the clinical features of LSD?
What is the treatment of LSD?
Phencyclidine - ketamine - analgesia without consciousness
What are the main features of ethanol?
Absorption is highly rapid, very lipid soluble, absorption delayed by food
Alcohol in alveolar air is in equilibrium with pulmonary capillary blood and is of great medicolegal importance
Removal of inhibitory effects
Impairment of muscle co-ordination - car driving
other drugs and driving
What percentage of Motor Vehicle Accidents have a detectable alcohol limit?
What are the main features of cannabis?
Grows wild psychoactive metabolities
Very lipid soluble
Euphoria, impaired memory
What is the mechanism of action of ecstasy?
Acts by releasing noradrenaline from nerve endings, euphoria, postpone fatigue, hyperthermia,psychotic states
What are the main features of heroin?
Used since prehistoric times
Reduces pain,state of relaxation,euphoria,depresses respiration
What are the main features of animal toxin poisoning?
Venoms several specific antisera available - alterations in resistance of blood vessels and blood coagulation mechanisms
What are the main features of marine venoms?
Varied molecular weight
Simple effects example : transient vasoconstriction or vasodilation,pain and localised erythemas
Other complex reactions example parasympathetic dysfunction
changes in cardiovascular dynamics
What are the main categories of compounds used in anaesthesia?
What is the mechanism of action of opiates?
Muscarinic receptor agonists
What are the acute side effects of opiates?
Respiratory depression and nausea
In which organ are opiates metabolised?
Example of opiate agonist?
What is the main feature to note in naloxone?
Infusion may be needed if the patient is on long-acting opiates
What are the main features of hypnotics?
Sleep inducing drugs
Can be classified into volatile and intravenous
What are the main features of volatile hypnotics?
Chemically heterogenous group of compounds
Unique in being administered and excreted by the lungs
Used for maintenance of anasthesia and induction of sleep in children and adults with no intravenous access.
What are the main representatives of volatile hypnotics?
halothane and enflurane are still used in developing countries
What is the main intravenous hypnotic in use today?
What are the main characteristics of propofol?
Presented as a white emulsion
Produces rapid onset of sleep but wears off in 5 minute because of rapid redistribution
Anaesthesia is then maintained by the introduction of a volatile or by a continuous infusion of propofol
What are the side effects of propofol?
Loss of airway reflexes and cardiovascular depression make this a drug that should only be used by skilled practitioners
What are the main features of thiopentone?
First intravenous induction agent which is now out of fashion
Rapid predictable onset of action
Some problems with cardiovascular depression and loss of airway control
Also,disaster if injected subcutaneously or intrarterially
Which is the only depolarizing muscle relaxant?
What are the characteristics of suxamethonium?
Rapid onset and rapid offset
Metabolize by plasma pseudocholinesterase
Individuals deficient in the enzyme exhibit prolonged relaxation with the risk of awareness
Remains best drug to use in an emergency despite side-effects
What is the minor side-effect of suxamethonium?
What are the major side-effects of suxamethonium?
Especially in people with muscle disorder
What are the main representatives of non-depolarizing muscle relaxants?
Atracurium and vecuronium
What is the duration of action of modern non-depolarizers?
30 to 45 minutes
What is the mechanism of action non-depolarizing muscle relaxants?
Antagonize acetylcholine at the nicotinic cholinergic receptor in the neuromuscular junction
Reversed by an acetylcholinesterase inhibitor
How do local anaesthetics work?
Work by blocking the sodium channel in the neural axons
Hence the action potential cannot be conducted
What are the main examples of local anaesthetics?
What are the main characteristics of lignocaine?
What are the main characteristics of Bupivicaine?
safer than lignocaine provided it is not given intravenously
What are the main side effects of local anaesthetics?
Practically no major local side effects
Large doses injected intravenously can result in seizures and ventricular fibrillation
Which adjuvant used in anaesthesia?
What is the mechanism of action of adrenaline during surgery?
Causes vasonstriction and renders the surgical field dry and also reduces uptake of drug into the bloodstream.
Therefore a higher dose can be used
What are the main examples of benzodiazepines used in anaesthesia?
What are the effects of benzodiazepines?
Hypnosis in larger doses
Rapid-acting and of short duration
Works rapidly and also wears off rapidly due to high-lipid solubility
Long duration of action
Why are some benzodiazepines useful premedicants?
Temezaepam and lorazepam can both be given orally.
Temazepam has a short duration of action
What are the main features of psychoactive drugs?
Drugs that alters one's physiological state.
Can be helpful in certain circumstances.
Some are legal: alcohol,nicotine,caffeine.
Abusers tend to be polyabusers.
Can result in addiction or dependance.
Which are the four criteria of substance abuse?(1 of 4)
Recurrent substance - related failure to fulfill major obligations at work,school or home.
Recurrent substance use in physically dangerous situations
Substance related legal problems.
Continued substance use despite social or interpersonal problems caused by the effect of the substance.
Which are the 7 criteria of substance dependance?(3 of 7)
Preoccupation with the substance(great deal of time spent in substance related behaviour)
Take more of the substance than they intended.
Persistent desire or effort to control substance use.
The abandonment of important social,occupational or recreational activities for the sake of substance use.
Continued substance use despite serious related problems.
What is an addiction?
A state in which an organism engages in a compulsive behaviour.
Even if faced with negative consequences.
Behaviour is reinforcing or rewarding.
Loss of control in limiting intake.
What is tolerance?
State in which an organism no longer responds to a drug
A higher dose is required to achieve the same effect
What is the classification of psychoactive drugs?
What is the aetiology of drug addiction?
Major predictors of becoming addicted is the level of stress a person is trying to cope with.
What is the risk of addiction also driven by?
Other biologic factors : the environment, and social context in which drug use is occurring.
What are the components of 'Reward Pathway'?
Ventral tegmental area, nucleus accumbens,prefrontal cortex.
VTA more than NA and the prefrontal cortex via the Medial forebrain bundle(MFB).
Dopamine is the neurotransmitter in this pathway
What is the role of dopamine in the reward pathway?
Important role in mood regulation,affect,motivation and reward processes
What is the role of mesolimbic dopamine system?
Important for motivational processes
What are the main features of the mesolimbic dopamine neurons?
Cells are spontaneously active - action potential are constantly generated at a slow rate.
This activation is responsible for normal affect and mood.
Some addictive drugs produce their effect on behaviour by enhancing mesolimbic dopamine activity.
What are the immediate effects of alcohol abuse?
Depressant or Belligerent
Slowed physical activity
What are the long-term effects of alcohol abuse?
Erodes personality,impairs mental,emotional and social capabilities.
Results in psychiatric illness.
Physical problems : Stomach ulcers,hypertension, heart failure,cancer,brain damage.
How can heroin be self-administered?
What are the withdrawal symptoms of heroin?
After 4 to 6 hours : chills,sweating,runny nose and eyes, abdominal cramps, muscle aches, insomnia, nausea and diarrhea.
What is the effect of heroin in pregnancy?
Stillbirths or premature deliveries
What are the symptoms of babies born with withdrawal syndrome?
poor feeding and convulsions
What is the mechanism of action of heroin?
Heroin increases neuronal firing rate of dopamine cells.
Increased number of action potential produce an increase in dopamine release.
Relaxation,sense of well being, mood elevation and euphoria, relief from anxiety and pain.
Addiction is mediated via reward pathway.
What is tolerance?
A higher dose is required to achieve the same effect
A state in which an organism no longer responds to a drug
What is dependance?
A state in which an organism functions normally only in the presence of a drug
Manifested as a physical disturbance when the drug is removed/withdrawn
When does dependence develop?
Develops when the neurons adapt to repeated drug exposure and only function in presence of drug
What are the short-term effects of cocaine,crack and amphetamines?
Euphoria,giddiness,boastfulness,self-consciousness(lasting 30 minutes) then mild euphoria,anxiousnss lasting 60 to 90 minutes.
Loss of coordination,tremors and seizures.
Initial elevation of mood fades,and depression emerges.
Effect felt in 10 seconds of smoking crack.
What are the long-term effects of cocaine,crack and amphetamines?
Toxic Paranoid Psychosis - anxiety,sleep deprivation,hyperactivity,aggression,homicidal tendency
What are the long-term risks of cocaine,crack and amphetamines?
Violent,erratic and paranoid behaviour, permanent vegetative state.
What are the binding sites of cocaine in the brain?
Ventral Tegmental Area
Which pathway do cocaine addiction and dependance involve?
Both involve the reward pathway
What is the mechanism of action of cocaine?
Cocaine inhibits the reuptake of dopamine,norepinephrine and serotonin.
Increased availability of dopamine in synapse increases dopamine's action on postsynaptic neurons - mood elevation and euphoria
Serotonin binding provides additional reinforcement
Effect is usually short lived
What is the short term effect of ecstasy?
Changes brain chemistry and behaviour
What is the long term effect of ecstasy?
Changes brain structure and behaviour
What are the main effects of ecstasy on the brain?
Can cause anxiety and altered perception
Positive effects : warmth and empathy
Which is the major target of ecstasy?
How many types of serotonin receptors are available?
What is the effect of the binding of serotonin to its receptor?
Causes a change in electrical properties of receiving neuron resulting in a decrease in its firing rate
Serotonin is removed from the synaptic space via special proteins called transporters
Transporters are the primary targets of ecstasy
What is the effect of ecstasy on serotonin transporters?
Prevent transporters from carrying serotonin back into the terminal
Cause the transporter to work in reverse mode -bring more serotonin from the terminal into the synaptic space
Inhibit dopamine transporter - increasing dopamine in synaptic cleft
What are the short-term adverse effects of ecstasy?
Adverse effects mediated via neocortex and limbic system,spinal motor neurons
Sweating, thirst, increased heart rate, fatigue, muscle spasms, hyperthermia
What are the life threatening effects of multiple doses of ecstasy?
What is the main effect of long term ecstasy use?
Impairment of memory
What is the action of Cannabis on CNS and PNS in low dose?
Euphoria,heightening of subjective sensory experiences, alteration in time sense, relaxed passivity
What is the action of Cannabis on CNS and PNS in high doses?
Impairment of memory, disturbed thought patterns, low attention and concentration, feeling of unfamiliarity and cataplexy
What is the action of Cannabis on PNS?
Tachycardia, increased blood pressure
Decrease intraocular pressure
What are the long-term effects of Cannabis?
Male infertility : decreased testosterone and sperm count
Cancer of lung
Increased risk of schizophrenia
Where does tetrahydrocannibol bind?
THC receptors concentrated in the reward pathway, hippocampus, caudate nucleus and cerebellum
To which receptors does cannabis bind to?
Canniboid receptors - CB1 and CB2
What are the properties of CB1(central)?
Cerebellum and substania nigra(motor disturbance)
Mesolimbic pathways(reward pathways)
What are the properties of CB2?
Mainly in lymphoid tissue
What are the properties of canniboid receptors?
G-Protein Coupled Receptors, linked to cAMP, Potassium ion channel activation, Calcium ion channel inhibition
Inhibition of synaptic transmission
What are the risk factors for drug abuse
Chaotic home environments
Lack of mutual attachments and nurturing
Inappropriate behaviour in classrom
Failure in school performance
Poor social coping skills
Affiliations with deviant peers
Perceptions of approval of drug using behaviours in school,peer and community environments
What are the protective factors for drug abuse?
Strong family bonds
Success in school performance
Conventioinal norms about drug use
What are the four types of substance abuse treatment?
Pharmacological ( against withdrawals and physical consequences)
How are acute withdrawal symptoms decreased?
Opiates : methadone
Alcohol : benzodiazepines
Amantadine : cocaine
What is the the long-term substitute for opiate addiction?
What is the long-term substitute for heroin addiction?
What are the properties of buprenorphine
Partial agonist at muscarinic opiod receptor and a weak antagonist at the kappa opiod receptor
What are the properties of LAAM?
Synthetic opioid that can be used to treat heroin dependance but needs only be taken three times per week
What is the pharmacological treatment to block the acute rewarding effect?
Naltrexone - blocks effect of opiate. used after supervised detoxification
Immunisation against cocaine(Anti Bodies block effect of cocaine)
What is the pharmacological treatment to reduce craving?
What medications are available to treat tobacco addiction?
Nicotine replacement therapies
What medications are available to treat alcohol and drug addiction?
What are the components in psychological treatment of drug addiction?
Group treatment(residential and non-residential)
Social interventions and family therapy
What is the motivation to enter or sustain treatment for drug addiction?
Effective treatment need not be voluntary
Sanctions or restrictions by family,employer can increase treatment entry
Treatment outcome same in who enters voluntarily or under legal pressure
What are the factors affecting drug permeability in dermal pharmacokinetics?
Diffusion of drug from vehicle to surface of the skin(vehicle-dependant)
Partitioning of the drug between vehicle and stratum corneum(drug dependant)
Stratum corneum(thickness,hydration and integrity of the stratum corneum)
What are the factors affecting systemic absorption in dermal pharmacokinetics?
Surface area to body weight ratio
Systemic effects(e.g. suppression of pituitary-adrenal axis in children)
Transdermal delivery systems
What are the three types of external formulation?
What are the two phases in disperse systems?
What are the different disperse systems available for use in dermatology?
Foam - disperse phase is air and continuous phase is liquid or solid
Water in oil emulsion - disperse phase is water and continuous phase is oil
Oil in water emulsion - disperse phase is oil and continuous phase is water
Gel - disperse phase is liquid and continuous phase is solid
What are the main features of lotions and wet dressings?
Used to clense,cool and relieve itch
Water is the most important component
May produce excessive dryness after evaporation
What are the main examples of lotions and wet dressings?
What are the main features of oil-in-water creams?
Hydrating and emollient
Vehicle for water-soluble drugs
Suitable for hairy areas
mix with serous discharge
Contain anti-oxidant and antimicrobial chemicals which may be sensitizing?
What is an example of an oil-in-water cream?
Aqeous Cream B.P
What are the main features of water-in-oil cream?
Spread easier than ointments
Useful barrier preparation
Vehicles for lipid soluble ingredients
Hydrate the skin by occlusion
What are examples of oil-in-water cream?
What are the features of ointments?
Greasier than creams
Hydrate stratum corneum by occlusion
Fewer preservatives mean less sensitization
What are the three kinds of ointments?
What are the features of pastes?
Stiff,semi-occlusive ointments containing powders which stick to lesion
When used as vehicles, active ingredients do not spread to surrounding skin
What is an example of a paste?
Dithranol in Lassar's paste
What are the features of collodions?
Main component is cellulose nitrate in an organic solvent
Flexible film holds active ingredient in place
Irritant and inflammable
What is an example of a collodion?
Salicylic acid and lactic acid paint for warts
How is activity of the basic corticosteroid moiety enhanced?
Fluorination of 9 position
Unsaturated bond between C1 and C2
Modification of side chains(especially in position 2)
What is the mechanism of action of corticosteroids?
Corticosteroids bind to cytoplasmic receptor
The steroid-receptor complex enters the nucleus and interacts with glucocorticoid response elements
Transcription of numerous genes is altered in various cell types
Cells affected include components of the immune system,fibroblasts, and endothelial cells(i.e. the effect is not selective)
What is the mode of action of adrenocortical steroids?
Inflammation is suppressed
What are the indications for adrenocortical steroids?
Other inflammatory conditions(lichen planus,lichen simplex,discoid lupus erythematosus)
What are the contraindications for adrenocortical steroids?
What are the local adverse effects of topical steroids?
Short-term(infection may be spread)
Long-term(atrophy&striae disease,hirsutism,peri-oral dermatitis,steroid rosacea,depigmentation,tachyphylaxis and rebound phenomenon)
What are the systemic effects of topical steroids?
Systemic absorption with hypothalamic-pituitary-adrenal axis suppression
What are the four variants of potency of topical steroids?
What is an example of a mild topical steroid?
What is an example of a moderate topical steroid?
What is an example of a potent topical steroid
What is an example of a very potent topical steroid?
What are the practical guidelines for the use of topical corticosteroids?
Symptomatically not prophylactically
Avoid potent steroids on the face,neck and intertriginous areas
Combine with anti-microbials or anti-fungals if necessary
Use sparingly(once or twice daily)
Prescribe small amounts to avoid abuse
Beware of occlusive dressings which enhance absorption
Avoid long-term use
Systemic analogue of calcitriol(vitamin D)
Inhibits cell proliferation and and encourages cell differentiation
When is calcipotriol indicated?
Indicated in mild to moderate plaque psoriasis
How is calcipotriol administered?
More than 100 grams per week may cause hypercalcemia
May be combined with topical steroid
What is a side-effect of calcipotriol?
What are examples of calcineurin inhibitors for topical use?
Tacrolimus ointment(protopic) and pimecrolimus cream(elidel)
What are calcineurin inhibitors indicated for?
Provide effective, well-tolerated treatment for mild to moderate atopic dermatitis, and promise to improve it's long-term management
Safe in children and sensitive skin areas
What is the mechanism of action of calcineurin inhibitors?
Prevent T-cell activation and suppress the release of pro-inflammatory lymphokines(i.e selective immune-modulation)
What is the side-effect of calcineurin inhibitors?
Increased risk of lymph node and skin malignancy
What are the systemic drugs involved in dermatology?
Immunosuppressive and cytotoxic drugs
Which are the first generation H1 receptor antagonists?
Which are the second generation H1 receptor antagonists?
Which are the third generation H1 receptor antagonists?
What is an example of an H2 Receptor antagonist?
What are the 3 roles of antihistamines?
What are the main features of the antibiotics involved in dermatology?
Should inhibit the growth of bacteria without harming the host
Must penetrate the body tissues in order to reach the bacteria(bioavailability)
May have a narrow,broad or extended spectrum
May be bactericidal or bacteriostatic
What may antibiotic resistance be due to?
What are the adverse effects of antibiotics due to?
Due to changes in normal body flora
What are the possible site of action of antibiotics?
Cell membrane integrity
Cell wall synthesis
Nucleic acid structure and function
Production of a key metabolite
What are the groups of antibiotics involved in dermatology?
Beta lactams ( penicillin,cephalosporin)
Polypeptides ( bacitracin)
Protein synthesis inhibitors ( tetracyclines, erythromycin, clindamycin)
Quinolones and other drugs(ciprofoxacin)
Which are the sex steroids used in the treatment of dermatological patients?
Anabolic steroids(danazol, stanazolol)
Anti-androgens(cyproterone acetate, finasteride)
What is the role of oestrogen in the hormone therapy of acne?
Reduces the production of androgens by suppressing the production of hypothalamic/pituitary gonadotrophin
What is the role of cyproterone in the hormone therapy of acne?
Blocks the effect of androgens. Since cyproterone would feminise a male foetus, it is combined with ethinyloestradiol in a contraceptive pill
What are the main features of psoralens?
Methoxsalen are plant products which are used to induce photochemical reaction in the skin
Psoralens may be applied topically or given by mouth
UVA exposure is necessary for activation(PUVA)
What does PUVA produce?
Inhibits DNA synthesis
Where is PUVA used?
Cutaneous lymphoma(mycosis fungoides)
What is the mode of action of methotrexate?
Competitively inhibits dihydrofolate reductase
What is the main indication for methotrexate?
How is methotrexate administered?
What are the side-effects of methotrexate?
Bone marrow suppression
What is the mode of action of cyclosporin?
What are the indications for cyclosporin?
Severe atopic eczema
What are the side-effects of cyclosporin?
Which are the first generation retinoids?
Tretinoin(retinoic acid, Retin-A)
Which are the second generation retinoids?
Which are the third generation retinoids?
What are the functions of retinoids?
Regulation of cell proliferation
Regulation of cell differentiation
Activation of tumour suppressor genes
What are the indications in dermatology for retinoids?
Severe forms of acne
Disorders of keratinization(Ichthyoses and Pityriasis rubra pilaris)
What are the side effects of retinoids?
What is the mechanism of action of isotretinoin in acne?
Half life is 15 hours
Highly effective when given over 4 months
What is isotretinoin indicated for in acne?
What are the necessary precautions before administering isotretinoin?
Fasting lipids before and during therapy
Contraception 4 weeks before starting treatment and 4 weeks after stopping
What is the risk of foetal abnormalities with the administration of isotretinoin?
25% risk of foetal abnormalities
What are the main features of itraconazole?
Triazole antifungal agent
Inhibits the fungal cytochrome P450 oxidase-mediated synthesis of ergosterol
Effective by mouth
Drug interactions possible
What does itraconazole pulse therapy involve?
Three weekly pulses of itraconazole over 3 months to keep the concentration of the drug in the nail above the Minimal Inhibitory Concentration 90 for several months, allowing the toe nail to grow out normally
What are the main features of terbinafine?
Synthetic allyamine antifungal
Highly lipophilic and accumulates in nails
What is the mechanism of action of terbinafine?
Inhibits the fungal squalene epoxidase synthesis of ergosterol
By which routes is terbinafine administered?
Effective topically and by mouth
What are the side-effects of terbinafine?
They may complicate long-term use
Which are the recombinant DNA biologics in medicine?
Signalling proteins e.g. erythopoeitin
Monoclonal antibodies e.g. etanercept (TNF antagonist)
Fusion proteins e.g. denileukin diftitox(Diphteria toxin-interleukin-2)
What is the indication for etanercept
Used for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease
What is the mechanism of action of etanercept?
Monoclonoal antibody which works as a TNF antagonist
What are the main concerns about biologics?
Adverse cardiovascular events
Paroxysmal disorder of the CNS characterized by abnormal cerebral neuronal discharges with or without loss of consciousness.
What are the two types of seizures?
Occurrence of two or more unprovoked seizures
What is the treatment goal of epilepsy?
To make the patient be completely seizure free without significant side-effects
What is the incidence of seizures?
Approximately 80 per 100,000 per year
What is the lifetime prevalence of seizures?
9% (1/3 benign febrile convulsions)
What is the incidence of epilepsy?
45 per 100,000 per year
What is the point prevalence of epilepsy?
0.5 to 1%
Which are the two groups of glutamate receptors?
What is the main feature of ionotropic glutamate receptor?
Fast synaptic transmission
What is the main feature of metabotropic glutamate receptor?
Slow synaptic transmission
Modulation of synaptic activity
What are examples of ionotropic glutamate receptors?
Gated Calcium ion and Sodium ion channels
What are examples of metabotropic glutamate receptors?
Regulation of second messengers(cAMP and Inositol)
Major inhibitory neurotransmitter in the CNS
What are the two types of GABA receptors?
What are the features of GABA-A receptor?
Specific recognition sites
Linked to chloride channel
What are the features of GABA-B receptor?
Medial by potassium ion currents
Causes pre and post-synaptic inhibition by inhibiting calcium ion channel opening and increasing potassium ion conductance
What are the factors modifying neuronal excitability?
Modulation of gene expression (e.g. for receptor proteins)
Remodelling of synapse location or configuration by afferent input
Modulation of transmitter metabolism or uptake by glial cells
Ion channel type, number and distribution and changes in extracellular ion concentration
Biochemical modification of receptors
Activation of second messenger systems
What is the pathophysiology of epilepsy?
Provoked or acute symptomatic seizures(head trauma, stroke,infection,alcohol,drug abuse, fever)
How is an epileptic syndrome defined?
EEG ictal and interictal
Response to Anti Epileptic Drugs
How is a seizure type determined?
Patient's behaviour during the ictal event
How are seizures classified?
Partial or Generalized
What are the main features of a partial seizure?
Begin in one hemisphere of the brain and may stay in that hemisphere or may spread to the other hemisphere i.e. secondarily generalized
What are the different types of partial seizures?
Simple partial - which occur without loss of consciousness
Complex partial - which are amnestic events
Both can secondarily generalize to a tonic clonic convulsive seizure
What are the main features of generalized seizures?
Begin in both hemispheres simultaneously
What are the four types of generalized seizures?
Tonic-clonic convulsive seizures
What are the signs to look out for during a seizure
Brief staring spells in which the child does not respond to direct attempts to gain his attention
Episodes of rapid blinking
Eyes rolling upwards
Periods of confusion
Sudden loss of muscle tone
Aimless dazed movement or repetitive movements
Inappropriate movements of mouth or face, accompanied by a blank expresion
Involuntary jerking of arm or leg
Graphical depiction of cortical electrical activity,usually recorded from the scalp
What is the advantage of EEG?
Advantage of high temporal resolution but poor spatial resolution of cortical disorders
What is EEG important for?
The most important neurophysiological study for the diagnosis,prognosis and treatment of epilepsy
What are the two main abnormalities in an EEG?
Background activity abnormalities
What are the background activity abnormalities?
Slowing not consistent with behavioral state(focal,lateralized or generalized)
What are the transient abnormalities?
Spike and slow wave complexes
May be focal,lateralized or generalized
What are the clinical features of simple partial seizures
No loss of consciousness may be preceded by an aura e.g twitching,jerking,déjà vu.
With motor signs, somatosensory or special sensory symptoms, autonomic symptoms or signs,psychic symptoms(disturbance of higher cerebral function)
What are the clinical features of complex partial seizures?
Automatisms e.g. swallowing,grunting,psychomotor(repeated movements),salivation,humming, may last up to twenty minutes. Impaired consciousness.
Clinical manifestations vary with site of origin and degree of spread.
Presence and nature of aura;Automatisms;Other motor activity; Duration typically 1 minutes
What are the clinical features of secondary generalized seizures?
Begins focally,with or without focal neurological symptoms
Variable symmetry,intensity and duration of tonic(stiffening) and clonic(jerking) phases.
Typical duration up to 1-2 minutes
Post-ictal confusion,somnolence,with or without transient focal deficit
What is the main feature of absence seizure?
absence(petit mal) patient is unconscious for few seconds, winking,staring,mostly in children
What are the main features of tonic-clonic(grand mal)?
Tonic phase - stiffing of limbs
Clonic phase - rhythmical jerking, foaming
Post ictal phase - body limb
What is the etiology of seizures and epilepsy in infancy and childhood?
Prenatal or birth injury, inborn error of metabolism,congenital malformation
What is the etiology of seizures and epilepsy in childhood and adoloscence?
Idiopathic or genetic syndrome, CNS infection, Trauma
What is the etiology of seizures and epilepsy in adoloscence and young adult?
Drug intoxication and withdrawal
What is the etiology of seizures and epilepsy in the older adult?
Acute metabolic disturbances(causes of acute symptomatic seizures, not epilepsy)
Which are the main seizure precipitants?
Metabolic and Electrolyte Imbalance
Stimulant/other proconvulsant intoxication
Sedative or ethanol withdrawal
Antiepileptic medication reduction or inadequate AED treatment
Fever or systemic infection
Concussion and/or closed head injury
What does the appropriate treatment of epilepsy and seizures require?
Accurate diagnosis - EEG, PET scan
Proper classification of seizure types following description by carers
EEG frequency and appearance description, EEG measurements very important
What are the principles of treatment in epilepsy?
Pharmacological i.e. medications
Surgical intervention - rare but possible
Extensive education and regular follow up with an encompassing view of individual's predicament is integral to success
What is important to inform patients of when being treated by anti-epileptic drugs?
Patients entitled to free medication under Schedule V(yellow cards)
On first therapeutic choice, 60% of patients become seizure free
With some dose/therapy adjustments it becomes 80%
Emphasis on monotherapy not polytherapy - patients are best controlled with one antiepileptic
Some drugs have severe side effects
Care in special populations e.g. children and pregnant women
Keep same doctor, many months need to adjust dose
What is the main mechanism of action of anti-epileptic drugs?
Elevation of threshold for seizure discharge
Reduction of excitation and spread of seizure discharge(glutamate)
Modify ion channels(sodium,potassium and calcium)
Which are the first generation anti-epileptic drugs?
Which are the second generation anti-epileptic drugs?
What are the factors that one should consider when choosing antiepileptic drugs?
Other medical condition
Expected adverse effects
What are the drugs used in partial seizures?
What are the drugs for tonic-clonic seizures?
What are the drugs for absence seizures?
What is the selection of anti-epileptic drugs based on?
Lower adverse reaction profile or a lesser potential for drug interaction than because it has been shown to be superior in reducing seizures
What is treatment failure with anti-epileptic drugs related to?
Side effects or inability to tolerate the anti-epileptic drug
Several studies have shown that CNS,neuropsychological, systemic and idosyncratic adverse events lead to treatment failure in up to 40% of patients
Which patients may become candidates for seizure surgery or vagus nerve stimulation?
An estimated 30 to 40% of patients continue to have seizures despite treatment with two or more AEDs
What is the ideal product profile of an AED and Factors favoring ease of use?
Effective in refractory patients
Low toxicity and no significant side effects
Interacts minimally with other drugs
Can easily be titrated
Works via a logical mechanism of action
Broad spectrum - no seizure aggravation
High efficacy,good tolerability
Friendly pharmacokinetics / once daily dosing
Availability of a friendly pediatric formulation
Availability of parenteral formulation
How do Anti-epileptic drugs exert their pharmacologic effects?
Acting on ion channels, enhancing inhibitory neurotransmitters, inhibiting neuroexcitatory transmitters or acting at specific receptor in the brain.
What is the mechanism of action of phenobarbital?
Decreases seizure activity by enhancing the effects of gamma-aminobutyric acid(GABA),prolonging the chloride channel opening, and blocking the sodium channel
What are the pharmacokinetics of phenobarbital?
rapidly and completely absorbed following oral doses; bound about 55% to plasma proteins and is distributed widely throughout the body
The half-life of phenobarbital ranges between 72 and 125 hours. Therefore it takes a long time to get to steady state, perhaps as long as three weeks, and dose changes must be made very gradually.
What are the side-effects of phenobarbital?
CNS depression, resulting in sedation,lethargy, and cognitive impairment.
It has been associated with an increase in falls in the elderly.
Other side effects associated with phenobarbital are porphyria,folate deficiency,osteomalacia and megaloblastic anaemia.
What is phenytoin mostly used in?
Treatment of primary tonic-clonic seizures,especially status epilepticus and partial seizures
What are the pharmacokinetics of phenytoin?
Michael-Menten(metabolism of the drug saturates)
Once administered, any additional remains in the circulating blood and is available for transport to the receptor sites
90% bound to plasma proteins
Dosage titration must be done carefully with close patient monitoring
What are the side-effects of phenytoin?
Fatigue,lethargy,blurred vision,drowsinesss,incoordination and nystagmus,gingival hyperplasia,hirsutism,acne,osteomalacia,folic acid deficiency and coarsening of facial features, appear to be more dependent on the duration of dosing
Stevens-Johnson syndrome,bone marrow suppression and hepatitis
What is the mechanism of action of carbamezapine?
acts by preventing repetitive firing of action potentials in depolarized neurons via use- and voltage-dependant sodium channels. It may also have some effect on the calcium channel
What are the main indications of carbamezapine?
It has been used to treat simple,complex and secondarily generalized seizures and primary tonic-clonic seizures.
What are the pharmacokinetics of carbamezapine?
slow rate of dissolution
immediate-release tablets have slow and sometimes erratic absorption
Absorption from the extended-release formulations have less fluctuations and lower peaks and higher troughs,which should result in better efficacy with lower side effects
Half-life of carbamezapine is significantly shorter after repeated dosing(autoinduction)
Protein binding - 10 to 50%
What are the side effects of carbamezapine?
What are the side-effects of carbamezapine associated with?
Extended release formulations that lower the peak may decrease the incidence of these Anti-epileptic drugs
Other side effects include skin rash, hyponatremia and very rarely bone marrow suppression
What is the mechanism of action of valproic acid?
Accelerates GABA-nergic function by potentiating the effects of GABA. It also reduces sustained,repetitive neuron firing by a use- and voltage-dependent effect on sodium channels
What is valproic acid indicated for?
Broad-spectrum anti-epileptic drug and has been used for all types of generalized seizures including absence, myoclonic and partial seizures and prophylaxis of migraine headaches and bipolar disorder.
What are the pharmacokinetics of valproic acid?
Well absorbed following oral administration and has a bioavailability of greater than 90% compared with an I.V dose
Valproic acid is about 90% bound to albumin at concentrations up to about 75micrograms per mL
What are the side-effects of valproic acid?
thinning or loss of hair
menstrual irregularities including amenorrhoea
Liver toxicity occurs primarily in children less than three years of age
What are the advantages of the newer anti-epileptic drugs over the older first generation anti-epileptic drugs?
Broad spectrum of activity
Fewer side effects and better tolerability
Increased ease of use
Lack of drug interaction
Little liver metabolism and no toxic metabolites
Rapid titration and less frequent dosing schedules
No Therapeutic Drug Monitoring needed
What is the mechanism of action of lamotrigine?
Selectively blocks the slow,inactivated state of the sodium channel, which inhibits the release of glutamate and aspartate
What are the indications of lamotrigine?
Effective in all seizure types including partial seizures,primary generalized tonic-clonic seizures,absence seizures and myoclonic seizures. It is approved for use in patients with Lennox-Gastaut syndrome,bipolar disorder,mood stabilizer
What are the pharmacokinetics of lamotrigine?
Absorption achieves bioavailability of about 98%
Half-life of this agent is about 22 hours in drug-naïve volunteers
Half-life is shorter in patients taking enzyme-inducing drugs such as phenytoin and carbamezapine and much longer in patients taking enzyme-inhibiting drugs such as valproic acid
About 55% bound to plasma proteins
What are the side-effects of lamotrigine?
Ataxia,somnolence,headace,diplopia and blurred vision
What is the mechanism of action of Topiramate?
Modulates the sodium ion channels,potentiates GABA,attenuates kainate-induced responses at the glutamate receptor, modulates Ca ion channels,inhibits brain carbonic anhydrase
What is topiramate effective in?
Partial and primary generalized tonic-clonic seizures.
And myoclonic seizures,atonic seizures associated with Lennox-Gustaut syndrome, and possibly infantile spasms and prophylaxis of migraine
What are the pharmacokinetics of topiramate?
Rapidly absorbed and has a bioavailability of 81% to 95% ( administration with high fat meal decreases the rate)
Half-life(normal renal function) 19 to 23 hours
Half-life(patient taking enzyme-inducing AEDs) 12 to 15 hours
What is recommended in patients who are taking topiramate and have moderate-to-severe renal dysfunction?
50% dose reduction
What are the side effects of topiramate?
Ataxia, poor concentration, confusion, dysphagia, dizziness, fatigue, paresthesia, somnolence, word-finding difficulties, and cognitive slowing.
Anorexia,weight loss,renal stone,metabolic acidosis,open-angle glaucoma, and decreased sweating
What is the role of levetiracetam?
Inhibit burst firing without affecting normal neuronal activity
Drug may have some effect on the potassium channel or high-voltage calcium channels
What are the pharmacokinetics of levetiracetam?
Peak concentrations are reached in about one hour
Apparent bioavailability is 100%(with food rate is decreased)
66% of dose excreted unchanged in urine(dose alteration in renal impaired patients)
Half life ranges between 6 to 8 hours
No protein binding,no drug interactions
What are the side effects of levetiracetam?
Psychiatric and behavioral events such as emotional lability, nervousness and hostility have also been reported
What is felbamate effective in?
Treatment of partial seizures,primary tonic-clonic seizures and atonic seizures in patients with Lennox-Gustaut syndrome.
Use is restricted due to side effects, still available.
What are the pharmacokinetics of Felbamate?
Rapidly and well absorbed following oral administration
40 to 50% of dose excreted unchanged in urine(rest metabolized by liver)
What are the side effects of Felbamate
Drug was associated with aplastic anemia and hepatotoxicity
What is the mechanism of action of gabapentin?
It interacts with a specific high-affinity binding site that is an auxilliary protein subunit of the voltage-gated calcium channel
What is gabapentin primarily used for?
Used primarily to treat seizures,neuropathic pain and other pain syndromes, spasticity,restless legs syndrome,tremors,mood disorders and anxiety
How is gabapentin metabolized?
Gabapentin is not metabolized and is completely eliminated by renal elimination. Patients with decreased renal function will have a decreased clearance of gabapentin
No plasma protein binding
No significant drug interaction
Does not induce or inhibit drug-metabolizing enzymes
What are the side-effects of gabapentin?
Behavioral disturbances especially aggressive behavior have been reported in children
What are the chemical properties of oxcarbezapine?
structural analogue of carbamezapine.
Prodrug that undergoes presystemic reduction to the monohydroxylated derivative(MHD)
MHD is the active form of oxcarbezapine
What is the mechanism of action and spectrum of activity of oxcarbazepine?
Similar to carbamezapine
What are the indications of oxcarbezapine?
Used in the treatment of partial,primary generalized tonic-clonic seizures, acute mania and for the prophylaxis of bipolar disorders and neuropathic pain
What are the pharmacokinetics of oxcarbezapine?
Peak concentration of oxcarbazepine occur in one to three hours and peak concentrations of MHD occur in four to six hours.
Clearance of MHD is decreased in patient with impaired renal function
Does not induce its own metabolism
What are the side effect oxcarbezapine?
somnolence,sedation,headache,dizziness,vertigo,ataxia,nausea,vomiting,fatigue,abnormal vision and diplopia.
Higher incidence of hyponatremia with oxcarbezapine than with carbamezapine
What is the mechanism of action of zonisamide?
broad-spectrum Anti-epileptic drug that has multiple mechanisms of action, including blocking voltage-dependent sodium channels, blocking voltage-dependent T-type calcium channels, and
actively inhibiting the release of excitatory neurotransmitters.
What is zonisamide indicated for?
used to treat a variety of seizure types including partial, primary generalized tonic-clonic, absence, atonic, and myoclonic seizures; pain and a variety of psychiatric disorders
What are the pharmacokinetics of zonisamide?
70% of zonisamide is metabolized and about 30% is eliminated unchanged in the urine.
Zonisamide has a half-life of 63 to 68 hours in healthy subjects. The half-life is shorter in patients taking enzyme-inducing drugs such as phenytoin and carbamazepine.
What are the side-effect of zonisamide
fatigue, dizziness, somnolence, anorexia, psychomotor slowing, and ataxia. Although the incidence of severe skin rash is very low, people with a true sulfa allergy should take the drug with caution.
Zonisamide has also been associated with renal stones, anorexia,weight loss, and oligohidrosis (decreased sweating)
What is the mechanism of action of pregabalin?
GABA derivative that does not act at either the GABA-A or GABA-B receptors. binds presynaptically to the alpha-2-
delta subunit of the voltage-gated calcium channel and modulates, rather than blocks, the influx of calcium in hyperexcited neurons.
This modulation reduces the release of several excitatory
neurotransmitters, including glutamate, noradrenaline, substance P, and calcitonin gene-related peptide.
What is the site of action of pregabalin?
The site of action of pregabalin is in the brain and spinal cord.
What are the pharmacokinetics of pregabalin?
Absorption of pregabalin is rapid and extensive. The oral
bioavailability is at least 90%.
Pregabalin is not extensively metabolized and more than 90% of an administered dose is excreted unchanged in the urine
Pregabalin does not bind to plasma proteins or induce or inhibit the metabolism of other drugs.
What are the side-effects of pregabalin?
dizziness and somnolence, ataxia, peripheral edema,
headache, and weight gain.
What is the efficacy spectrum of available AEDs?
Which antiepileptic drugs induce metabolism of other drugs?
What antiepileptic drugs inhibit metabolism of other drugs?
What antiepileptic drugs are highly protein bound?
When should AEDs be discontinued?
Seizure freedom for more than 2 years
What are the favorable factors in achieving successful withdrawal?
Control achieved easily on one drug at low dose
No previous unsuccessful attempts at withdrawal
Normal neurologic exam and E.E.G
Primary generalized seizures except Juvenile myoclonic epilepsy
More than 30 minutes of continuous seizure activity or Two or more sequential seizures spanning this period without full recovery between seizures
What are the epileptic encephalopathies?
Myoclonic epilepsies of infancy and early childhood
What are the two types of febrile convulsions
What are the features of a simple febrile convulsion?
Duration less than 15 minutes
Do not recur within 24 hours
What are the features of a complex febrile convulsion?
Duration longer than 15 minutes
Focal in nature or recur within 24 hours
What are the points to take into consideration when administering AEDS in paediatrics?
Susceptibility to specific adverse effects
Age-related PK factors
Neonate : low protein binding
Possible decrease absorption if given with milk/formula
Children : faster metabolism
What steps should be taken before pregnancy in an epileptic female?
Attempt Anti-epileptic drug monotherapy with lowest effective dose
Folate supplementation(at least 1mg per day orally)
What steps should be taken during pregnancy in an epileptic female?
Monitor Anti-epileptic drug dose requirements to maximise seizure control
Continue folate supplementation
Consider prenatal diagnosis of fetal malformations
Vitamin K (10mg per day orally) starting at 36 weeks
General prenatal care
What are the AEDS-Oral contraceptive interactions?
Carbamezapine,phenytoin,phenobarbital,primidone,felbamate,oxcarbazepine and topiramate - reduce contraceptive efficacy
Lamotrigine - decrease serum lamotrigine levels
What are the special risk groups for anti-epileptic drugs?
Hepatic and renal disease
What are other precautions that need to be taken before administering anti-epileptic drugs?
Care with vaccination procedures
Inform surgeon prior to surgical intervention
Factors which may precipitate onset of seizures
Social consequences of the seizures
Other treatment e.g. homeopathy
regular discussions with parents and teachers,cooperations in medication taking, correct observations
A clinical term referring to a group of brain diseases that result in the progressive deterioration of cognitive functions.
These cognitive changes are commonly accompanied by disturbances of mood,behavior and personality
What percentage of the elderly population is affected with dementia?
2-3% at the age 65
Incidence doubles every 4 years in reaching 30% at 80 years
What are the different forms of dementia?
Alzheimer's disease (approximately 50-60%)
Dementia with Lewy bodies(approximately 10-15%)
Dementia secondary to disease
What are the risks of dementia?
Changes associated with ageing
Gender (alzheimer's disease : females more than males , Vascular dementia : males more than females)
Genetic (first degree relative increased risk)
Presence of ApoE4 gene
Medical history(Down's syndrome, HIV infection)
Low levels of mental stimulation,social activity and exercise
How is dementia diagnosed?
No single test to determine presence of dementia
Average time taken for diagnosis after symptoms appear: 20 months
Full physical examination and blood tests
Assessment of memory function : psychological test(MMSE)
Brain scan can check for anatomical changes in the brain
What are the features of early stage alzheimer's disease?
loss of short-term memory often leading to repeating information.
Confusion poor judgement, unwillingness to try out new things
What are the features of middle stage alzheimer's disease?
Increase in memory loss.
Failure to recognise or confuse them with others.
May become angry or aggressive
May experience hallucinations
What are the features of late stage alzheimer's disease?
Loss of memory almost complete
Difficulty in eating
Loss of speech
What is the mechanism of action of acetylcholinesterase inhibitors?
Increase acetylcholine that is present in low quantities in the brain of Alzheimer's disease patients by blocking its degrading enzyme
What are examples of AcetylChol-inhibitors?
What does rivastigmine also block?
butrylcholinesterase(BuCheE) which is elevated in alzheimer's disease
What are the side-effects of acetylcholinesterase inhibitors?
Loss of appetite(occur mostly in dose titration)
Gradual dose increase and administration with food is advisable
What is the role of glutamatergic neurotransmission?
Important in learning and memory
NMDA receptor non-competitive antagonist that blocks glutamate-associated neurotoxicity without blocking the physiological functions of the NMDA receptor
What are the indications of glutamatergic-system modifiers?
What are the side-effects of glutamatergic-system modifiers?
What are the characteristics of pharmacological agents commonly used in the management of alzheimer's disease
Memantine hydrochloride(Glutamatergic-system modifier)
What is the maximum dose of donepezil hydrochloride?
What is the maximum dose of rivastigmine tartrate
What is the maximum dose of galantamine hydrobromide
What is the maximum dose of memantine hydrochloride?
What is the inital dose of donepezil hydrochloride?
If tolerate: 10mg/day after 4 to 6 weeks
What is the inital dose of rivastigmine tartrate?
1.5mg twice daily
if tolerated: 3mg twice daily
If tolerated: 4.5mg twice daily
If tolerated: 6mg twice daily
What is the inital dose of galantamine hydrobromide?
4mg twice daily
If tolerated : 8mg twice daily
If tolerated: 12mg twice daily
(dose increase every 4 weeks)
What is the inital dose of memantine hydrochloride?
Initial dose : 5mg daily
If tolerated: 10mg daily
If tolerated: 15mg daily
If tolerated: 20mg daily
(dose increase every week)
What are the future treatment options for alzheimer's disease?
Inhibitors of BACE
Inhibiton of gamma-secretase
Aβ beta immunisation
Non-steroidal anti-inflammatory drugs
Inhibitors of BACE
Deletion of BACE gene in animal models completely abolishes Aβ beta production and deposition
Inhibitors of γ-secretase
Should also be considerd as a therapeutic possibility. However this enzyme is also involved in other processes typically involving notch protein, which is vital for cellular signalling(presenilin gene knockouts are lethal at this stage)
Reduced amyloid pathology in animal models(but not tau)
Clinical trials stopped in march 2003 due to encephalitis
Non-steroidal anti-inflammatory drugs and AD
AD is also a chronic neuroinflammatory disease.
Studies suggest that NSAIDs may be of benefit(? via inhibition of plaque formation)
What are the main symptoms of Parkinson's disease?
resting tremor, muscular rigidity and involuntary movements
Other symptoms include bradykines,postural disturbances and lack of facial expression
What is the main pathology in Parkinson's disease?
Loss of Dopaminergic neurons in the substantia nigra(appear dark due to the presence of neuromelanin).
Loss of these cells occurs in normal aging but significantly higher in Parkinson's disease
What is the mechanism of action of levodopa?
Dopamine does not cross the blood brain barrier
Given systemically it will produce no pharmacological effect
Levodopa(L-DOPA) the immediate precursors of Dopamine,enters the brain where it is decarboxylated to dopamine.
Available Dopamine will then interact with central dopamine receptors in the substantia nigra(only 1 to 3% of levodopa reaches brain due to breakdown by peripehral decarboxylase enzyme)
How is the peripheral conversion of L-DOPA to DA reduced?
Co-administration of carbidopa (Sinemet) which is a dopa decarboxylase inhibitor
What is Stalevo made up of?
What is levodopa particularly effective in?
What are the side-effects of levodopa?
What are the drug interactions of levodopa?
Not to be taken with MAO-A inhibitors due to possible hypertensive crises
Vitamin B6 should also be avoided as it increases the metabolism of levodopa
What are the contraindications of levodopa?
Glaucoma(it increases intraocular pressure)
What is the usual dosage regimen of levodopa?
Sinemet 25/100 (carbidopa 25mg/levodopa 100mg) tds up to Sinemet 25/250 tds, one hour before meals
What is the role of dopamine receptor agonists?
Drugs acting directly on dopamine receptors may have a beneficial effect in the management of Parkinson's Disease
Have important role as first line therapy in Parkinson's Disease
Most often introduced with levodopa therapy(this enables the reduction of levodopa dose)
What are the available dopamine receptor agonists?
What is the usual daily dose of Bromocriptine?
Usual daily dose 7.5 - 30mg depending on response and tolerance
Mainly D2 agonist
What is daily dose of Pergolide?
Mainly D1 and D2 agonist
More effective than bromocriptine but associated with valvular heart disease
What is pramipexole effective in?
Effective in mild PD with possible neuroprotective effects
What is the daily dose of Pramipexole?
Mainly D3 agonist
May be associated with renal problems
What is Ropinorole effective in?
Mild PD and in combination with L-DOPA therapy
What is the daily dose of Ropinorole?
Dose 2-8mg tds
What are the adverse effects of dopamine receptor agonists?
headache are all adverse effects associated with dopaminergic agonism
What are the contraindications of dopamine receptor agonists?
recent myocardial infraction
active peptic ulceration
What is the mechanism of action of MAO-A?
Metabolises noradrenalin and serotonin
What is the mechanism of action of MAO-B?
What is the mechanism of action of MAO-B inhibitors?
Stop the breakdown of DA in the brain
What are the monoamine oxidase inhibitors available on the market?
What is the standard dose of selegiline?
5mg with breakfast
5mg with lunch
What are the main features of selegiline
Mainly a MAO B Inhibitors in low doses[effects MAOA in higher doses]
Usually co-administered with levodopa
What is the standard dose of Rasagiline?
What is the main feature of rasagiline?
More potent and may be used as a protective agent in early Parkinson's Disease
Why should MAOAI be avoided with levodopa therapy?
Due to peripheral accumulation of Noradrenaline leading to hypertension
What is the mechanism of action of selective COMT inhibitors?
Reduce breakdown of molecules containing a catechol group such as dopamine
What is the mechanism of action of entacapone?
Inhibits peripheral COMT increasing the bioavailability of levodopa
What is the dose of entacapone?
What is the mechanism of action of tolcapone?
Inhibits both peripheral and central COMT
Slightly more potent and longer duration of action than entacapone
What is the dose of tolcapone?
What is tolcapone associated with?
What are the side effects of COMT inhibitors?
orange discolouration of urine
What is the role of apomorphine in the treatment of parkinson's disease
Potent dopamine agonist usually reserved for patients whom oral treatment is no longer effective
What is the clinical effect of apomorphine?
Within 10 minutes following injection
What are the side effects of apomorphine?
What is the mechanism of action of amantadine?
mode of action in Parkinsons Disease is unclear but may potentiate Dopamine release and inhibits reuptake
What is the main features of amantadine?
Less potent than levodopa and effects disappear after a few weeks
Reduces bradykinesia,rigidity and tremor
What is the standard dose of amantadine?
What are the side effects of Amantadine?
When is Amantadine contraindicated?
Contraindicated in heart failure
What is the role of acetylcholine-blocking agents in PD?
Antimuscarinic agents may improve the tremor and rigidity in Parkinson's Disease but have little effect on bradykinesia. These block the action of Acetylcholine in the striatum
How is dose of acetylcholine-blocking agents in PD administered?
Dose is titrated until benefits occur or adverse effects limits their use
What are the side effects of acetylcholine-blocking agents?
These often limit their dosing
They include confusion,drowsiness,agitation,hallucinations,dry mouth,blurred vision,memory problems.
Acute withdrawal leads to precipitation of acute parkinsonian effects
What is the mechanism of action in Drug-Induced Parkinsonism?
Chemicals that deplete biogenic monoamines from their storage site such as reserpine or drugs that block the dopamine receptor such as neuroleptics produce a parkinsonian syndrome that clear after drug withdrawal
Which neuroprotective agents are being investigated for Parkinson's Disease?
Vitamins A,C and E
Parkinson's disease vaccine
Which surgical method is consider for the therapy of parkinsons' disease?
Deep brain stimulation
Only 5 to 10% of Parkinson's disease patients are eligible for surgical intervention
Deep brain stimulation
Electrodes are inserted in the brain(usually the thalamus) and connected to a pulse generator.
This will control tremor and involuntary movements
What are the complications of deep brain stimulation?
What are the two types of spasticity that can develop in response to injury to the CNS?
What are the main features of the phasic phase?
Often initial manifestation of spasticity
Muscle has a normal lengthening reaction
What are the main features of the tonic phase?
Occurs months to years later
Decreased amount of stretch that can lead to contractures
In what diseases is spasticity observed?
Spinal Cord/Brain Injury
What are the main features of cerebral palsy?
Commonest cause of physical disability
Group of disorders
Non progressive disorder of movement and posture resulting from a brain injury in the early period of brain development 3 to 5 years
Enormous individual variation often associated with other disabilities
With what other disabilities is cerebral palsy associated with?
Visual and hearing difficulties
Behavioral or emotional problems
Communication and feeding difficulties
What are the main features of crouching gait?
Contractures at hip,knee and ankle
Child walks with flexed hip,knees and ankle in DF
Discrepant skeletal and muscle growth, joint contractures
What is a crouching gait caused by?
What are the disadvantages of a crouching gait
Highly unstable posture
High perusal of energy
Cosmetically poor or socially unacceptable
What are the four types of cerebral palsy?
What are the features of spastic cerebral palsy?
Diplegia (spasticity Lower Extremity more than Upper Extremity)
Quadriplegia ( spasticity Lower Extremity=Upper Extremity)
What are the features of dyskinetic cerebral palsy?
Abnormal writhing movement of limbs and face
Twisted position of trunk or limbs
What are the different gait patterns?
What are the main features of spastic quadriplegia?
Excessive pull of hip adductors and internal rotators
No standing stability
Dystonia of upper extremity
What is spastic diplegia usually a result of?
Characterisctically a result of periventricular leukomalacia in premature infants
What are the main clinical features of spastic diplegia?
Extreme toe walking - equinus foot
What are the main components of a waddling toe gait?
Fixed flexion deformity of hips
Fixed equinus feet
Standing with feet flat - backward angulation of ankles and compensatory hyperextension of the knees
What is the main cause of a waddling toe gait?
Spinal cord deformity
Which drugs are used for spasticity?
GABA ergic drugs(benzodiazepines and baclofen)
Which drugs interact with GABA-A receptors and channels?
Which drug is a selective GABA(B)-receptor agonist?
What is the mechanism of action of benzodiazepines?
Act centrally on GABA-A receptors binding to brain stem and spinal cord
What is the beneficial effect of benzodiazepines in movement disorders?
Improve passive range of motion and reduce hyperreflexia and painful spasm
What is the half-life of diazepam?
20 to 80 hours
What is the half-life of clonazepam?
Ranges from 18 to 28 hours
What are the side effects of benzodiazepines?
What are the chemical properties of baclofen?
A chlorophenyl derivative of GABA
What is the mechanism of action of baclofen?
Selective agonist at presynaptic GABA-B receptors
Antispastic action exerted mainly on spinal cord where it inhibits both mono-synaptic and polysynaptic activation of motor neurons
What are the main features of baclofen?
Effective if given by mouth,intrathecally via pump
Better for spasticity (spinal cord spasticity more than cerebral spasticity)
Tolerance may develop
Sudden withdrawal effects can cause seizures,hallucinations
What does baclofen improve?
Joint range of motion
When should one exercise caution when administering baclofen?
Caution in renal impairment as cleared by kidney, or when used with BZD or tizanidine
What are the side effects of Baclofen?
What is the site of action of dantroline?
Acts peripherally at the level of the muscle fibre
What is the mechanism of action of dantroline?
Affects the release of calcium from the sarcoplasmic reticulum of skeletal muscles and decreases contraction
What is dantrolene indicated for?
Spasticity of supra spinal origin e.g. cerebral palsy,traumatic brain injury
What are the pharmacokinetics of dantroline?
Peak effect in 4 to 6 hours
Half-life of 6 to 9 hours
What is the effect of dantrolene in movement disorders?
Decrease muscle spasm,tone and clonus
not specific to spastic muscle and can cause generalized weakness especially of respiratory muscles
What are the side effects of dantrolene?
drowsiness, dizziness, weakness, fatigue diarrhea
Potentially hepatotoxic < 1% of patients
What is the mechanism of action of tizanidine?
Central alpha 2-noradrenergic agonist, facilitates short-term vibratory inhibition of the H-reflex associated with antispasticity without weakness
What is tizanidine indicated for?
Indicated for spasticity of spinal origin: MS and spinal cord injury,decreased spasms and clonus and some effect in CVA patients
What are the advantages of Tizanidine
Less muscle weakness vs Baclofen & diazepam
Decreased Tone = to Baclofen and better than diazepam
What are the pharmacokinetics of Tizanidine?
Short acting with extensive first-pass hepatic metabolism and excreted by the kidneys.
Peak effect in 1-2 hours and half life is 2.5 hours
What are the side effects of Tizanidine?
dry mouth, drowsiness, asthenia
What are the adverse events that Tizanidine can cause?
Liver dysfunction and hallucinations are rare but serious adverse events
How is intrathecal baclofen delivered?
Baclofen to the intrathecal space when oral medication fails / Side effects
Drug is delivered via a programmable pump and doses needed are much lower than oral doses
When is intrathecal baclofen indicated?
Indicated in severe spasticity of spinal cord injury, stroke, MS, CP or brain injury
What should be done prior to implantation of intrathecal baclofen?
Prior to implantation a screening test dose of baclofen is given via lumbar puncture and effect monitored
What are the benefits of intrathecal baclofen?
Benefits include decreased tone, spasms and pain and increased mobility
Improved speech, sleep quality, bladder control and self-image
What are the side effects of intrathecal baclofen?
drowsiness, nausea, headache, weakness or pump malfunction
respiratory and cardiovascular depression, ataxia, sedation
When is botulinum toxin indicated?
Injected into specific muscles for the Rx of focal dystonias and spasticity.
What is the onset of effect of botulinum toxin?
Onset of effect within days of injection, peaking in approx 4 weeks and lasting 3-4 months
What are the side effects of botulinum toxin?
temporary discomfort, weakness, flu-like symptoms, loss of effect due to Anti-Bodies
What are the two types of dystonia?
What are the two types of primary dystonia?
What are the main disease which exhibit focal dystonia
Cervical torticollis, writer's cramp, blepharospam, cranial dytonias
What are the two types of generalized primary dystonia?
Primary: Dystonia Muscolrum deformans,
Segawa: Dopa Responsive dystonia Segawa's Disease: fluctuating symptoms with relative mobility in the morning to immobility by the evening. Mimics cerebral palsy
What are the features of secondary dystonia?
environmental or disease-related damage to the basal ganglia e.g. CO poisoning, heavy metal poisoning, HIE , Wilson's Disease
What are the features of torsion dystonia?
Postural abnormality of outstretched hand
Equinovarus Left foot
Which are the anticholinergic drugs used in dystonia?
Benzhexol Hydorchloride (Artane)
Benztropine Mesyalte (Cogentin)
What is the mechanism of action of the anticholinergic drugs used in dystonia?
Block the muscarinic receptors of acetylcholine
What are the side-effects of the anticholinergic drugs used in dystonia?
dry mouth, constipation, impaired vision urinary retention, drowsiness and confusion, tachycardia
Which are the GABA-regulating drugs used in dystonia?
Which are the dopaminergic drugs used in dystonia?
Which are the anticonvulsants used in dystonia
What are the features of a chorea?
Small, fidgety movements
Random, jerky movements.
Huntington's Disease(AD, progressive dementia & chorea)
What is the main feature in athetosis?
Throwing of the limbs of one side of the body
Usually due to Cerebrovascular Accident invloving the subthalamic nucleus
What are the three types of dyskinesias?
Which are the neuroleptic drugs used in chorea?
What is the mechanism of action of the neurolepti drugs used in chorea?
block dopaminergic transmission.
What is the main side effect of neuroleptic drugs used in chorea?
What is the mechanism of action of tetrabenazine?
deplete supply of dopamine,norepinephrine and serotonin in nerve terminals
blocks D1 and D2 receptors
When is tetrabenazine indicated?
used in dystonias, Huntington's chorea, tics
What are the side effects of tetrabenazine?
Parkinsonism, hypotension, depression, drowsiness, neuroleptic malignant syndrome
When are channel modulators indicated?
paroxysmal movement disorders such as periodic paralysis, episodic ataxia, alternating hemiplegia and paroxysmal dyskinesias which are probably caused by channelopathies
What are the available channel modulators available for use in chorea?
Acetazolamide, AEDs e.g CBZ, topiramate, calcium channel blockers
Which are the benzodiazepines used in chorea?
clonazepam, clobazam, diazepam
Sudden, abrupt, brief involuntary jerk-like contraction of muscle or group of muscles.
Where do myoclonus originate from?
May originate from cerebral cortex,brainstem or spinal cord
Interfere with performance of normal voluntary movements
What are the two types of myoclonus?
Primary myoclonus causes
Juvenile myoclonic epilepsy
Periodic leg Movements of Sleep
Secondary myoclonus causes?
Subacute Sclerosing Panencephalitis
Which drugs are used in myoclonus?
What is fluoxetine used for?
Cortical myoclonus e.g. neurodegenerative diseases
What are the side effects of fluoxetine?
defined as an involuntary, rhythmic oscillatory movement of part or parts of the body resulting from alternating or irregularly synchronous contractions of antagonist muscles
How are tremors classified?
A: Clinical - Rest / Action
B: Site - Chin, face
C: Relative frequency → number of repetitions of complete waveforms per sec
D. Syndrome classification:
What are the ranges in the relative frequency of tremors
Physiological: High frequency range 7-12Hz
Pathological: Low f range 2-7Hz
What is the syndrome classifcation of tremors
Parkinsonian: rest and postural / kinetic
Cerebellar: intention and postural
Midbrain: intention and postural and kinetic
Neuropathic: kinetic and postural
Task and position specific tremors
What drugs are used in essential tremor?
Benzodiazepines - lorazepam, clonazepam
Calcium channel blockers
Carbonic anhydrase inhibitors
Intramuscular Botulinum Toxin
What are the different types of tics?
Single / Multiple
Transient / Chronic
What investigation is done in the diagnosis of tics?
SPECT to check for hypoperfusion of caudate
Which drugs are used in the treatment of tics?
Clonidine: a2 adrenergic agonist
What is the ABCD of malaria prevention?
A - Awareness of risk.
B - Bite prevention.
C - Chemoprophylaxis.
D - Prompt diagnosis and treatment.
At what time of the day is the risk of getting bitten the highest?
The risk is greatest between dusk and dawn
What are the main elements in bite prevention?
Room protection: A/C, fans, window and door nets.
Clothing - long sleeved, long trousers, socks. May be sprayed with permethrin.
Pyrethroid-impregnated bed nets.
Repellants: 50% DEET lasts up to 12 hrs (after sunscreen).
Insecticides - Permethrin and other synthetic pyrethroids.
Buzzers, vitamins, garlic, tea tree oils and bath oils are not effective
What are the drugs used in chemoprophylaxis?
Atovaquone plus proguanil (Malarone®)
What does the choice of prophylaxis depend upon?
Patient specifications - e.g. age, pregnant, medical history, personal preference.
What is the treatment regimen with chloroquine?
300mg (2 tabs) weekly,
Start 1 week before travel to 4 weeks after return.
What is the mechanism of action of chloroquine?
Interferes with malaria pigment formation, forming a complex highly toxic to the parasite.
What may chloroquine precipitate?
May precipitate epilepsy, psoriasis and myasthenia gravis.
What are the main features of chloroquine?
Rarely used as a single agent for prophylaxis in view of resistance.
Side effects mostly G.I.
Acceptable in pregnancy and in infants.
What is the treatment regimen for chemoprophylaxis using proguanil?
200mg (2 tabs) once daily (with evening meal)
Start 1 week before to 4weeks after return.
What is the mechanism of action of proguanil?
Inhibits dihydrofolate reductase and interferes with the synthesis of folic acid.
What are the main features of proguanil?
Used in combination with chloroquine for sensitive areas.
Can be used in pregnancy + folate 5mg
Acceptable for infants (but no syrup)
What are the side effects of proguanil?
Acceptable side effects (GI, mouth ulceration, hair loss).
What is the treatment regimen for chemoprophylaxis using doxycycline?
Once daily (100mg) - Not with milk or iron.
Swallow whole with plenty of fluid or food whilst sitting or standing.
Start 1 to 2 days before to 4 wks after.
What is the mechanism of action of doxycycline?
Binds to rRNA and inhibits protein synthesis.
What is absolute contraindication of doxycycline?
Absolutely contraindicated in pregnant, lactating mothers and children less than 12 year.
What are the side effects of doxycycline
GI (may be severe), photosensitivity, vaginal candidiasis.
What is the treatment regimen of mefloquine?
Once weekly dose 250mg.
Start 3-4 weeks before to 4 weeks after leaving area.
Where is resistance for mefloquine observed?
Some resistance in areas of South-east Asia
In what group of patients can mefloquine be used?
Can be used from 3 months of age and over 5kg body weight.
Contraindicated in pregnancy and lactation.
Some scuba-diving centres may not permit those taking mefloquine to dive.
Not given to airline pilots
What are the side effects of mefloquine
neuropsychiatric, sleep disorders, GI, lowers seizure threshold.
What is the treatment regimen of atovaquone-proguanil(malarone)
Once daily dose 250/100mg
Start from 1 to 2 days before to 1 week after.
What is the mechanism of action of atovaquone-proguanil?
Works by inhibiting electron transport causing collapse in the mitochondrial membrane potential.
In what group of patients can atovaquone-proguanil can be used?
Used from 10kg.
Contraindicated in pregnancy and lactation.
What are the side-effects of atovaquone-proguanil?
well tolerated. G.I and headaches.
What are the side-effects of quinine?
Often causes nausea, impaired hearing and tinnitus (cinchonism) which may lead to non adherence.
With what drug does quinine need to be combined with for eradication of parasites?
Needs to be combined with doxycycline or clindamycin (pregnant or children) for complete eradication of parasites.
What does Riamet contain?
One tablet contains 20 mg artemether and 120 mg lumefantrine.
What should Riamet be taken with?
Should be taken with food or milk.
When is Riamet contraindicated?
Contrainicated with drugs that prolong the QT interval and in pregnancy.
What are the side-effects of Riamet?
Side effects include cardiac arrythmias, GI disturbances, headaches and dizziness.
How are benign malarias treated?
Chloroquine 600mg followed by 300mg at 6, 24, 48 hrs.
In vivax and ovale this should be followed by primaquine 30mg/day for vivax and 15mg/day for ovale for 14 days.
Check G6PD levels before.
Why is primaquine important in the treatment for the eradication of malaria parasite?
Important to destroy the hypnozoites (liver parasites) which cause relapses.
What are the side effects of primaquine?
Side effects include mainly G.I disturbances, rare leucopenia and methaemoglobinaemia.
What should one test for before administering primaquine?
Use with caution
What is the quadruple therapy for the treatment of tuberculosis?
Rifampicin 600mg daily (450 daily if less than 50kg) - 6 months
Isoniazid 300mg daily + pyridoxine 10mg - 6 months
Pyrazinamide 2g daily (1.5g if less than 50kg) - 2 months
Ethambutol 15mg/kg - 2m
What are the main features of rifampicin?
Transient rise in serum transaminases is common, occasionally severe hepatic dysfunction.
Induces liver enzymes - many interactions including phenytoin, OCP, warfarin.
Warn patient re. discoloration of urine and contact lenses.
Can be used in pregnancy and lactation
What are the main features of isoniazid?
Cheap, effective. Should always be included in regime.
Peripheral neuropathy is common especially in DM, alcoholics, CRF and malnourished. Add pyridoxine.
Can be used during pregnancy and lactation
What are the side effects of isoniazid?
G.I, hepatic and renal impairment, blood dyscrasias
What are the main features of pyrazinamide?
Bactericidal drug, only active against intracellular dividing forms of Mycobacterium tuberculosis
Used only in first 2 months
Good meningeal penetration
What are the side effects of pyrazinamide?
Occasional liver toxicity, fever, photosensitivity, G.I disturbances, rashes
What are the main features of ethambutol?
Reduce dose in severe renal impairment, elderly and pregnancy.
Test visual acuity before starting therapy and warn patient.
What are the side-effects of ethambutol?
gout, rash, loss of visual acuity, colour blindness and restriction of visual fields.
What advice would give a patient prior to starting anti-TB treatment?
Importance of compliance to medication.
Any interactions with medications. N.B. effect on OCP and warfarin
Be aware of discoloration of urine and tears.
Watch out for any visual problems.
Inform you if they want to stop medication due to side effects.
What are the two types of leishmaniasis?
How is severe cutaneous and mucocutaneous disease treated?
Sodium stibogluconate (Pentostam) 20mg/kg i.v for 28 days
Amphotericin B 1mg/kg i.v daily X 20 doses
Liposomal amphotericin (ambisome) 3mg/kg/day for 6 days (cut.), or 3 wks (mc.)
Miltefosine 2.5mg/kg p.o daily X 28 days
How is visceral leishmaniasis treated?
Liposomal amphotericin (ambisome) 3mg/kg/day days 1-5, day 14 and 21
Sodium stibogluconate (Pentostam) 20mg/kg I.V for 28 days
Miltefosine 1.5-2.5mg/kg po daily X 28 days
What are the main features of sodium stibogluconate?
An organic pentavalent antimony compound.
Avoid in severe renal impairment.
Monitor ECG during treatment - QT prolongation.
What are the side effects of sodium stibogluconate?
nausea, diarrhoea, anorexia, myalgia
What are the properties of liposomal amphotericin?
Lipid formulation of the polyene antifungal amphothericin.
Give a test dose first and gradually increase the dose.
Monitor renal function and electrolytes (low K+).
What are the infusion related side effects of liposomal amphotericin?
fever, chills, backache, flushing, chest tightness, SOB
Which are the main antihelminthics?
What is Mebendazole used for?
for threadworm, roundworm, whipworm and hookworm infections.
What is Praziquantel used for?
tapeworm (taenia) and Schistosomiasis.
What are the pharmacological considerations in elderly?
Three times as many drugs prescribed over age 65 years
Multiple drugs are usual, drug interactions common
Memory problems and confusion (or lack of patient education) a major issue
Need for highly individualized decision making
What should be avoided when prescribing in elderly?
Need to avoid polypharmacy and need of patient education
What physiological factors affect pharmacological therapy in the elderly
Increase in free drug in blood stream from reduced metabolism
Decreased tissue and protein binding
What are the elderly more susceptible to?
cerebral and myocardiali ischaemic effects
What are older persons more likely to?
More likely to experience adverse drug reactions
More likely to be taking multiple drugs with
potential drug interaction
Suffer serious and prolonged consequences of
the occurrence of the adverse effects of drugs
More sensitive to a variety of drugs acting on the
CNS: morphine, benzodiazepines
What is the effect of ageing on the kidney?
Renal function declines with age. About half the nephrons are lost between the ages of 30 and 70.
Reduction in renal function leads to impaired homeostasis, making the elderly much more vulnerable to the effects of dehydration.
Circadian rhythm of water excretion is lost leading to nocturnal diuresis
Which drugs are excreted by the kidney?
aminoglycosides - renal failure deafness
tetracyclines - catabolic urea increased
NSAID - renal failure, hypertension
Anti-cholinergics - acute confusional state
Diuretics - severe dehydration and electrolyte imbalance due to impaired homeostasis - often precipitate hospital admission
What is the effect of ageing on the liver?
Hepatic blood flow decreased with age
Mixed enzyme oxidase activity
Decreased first pass effect
Decreased microsomal activity
Which are the commonly used drugs in the elderly?
hypnotics and sedatives
What is the treatment of infrequent angina in the elderly?
low dose aspirin + sublingual tablet or spray
What is the treatment of stable angina in the elderly?
low dose aspirin + sublingual tablet or spray + B-blocker Calcium reflux blocker + nitrates
What are drugs used in ischaemic heart disease in the elderly?
Low dose aspirin
Calcium Channel Blockers
ACE inhibitors or ACE receptor blockers
Which are the cardiac glycosides?
What are the main features of digoxin?
Dose related to renal clearance
The geriatric tablet 62.5 micrograms seldom gives therapeutic concentration unless renal function is markedly compromised.
Often dose is around 125-250 micrograms
What are the main features of diuretics in the elderly?
Grossly overprescribed for mild hypostatic ankle oedema
Combination drugs do not contain enough potassium
Potassium sparing diuretics a more rational choice than adding potassium but monitor for hyperkalaemia
Hyponatraemia not uncommon resulting in confusion and falls
What is the usefulness of thiazide diuretics as an anti-hypertensive drug in the elderly?
Thiazide diuretics remain useful but complicate renal impairment; if creatinine clearance drops below 30 cc/min. no longer effective and make it worse
What is the usefulness of ACE inhibitor as an anti-hypertensive drug in the elderly?
very useful when LVH or CHF co-exist
What is the usefulness of loop diuretics as an anti-hypertensive drug in the elderly?
Less potent in elderly; the decreased number of nephrons leaves fewer sites for the loop diuretic to have effect. Works also when renal function falls below 50cc of GFR.
What is the usefulness of beta blockers as an anti-hypertensive drug in the elderly?
remain useful drugs and have a place in diastolic heart failure. Less potent in old people
What are the main indication of NSAIDS
Used in chronic arthropathies
What is the mechanism of action of NSAIDs
inhibition of prostaglandin biosynthesis via enzyme cyclo-oxgenase (COX) two isoforms - Cox 1 and Cox 2
What are the main adverse reactions of NSAIDs in the elderly?
Renal perfusion in elderly is dependent on
prostaglandin mediated blood flow.
heart failure and loss of control of hypertension
Proprionic acid derivatives - ibuprofen - fewer side effects but anti-inflammatory properties weaker.
Feldene should not be used because of its long ½ life.
What are the factors implicating the toxicity of NSAIDs
Erosions in stomach and duodenum
Bleeding or perforation with preceding warning symptoms
Neither enteric coating nor suppositories prevents these side-effects
Acute or chronic renal failure
Rashes, asthma, liver damage
What are the precautions that should be taken before using NSAIDs in elderly?
Weigh risks and benefits
Use only when all other treatments have failed
Avoid in dyspepsia, active peptic ulcer
Avoid in kidney or liver disease or CHF
Start lowest recommended dose
What are the objectives of pain control in palliative care?
Pain free at night
Pain free at rest
Pain free on movement
What steps should be taken to ensure adequate pain control?
Adequate dose of analgesic
Continuous pain needs continuous medication
Co-analgesics (psychotropic, steroids as necessary, muscle relaxants)
Consider non drug treatment (radiotherapy, nerve block, acupuncture, transcutaneous nerve stimulation
What analgesics are used in mild pain in the elderly?
paracetamol or aspirin
What analgesics are used in moderate pain in the elderly?
What analgesics are used in severe pain in the elderly?
morphine - most need it 4/hrly, start with low dose regime - MST tablets, rectally, pump
What should one exclude before treating insomnia?
restless leg syndrome
When choosing sedative drugs for the treatment of insomnia in elderly, what should one take into consideration?
intermediate half-life - temazepam
little indication for use of anti-anxiety pills - diazepam and lorazepam.
Patients should be warned about decreased alertness and possible impairment of gait, memory and cognitive function - risk of falls.
What are the main features of benzodiazepine prescription in the elderly?
good anti-anxiety agents but exacerbate dementia and can worsen agitation.
Chronic use is ineffective and withdrawal from long-term effects can cause delirium in the elderly.
Why should valium be avoided in the elderly
avoided because of too long half-life and accumulation is a risk. Ativian (lorazepam) better.
What are the main features of Trazodone?
good sedative, relatively free of withdrawal and delirium producing effects. Should be given in small doses and can be used in daytime for sedation.
What are the main features of Zolpidern tartrate(stilnox)
10mg tablets - those over 65 years 5mg
Due to rapid action, to be taken immediately before retiring
Short term treatment of insomnia - use not to exceed 4 weeks
What is the WHO definition of an adverse drug reaction?
A noxious, unintended effect of a drug that occurs in doses normally used in humans for the diagnosis, prevention or treatment of disease
How common are adverse drug reactions in the elderly population?
Twice as common in old people
Major cause of hospital admission
Poorly recognised by health professionals
What are the factors increasing risk of adverse drug rections in old age?
Multiple drug therapy
Small body size
Liver or kidney impairment
Previous adverse drug reactions
Why are old people susceptible to Adverse Drug Reactions?
Pharmaceutical factors - swallowing capsules
Age-related changes in drug handling, e.g. renal excretion
Age-related changes in drug sensitivity, e.g. increased sensitivity to warfarin and CNS drugs
Practicalities - vision and dexterity
Which are the commonly implicated drugs in adverse drug reactions?
Non-steroidal anti-inflammatory drugs
OTC(over the counter) drugs/self treatment
What are the factors that lead to problems of compliance in the elderly?
Multiple chronic illness
Multiple indications on a chronic basis
Visual impairment - special container
Inadequate information and instructions
Cost of drugs
What are the elements of safe prescribing for the elderly?
Know your drugs side-effects and doses
Use low starting dose
Simplify dose and drug regime
Review medication regularly
When in doubt, do not prescribe
When prescribing - balance benefit and potential risk
Proper clinical assessment - consider non-drug treatments
Dose - start low, go slow
Appropriate use of potentially beneficial therapy
Which are the golden rules of prescribing?
Think carefully before prescribing
Prescribe with maximum knowledge about your patient and the drugs
Monitor patient for efficacy and side effects
Help patient make better use of medicine
Review medication to discontinue, to reduce dose or to substitute with safer drug
Which are the preconception vitamins?
What are the advantages of preconception vitamins?
Cardiac endocardial cushion defects
Gastrointestinal Tracheoesophageal Fistula
Neural Tube Defects
Which are the preferred drugs for use in asthma during pregnancy?
Inhaled beta-agonists: Short-acting, safe, very limited human
data on long-actingbeta-2 agonists (salmeterol)
Inhaled corticosteroids: Minimal systemic absorption, only 10% of maternal dose reaches fetus.
Systemic corticosteroids: Small increased risk of cleft/lip palate in first trimester exposure,should be used for significant exacerbations.
Which are the preferred drugs for use in depression during pregnancy?
Tricyclic antidepressants: Extensive human pregnancy
exposure, not teratogenic, normal neurodevelopment in preschool children exposed to TCAs or fluoxetine.
Fluoxetine: Most human safety data among SSRIs, neurodevelopment data as above.
Which are the preferred drugs for analgesia in pregnancy?
Codeine, other narcotics: Avoid prolonged use near-term, risk of neonatal depression or withdrawal, frequent use may lead to analgesic-withdrawal headaches.
Which are the preferred drugs for hypertension in pregnancy?
Alpha-methyldopa: Best safety data including
normal childhood development.
Labetalol: Widely used, safe, used IV may cause fetal
Nifedipine: Safe and well-tolerated, may cause hypotension
when administered with Magnesium sulphate
Which are the preferred drugs for nausea and vomiting in pregnancy?
Metoclopramide: Not teratogenic, caution regarding risk of dystonic reactions, particularly if combined with other
Prochlorperazine: See metoclopramide above.
Which are the preferred drugs for pneumonia in pregnancy?
Which are the preferred drugs for urinary tract infection in pregnancy?
Which are the drugs to avoid during pregnancy?
Asthma Leukotriene Inhibitors
Depression - new SSRIs
ACE Inhibitors(Hypertension) and Angiotensin receptor blockers
Why are asthma leukotriene inhibitors avoided in pregnancy?
Minimal human pregnancy data, generally not essential for asthma control.
Why are ASA/NSAIDS avoided in pregnancy?
Not teratogenic but toxic effects on the fetal kidneys may lead to reversible decreases in amniotic fluid volume. Risk of premature closure of the ductus arteriosis in the third trimester.
Why are cough suppressants avoided in pregnancy?
Minimally effective, many syrups contain alcohol. Narcotic use near term may cause neonatal depression, frequent maternal use could lead to neonatal withdrawal
Why are the ergotamines avoided in pregnancy?
Vasoactive, may decrease placental blood flow
Why is retinoic acid avoided in pregnancy?
Hydrocephalus, ear malformation, Low I.Q.
Why are anticonvulsants avoided in pregnancy?
Cleft Lip/Palate, Neural Tube Defects
Why is warfarin avoided in pregnancy?
Scoliosis, hypoplastic nose, eye abnormalities- Chondrodysplasia punctata
Why is atenolol avoided in pregnancy?
Risk of intrauterine growth restriction, neonatal
bradycardia and hypoglycemia.
Why are ACE inhibitors and Angiotensin receptor blockers avoided in pregnancy?
Toxic to developing kidneys in
second and third trimester.
Why are quinolones avoided in pregnancy
Risk of arthropathy in animal model
Why are tetracyclines avoided in pregnancy?
Staining of bone and teeth
Why is clarithromycin avoided in pregnancy?
Teratogenic in some animals.
Why are aminoglycosides avoided in pregnancy
Ototoxicity and nephrotoxicity
Why are the newer SSRIs avoided in pregnancy?
No apparent increase in malformation rates, but no data on neuro development
What should be assessed when prescribing antimicrobial treatment in pregnancy?
allergies and medical contraindications
What is the drug treatment for URTI in pregnancy?
amoxycillin, cephalosporin, co-amoxyclav, erythromycin (not estolate)
What is the drug treatment for UTI in pregnancy?
amoxycillin, cephalosporin, co-amoxyclav, Nitrofurantoin ( caution G6PD)
What is the antifungal treatment in pregnancy?
Nystatin Class A
What are the anti-tuberculous drugs in pregnancy?
Isoniazid and Ethambutol Category A
What is the antihelminthic treatment in pregnancy?
Praziquantel Category B1
What is the antiviral treatment in pregnancy?
Famciclovir, Category B1
What is the only drug used for anti-malaral prophylaxis in pregnancy?
What drugs should be avoided in the antimicrobial treatment in pregnancy?
Quinolones- possible articular damage,
Tetracyclines chelating with calcium in developing bone,
Nalidixic acid - ? Pyloric Stenosis,
Aminoglycosides Caution re: Ototoxicity and nephrotoxicity,
Avoid sulphonamides and Fusidic acid in 3rd trimester due to neonatal hyperbilirubaemia
Erythromycin: Avoid use of estolate ester, risk of sub-clinical
Anti Fungal - Fluconazole class D
Anti-tuberculosis - Rifampicin Category C
Antihelminthic Rx- Praziquantel Category B1
Anti viral - Famciclovir, Category B1
What are the complications of narcotic abuse in pregnancy?
Fetal growth -IUGR
Which are the tocolytic agents used in preterm labour?
Atosiban (Tractocile) blocks oxytocin receptors on uterine
Nifedipine- calcium channel blocker
What is used to gain time in preterm labour?
To gain time for dexa/betamethasone 12 mg BD for fetal lung
What is the treatment regimen to induce tocolysis in preterm labour?
Initial bolus of atosiban 6.75mg then infusion of 7.5mg at 300
ug/min for 3 hours
Same solution of atosiban at reduced rate at 100ug /min for
Nifedipine 10mg orally (not sublingually) every 15
minutes until cessation of contractions
Synthetic analogue of decapeptide oxytocin
What is syntocinon indicated for?
Induction of Labour
Augmentation of labour
Active management of third stage of labour
How is syntocinon administered?
Applied via infusion pump to avoid hyperstimulation
What should one watch out for when administering syntocinon?
What are the main features of prostaglandins in labour?
Synthesized from arachidonic acid
PGE2 and PGF2alpha commonly used
Vaginal gel or pessary for cervical ripening
prior to induction of labour - may also cause
Carboprost up to 8 mg I.M. for postpartum
haemorrhage following uterine atony.
What does of syntocinon is given in PPH?
Syntocinon 10ml i.V. should be sufficient
If PPH persists syntometrine may be given for
sustained uterine contraction.
How is hypertension and pre-eclampsia prevented?
Low dose aspirin in women with a past history of PIH or PET and/or IUGR. Collagen disorders and renal disease
75mg daily always with meals
Low dose aspirin improves upon the prostacyclin pathway as opposed the thomboxane pathway reducing risk for pre-eclampsia
When is heparin used in pregnancy?
Antenatal use for recurrent miscarriages with MTHFR,
thrombophylias, Protein C and Protein S deficiency
Antenatal use for pateints at risk for DVT/P.E.
Prolonged bedrest - hypertension
Postpartum - LSCS
Treatment for DVT and P.E
What is the mechanism of action of methyldopa?
centrally acting blocking B-sympathomimetic pathways- Time tested in pregnancy - first line
What is the dosage regimen of methyldopa in the treatment of hypertension and pre-eclampsia?
Oral Treatment max dose start 250 mg bd/tds up to 3g daily
What adverse effects should one look out for in the treatment of hypertension and pre-eclampsia in pregnancy with methyldopa?
Care for haemolytic anemia (increase B12 and Folic supplements), drowsiness, and depression
What is the mechanism of action of labetolol?
What is the dosage regimen of labetolol in pregnancy?
Start with 100mg BD daily increasing to
May be used orally and I.V.
What is the indication of magnesium sulphate?
Severe pre-eclampsia and eclampsia
What is the dosage regimen of magnesium sulphate
Start with 4g I.V of MgSO4
Followed by infusion of 1 mg MgSO4 / 1 hour
What should one monitor when administering magnesium sulphate?
Monitor Mg serum levels, respiratory rate and
What is the aim of treatment of diabetes in pregnancy?
It is important to achieve strict normoglycaemia during pregnancy. This may best be achieved by conversion to insulin therapy.
What is the effect of sulphonylureas in pregnancy?
The sulphonylureas may enter the fetal circulation and may cause neonatal hypoglycaemia. Currently under study
Which are the thyroid hormones used in pregnancy?
Liothyronine, thyroxine Class A
Which are the drugs used in diabetes in pregnancy?
Metformin increasing use
Acarbose, Class C
Chlorpropamide, glibenclamide, gliclazide,, Class C.
How is lactation suppressed pharmacologically?
Suppression of lactation with conservative methods first the with carbegoline or dopergin
What factors should be considered for drugs given during breastfeeding?
Fat soluble - high delivery to child
Water soluble lower delivery to child
Similar risk profile as in pregnancy
What are the treatment options for threatened miscarriage?
Low dose Aspirin,
What is the management for menstrual disorders?
Diagnosis may require investigation - Endo Bx
Treat the cause :
Reduce blood loss:
Cyclokapron 1 g QDS x 4 days
Mefenamic Acid (NSAIDS) care for GIT
What are the treatment options for endometriosis?
Tailor treatment to patient's needs
Levonorgestrel Intrauterine System - MIRENA
What is the management of subfertility?
Establish a diagnosis
Clomiphene citrate/ Mid-cycle HCG/ ovum tracking
IVF/ ICSI- Ovulation induction with hMG/Mid-cycle HCG/
Care of Hyperstimulation syndrome and multiple
What is the short-term treatment of menopause?
What is the long-term treatment of menopause?
Osteoporosis- HRT with Mirena/ Bisphosphonates/
Selective Estrogen Receptor Modulator, Calcium and Vitamin D supplements
What is the antibiotic treatment of bacterial vaginosis?
What is the complication of bacterial vaginosis?
May result in mid-trimester miscarriage/ preterm labour
What is the management plan of pelvic inflammatory disease?
Subclinical PID with chlamydiae
Mild cases treated in the Community
Acute PID Hospitalize
What are the 3 main important pharmacological effects of NSAIDs
How many classes of oral NSAIDs are available?
20 different classes
What is the major concern in toxicity of NSAIDs
What are the side-effects of NSAIDs?
Most of NSAIDs (even most selective ones), will cause GI side-effects. DYspepsia, nausea, vomiting, diarrhea, peptic ulceration with bleeding.
Effect on renal vascular function. They will block the normal flow through the kidneys with a lower GFR. So increase salt and water retention and also blocks the antihypertensive effects of the ACE Inhibitors.
What can the long term use of NSAID result in?
What are the drug interaction of NSAIDs?
Renal impairment, pt on diuretics or ACE inhibitors
Methotrexate and lithium. It inhibits their elimination.
Reduce effects of antihypertensives
interferes with urosuric agents
can displace warfarin
What are the features of ibuprofen?
Most commonly used
1st line NSAID
Good safety profile
Used in mild to moderate pain and inflammation
It is a short acting drugs (given tds, 8 hourly). Enough for everyday conditions.
What are the side effects of ibuprofen?
What are the features of mefenamic acid?
Very similar to ibuprofen
What are the side effects of mefenamic acid?
diarrhea, haemolytic anaemia, peptic ulcer, oliguric renal failure (be careful elderly)
What is the main features of diclofenac?
What are the main features of indomethacin?
Very good ant-inflammatory effects
Higher incidence of side effects
3rd line agent.
What are the main features of piroxicam?
Can be given once daily.
Can encourage compliance.
More side effects than ibuprofen
What are the main features of phenylbutazone?
Risk of blood dyspcrasias
Need to monitor the pt if long term.
Report any bleeding or sore throat.