HD021

Growth Percentiles

Mid-Parental Height

Height and Bone Age

Normal growth velocity for healthy term infants

Height – a measure of chronic nutritional status
Weight - more sensitive to recent nutritional changes
Head Circumference - measured up to 36 months of age. In failure to thrive, it is the last anthropometric measure to falter

Boys:  average of parents’ ht, add 7 cm
Girls: average of parents’ ht, subtract 7 cm

• Bone or skeletal age usually done with X-ray of hand & wrist
• Since skeletal maturation, fusion of the epiphysis and the appearance of ossification centres occur in a predictable order, bone age can be compared to chronological age

  0-6 mo         ~20-30 g/day
  7-12 mo       ~13 g/day
  > 1 year       ~ 7 g/day (until linear growth complete)

HD021

Energy Requirements for Infants

Meeting Energy Requirements

IBW

Assessing Weight

Average energy requirement = 100-120 kcal/kg per day
Ventilator dependent = 80-100 kcal/kg/day
Neurodevelopment impairment = 100-120 kcal/kg
Failure to thrive, ↑ Respiratory Rate = 120- 150+ kcal/kg

Breastmilk or breastmilk substitute (infant formula) provides ~ 67 kcal/100 ml
Require 150 ml/kg to = 100 kcal/kg

% IBW = Actual wt/Ideal wt x 100

Use growth chart height and weight (not age)

Guidelines:

< 80 % IBW  - severely underweight
80 - 89 % IBW - caution/underweight
90 - 110% IBW - appropriate
111-120% - caution/overweight
> 120 % IBW - obese

Wt/ht growth curve up until height of 120 cm is used:

• 25-75th %ile considered appropriate for ambulant child
• 10-25th %ile considered appropriate for non-ambulant child d/t decreased muscle mass

HD021

Holliday-Segar Fluid Equation

1st, 2nd and 3rd choices to breastmilk

Why not give just whole cows milk?

Needs:

• 100 ml/kg for first 10 kg
• Additional 50 ml/kg for next 10 kg
• Additional 20 ml/kg after 20 kg

Meeting fluid requirement will NOT meet E req

Cow’s milk iron fortified formula - 1st choice

Commercial Infant Formulas - 2nd choice

Evaporated whole milk formula - 3rd choice

• No iron; can lead to “milk babies” – drinking 6 x 8 oz. per day = ~ 1000 kcal and therefore no hunger for solids
• High in protein ~ 3x breastmilk
• Hard on kidneys
• Protein difficult to digest -> curd in stomach and cause bleeding -> leads to anemia
• Low in vitamin C
• High mineral content
• Thus only after 12 months!
  

Note: not goat milk b/c of no Vit D/iron

HD021

Introducing Solids to infants

 Why do we recommend breastfeeding?

When do we discourage breastfeeding?

Not recommended prior to 6 mnths b/c:

• No nutritional benefit
• Increases renal solute load
• Can cause allergic reaction
• May lead to overfeeding
• Food swallowing reflex may not be fully developed

Begin with strained meat or iron fortified infant cereal should be the first food offered (begin with single grain cereals). Then vegetables and fruits

1. Most nutrients
2. Protection against iron deficiency anemia
3. Protects against gastroenteritis, respiratory infections and otitis media
4. may reduce allergies
5. More efficiently digested and absorbed
6. Has an appetite regulating mechanism
7. Does not increase renal solute load to the same degree as alternate feedings.
8. Economical, time saving and sanitary
9. Facilitates a strong mother-child bond

HIV +, drug and alcohol use, chickenpox, galactosemia (in baby), PKU (in baby)

HD066

Nutrition-related diseases are...

Obesity trend by age

Acceptable Macronutrient Distribution Ranges for Canadians

• The leading causes of morbidity and mortality in western societies
• 40-65% of hospitalized population is malnourished

Parabola of obesity, lowest in the young and old, worst in 55-64 y/o

Carbs - 45-65%

Fats - 20-35%

Proteins - 10-35%

HD066

Dietary Reference Intakes (DRI)

Food group and Main Nutrients Provided

What affects our BMR?

1. Estimated Average Requirements (EAR)
2. Recommended Dietary Allowances (RDA)
3. Adequate Intakes (AI)
4. Tolerable Upper Intake Levels (UL)

Milk - Calcium and Protien

Grain - Carbs, B-Vitamins, Fiber

Fruits/Veg - Carbs, Vitamins, Fiber

Proteins/Alt. - Protein and Iron

• In a sedentary adult, about 2/3 of total energy expenditure is accounted for by Basal Metabolic Rate (BMR).
• BMR is affected by:
• Age
• BMR declines with age
• Body Composition
• Men have more lean body mass than women
• Fasting/Malnutrition reduces BMR
• Metabolic Stress
• Can increase BMR significantly (up to 200%) for 2-3 weeks after injury
• Fever
• Every 1°C rise in body temperature increase BMR by 13%

HD066

Nutrition assessment tools:

Weight

Waist Circumference
Body Mass Index (BMI)

Triceps Skinfold (TSF)
DEXA/BIA

More than 2% of body wt loss in 1 week
More than 5% body weight loss in 1 month
More than 10% body weight loss in 6 months

≥ 102 cm (men) and ≥ 88 cm (women) = bad
Not especially useful in those with BMI >35

BMI = weight (kg) / height² (m²)
BMI is based on normal proportions of body fat and lean body mass. Individuals who exceed these limits cannot be evaluated using BMI

Normal = 18.5-24.9, Overweight (+5 = 25-30), Obese (+5 per class I, II and II (>40))

Crude indicator of body fat reserves

DEXA (Dual Energy X-ray Absorptiometry), BIA (Bioelectricl Impedance) – measure body fatness

HD066

PEM

PEM = Protein Energy Malnutrition. During illness, several different mechanisms can interfere with energy balance

• Requirements/Metabolism
• Increase in requirements
• Ex. fever, sepsis, trauma, burns
• Intake
• Impairment/inability to regulate intake
• Ex. Altered level of consciousness, facial injury, dysphagia, GI obstruction, hyperemesis, anorexia nervosa, bulimia)
• Digestion/Absorption
• Impairment/inability to release nutrient from foods eaten.
• Ex achlorhydria, cystic fibrosis, pancreatitis, biliary insufficiency, lactase deficiency

Malnourished pts have reduced muscle function, impaired immune status, increases risk of infection, pressure sores, poor wound healing and increases length of hospital stay

At risk = Elderly and chronic disease patients (40-65%)

HD066

How to assess PEM

ABCD

A = Anthropometry

• Weight loss
• Loss of lean muscle mass and fat stores
• Rapid weight loss following surgery results in increased loss of protein stores

B = Biochemical Indicators of PEM

• Serum Albumin
• Half-life is 14-20 days
• Normal levels 35-50 g/L
• Serum Pre-Albumin
• Synthesized by liver, involved in transport of thyroid hormone, acts as carrier for retinol-binding protein.
• Half-life 2 days
• Normal levels 0.17-0.42 g/L
• Immunologic Status
• In malnutrition, synthesis of antibodies decreases, and can be reflected in Total Lymphocyte Count (TLC)
• Normal levels = 2.5 x 109 /L or above

C = Clinical Signs of PEM

• Loss of lean body mass is associated with muscle wasting and weakness
• Upper body changes (reduced upper arm circumference) are more noticeable than lower body
• Subjective Global Assessment (SGA)
  

D= Dietary Assessment

• A review of individual’s typical food intake can reveal if protein and energy intake are inadequate
• Food recall, 3-day food record, food frequency questionnaire

HD066

Estimation of Current Energy Expenditure (4 ways)

To help re-gain weight, provide...

Protein Requirements (Healthy, not healthy....)

There are many different ways that this can be done.

1. 2002 Dietary Reference Intake Values for Energy
2. Based on Body weight
• 30 kcal/kg/day for mildly stressed hospital patient, or sedentary client.
3. Harris Benedict Equation
4. Indirect Calorimetry (Metabolic Cart)
• Used only in critically ill patients with very high energy expenditures.
• Oxygen intake and CO2  are used to determine energy expenditure over a 24-hour period.

500 kcal/day extra and this will result in 0.5 kg/week weight gain

Healthy = 0.8-0.9 g/Kg

Post-operative, cancer patients or heavy-weight trainer- moderately stressed = 1.0-1.5 g/Kg

Major burn victims= Severely stressed = 1.8-2.5 g/Kg

HD066

Amount of protein per serving for each food group

When oral intake isn’t enough… (2 options)

Sources of Iron

Milk - 8 g

Grain - 2 g

Veg - 1 g (none from fruit)

Proteins/Alt. - 12 g

1. Enteral (tube) feeding
2. Parenteral nutrition (Infusion of nutrients into a peripheral or central vein)

Only ≈10%-15% absorption
Heme iron is found in meats (Absorbed better)

Non-heme iron is found in beans, peas, lentils, vegetables, or grain products
Things that influence iron absorption

• Phytates are found in whole grains, legumes, nuts and seeds and bind and slow abs of Iron
• Tannins are found in wine, tea, berries. Same problem
• Calcium and Phosphorous -> same problem

Infants over 6 months of age, young children, adolescents, menstruating and pregnant women have increased iron needs

HD066

Vitamin B12

Vitamin D

• Activated by folate
• Deficiency causes an anemia (pernicious anemia) identical to that of folate
• Large, immature red blood cells
• Only found in animal products, less absorbed by elderly

• DRI = 600 IU/day (Increased need w/ Inc age)
• Produced by the action of sunlight on 7-dehydrocholesterol in the skin
• Regulation of blood calcium and phosphorus levels
• Functions as a hormone
• Deficiency = Rickets (kids), Osteomalacia (adults)
• Everyone over the age of 50 should take a daily vitamin D supplement of 400 IU
  
  

HD075

Who is at Nutritional Risk? (4 B’s)

M.A.T.T.E.R.S

Recommendations for MATTERS

BMI (recent changes?)
Blood Pressure and Hypertension
Balanced Diet
Breakfast (Eat breakfast everyday?)

Margarine, butter, oils
Alcohol
Tea/Coffee
Table Salt
Eating Pattern
Roughage
Sugar

M - Reduce total fat, focus on unsaturated fats

A - No more than 1-2 drinks

T - No more than 4 cups of coffee/tea per day

T - Minimize salt used in cooking

E - Eat 3 balanced meals a day

R- Eat at least 1 serving of vegetables and fruits at each meal and inc intake of whole grain products, aim for 25-30 grams of fibre each day,

S - No more than the equivalent of 100 calories (8 tsp sugar) per day

HD075

C.H.E.P.

Sodium intake distribution for men and women

What lifestyle choices help to prevent Hypertension?

Canadian Hypertension Education Program

• More than 1 in 5 adult Canadians has hypertension (HTN)
  and the lifetime risk of developing HTN is ~ 90%
• Hypertension very common reason to visit physician (> depression)

Men and women above Adequate Intake (1500 mg) and Upper Limit (2300 mg). Men worse than women  (even 100% ages 19-30

• Weight loss
• 10 lbs has shown significant improvement
• Exercise
• 10,000 steps or 30-60 minutes moderate intensity 4-7 times per week
• DASH Diet
• Sodium levels (under age 50, even lower for 50+)
• Lower sodium intake to <1500 mg (100 mmol) per day provides benefit

HD075

DASH Diet

Controllable and Uncontrollable factors in Cardiovascular Disease

Dietary Approaches to Stop Hypertension:

Fruits (4-5 serving/d)
Vegetables (4-5 serving/d)
Adequate dairy (3 servings/d)
Reduction of sodium
Alcohol

≤2 standard drinks/d for men and ≤1 standard
drink/d for women

Potentially Controllable:
Elevated blood lipids
High blood pressure
Smoking
Excess body fat
Lack of Exercise
Stress

Uncontrollable:

Family History

Sex (male)

Age

HD075

Nutrition on Cholesterol

Nutrition on Fats

• Dietary cholesterol does not have a great influence on serum changes in cholesterol
• Consumption of 7 eggs/week is harmonious with a healthful diet (2 or less egg yolks for those with with Diabetes)
• High serum cholesterol is better correlated with high saturated fat and trans fat intakes
• Cholesterol is only found in animal products

• We should have <30% of total calories as fat (<65 g fat) and limit saturated and trans fats
• Saturated fatty acid  = no double bonds
• Monounsaturated fatty acid  = 1 double bond
• Polyunsaturated fatty acid = 2+ double bonds
• Oil = most unsaturated = liquid = GOOD
• Margarine = unsaturated = some liquid
• Lard = saturated = longest time to melt
  and requires a much higher temperature
• Trans Fats (TFA) = Worst

HD075

Trans Fats (TFA)

____ kcal = 1 pound of fat

• In partially hydrogenated oils
• Ex Fried foods like French fries
• High TFA
• ↑ risk of heart disease even more than saturated fats do
• Increase LDL-CH, and total CH
• Decrease HDL-CH
• There is NO safe level of trans fat
  consumption
• Trend is decreasing amounts in our diets (yay)

3500

Realistic weight loss:

3 Months = 5% of body weight

6 Months = 10% of body weight

HD079

Amine hypothesis of Depression

Theraputic Lag

• Depression is related to reduced synaptic levels of Norepinephrome (NE), 5-HT (Serotonin) and Dopamine (DA)
• Most antidepressant drugs appear to work by enhancing synaptic monoamines
• This works through blocking normal neurotransmitter reuptake processes (Specifically NET and SERT on pre-synaptic terminal)

There is a 1-4 week lag in the effects of anti-depressants even though these drugs increase Neurotransmitter levels right away

Why?

This is because antidepressants have long-term synaptic effects that influence synaptic strength

Over the first few weeks alpha 2 (NE) and 5HT-1 receptors (Serotonin) which are both inhibitory, but these get downregulated

[image]

HD079

Tricyclic antidepressants

Mechanism:

• Mixed norepinephrine and serotonin reuptake inhibitors
• Great variation in relative NE:5-HT reuptake blockade potencies
• Also some blockade of cholinergic, histaminergic, alpha-1-adrenergic receptors = SIDE EFFECTS

Adverse effects:

• Antimuscarinic
• Cardiovascular – orthostatic hypotension, conduction defects
• Sedation
• Sympathomimetic – tremour, insomnia
• Neurologic – seizures
• Metabolic – weight gain, sexual disturbances
• Overdose – extremely dangerous cardiac arrhythmias

Drug interactions:

• Pharmacokinetic – CYP 2D6 inhibitors, highly protein bound
• Pharmacodynamic – Sedatives, sympathomimetics, antimuscarinics

HD079

Serotonin selective reuptake inhibitors
(SSRIs)

Examples:

• Fluoxetine (Prozac), Citalopram (Celexa), Paroxetine (Paxil), Sertraline (Zoloft)

Mechanism:

• Block serotonin reuptake 300 – 7000-fold more effectively than NE
• No more effective than TCAs
• Paroxetine and sertraline have shorter halflives
• citalopram is most SERT-selective

Adverse effects:

• Much less cholinergic, histaminergic, adrenergic receptor blockade than TCAs = more tolerable side effect profile 
• Safer in O/D
• GI symptoms, headache, sexual dysfunction, fatigue, insomnia and platelet inhibition

Drug interactions:

• Pharmacokinetic – Strong CYP 2D6 inhibitors. TCA’s, antipsychotics, Beta-blockers interfere with metabolism. Fluoxetine> paroxetine > sertraline/citalopram
• Pharmacodynamic – Low non-SERT interactions

Advantages over TCAs:

• Equal efficacy with milder side effect profile
• Much more favourable therapeutic index
• Smaller chance of additive drug interactions

HD079

Serotonin and norepinephrine reuptake inhibitors (SNRIs)

Mechanism:

• Inhibit both serotonin and NE reuptake (5-HT>NE) but NOT TCA
• Also weak dopamine reuptake inhibitors
• No affinity for muscarinic, alpha-1-adrenergic or histaminergic receptors

Adverse effects:

• Similar to SSRIs
• nausea, sweating, dizziness, anxiety, sexual dysfunction, hypertension
• May be more dangerous than SSRIs in O/D

Potential advantages over SSRIs/TCAs:

• Same milder side effect profile as SSRIs
• May be useful for depression with neuropathic pain
• Fewer drug interactions
• Potentially lower safety margin than SSRIs in O/D

HD079

Atypical antidepressants (Mirtazapine)

aka Remeron

Mechanism:

• Structurally a tetracyclic compound
• Blocks 2-adrenergic receptors, thus increasing serotonin and NE release
• Low affinity for muscarinic, alpha-1-adrenergic receptors
• Potent blocker of histamine receptors

Adverse effects:

• Sedation, weight gain, dry mouth
• No anticholinergic effects
• Less propensity for sexual side effects than SSRIs and TCAs

Drug interactions: None known

Advantages of Mirtazapine?

• As tolerable as SSRIs
• Anxiolytic effects
• Depression with insomnia
• No drug interactions
• BUT - weight gain major drawback

HD079

Atypical antidepressants (Bupropion)

aka Wellbutrin

Mechanism:

• Largely unknown – does not inhibit NE or serotonin reuptake
• Blocks dopamine reuptake weakly
• Mild stimulant – treat comorbid fatigue/poor concentration, ADHD
• No affinity for muscarinic, alpha-1-adrenergic or histaminergic receptors

Adverse effects:

• Much lower incidence than TCA’s
• Nausea, headache, seizures
• No sexual dysfunction, weight gain or sedation

Drug interactions:

• Meds that lower seizure threshold, L-Dopa
• CYP 2D6 inhibiton

Advantages of Bupropion?

• As tolerable as SSRIs
• Stimulant effects may be helpful
• May offer relief from SSRI or SNRI-induced sexual dysfunction or weight gain

HD079

Monoamine oxidase inhibitors (MAOI’s)

Note

Mechanism:

• MAO-A breaks down NE, MAO-B breaks down DA
• Phenelzine (Nardil), Tranylcypromine (Parnate) inhibit these
• Usually reserved for patients where other drug interaction make it the only option

Adverse Effects:

• Orthostatic hypotension
• Antimuscarinic (<TCA’s)
• Mild-moderate sedation
• Dose-related sexual dysfunction in males and females
• Hypertensive crisis with tyramine-containing foods or sympathomimetics

Drug interactions:

• Serotonin syndrome with SSRIs + MAOIs
• Leads to exaggerated serotonin transmission
• Hyperthermia, mania, muscle rigidity can develop
• Can be lethal – 2-5 weeks washout required to minimize risk

Good table in notes, look at it

HD110

Tolerance (Mech and Types)

Reinforcement

Dependence

Intoxication

Tolerance: Decreased response to the drug, requiring higher doses, and the level of stable, high need that is eventually reached. Eventually we also get reduced “reward” with repeated drug usage and reduced function in the absence of drug

Comes from:

• Metabolic tolerance
• Inc in enzymes
• Behavioral tolerance
• Sobering up at a party when the cops come
• Functional tolerance = changes in specific receptor system
• Most important and critical effect -> Massive tolerance, yet the body will still be injured by the drug. This leads to a person being able to ingest more and not feel the FX but still OD

Types of Tolerance:

Tolerance can be 200 fold: e.g. diazepam & meth

Tolerance typically lost in 10 to 14 days

• Cross tolerance – (alcohol, Benzo)
• Inverse tolerance
• Sensitization (that can persist for years) is a characteristic of abuse of stimulants where an increase in an expected effect of a drug after repeated administration
• 1 type is anticipation - placebo effect
• Another is motor system - meth can downregulate inhibitory motor systems

Reinforcement: A measure of the substance's ability in human and animal tests, to get users to take it again and again, and in preference to other substances. (timing is everything)

Dependence: How difficult it is for the user to quit,
Psychological dependence: Compulsive drug use despite risks = ADDICTION

Physiological dependence: Symptoms (usually opposite of drug effect) when drug withdrawn (abstinence syndrome)

Note: Addict often has NO physiological dependence, while physical (medical) dependency may not be addiction

"Most Addictive drug in the world is Nicotine (Heroin is not that addictive)" but opposite in the table of 1-6 in addictiveness. Heroin was #1?

Intoxication: Not a measure of addiction but associated with addiction and increases the damage a substance may do

HD110

 Stimulants: Cocaine

The faster the drug gets in...

• Duration of action short - half life 10-30 minutes
• Tolerance to euphoric effects but also sensitization to
  psychomotor effects
• Toxic effects due to cardiovascular effects, cerebral ischemic effects and seizures
• Cocaine is a vasoconstrictor and can cause severe acute hypertension precipitating heart attack or stroke
• Growing evidence of cocaine syndrome in offspring including cognitive and motor deficits
• Withdrawal is mild leads to dysphoria, depression, fatigue and craving -> No drugs available for reliable treatment
• Desirable qualities are a “rush”, increased mental alertness, increased motor activity and euphoria
• High doses cause toxic symptoms, including anxiety, insomnia, irritability, paranoia, suspiciousness (toxic paranoid psychosis)

The more addictive it is

HD110

Stimulants: Amphetamines

• Same basic CNS and peripheral effects
  and withdrawal effects as seen with
  cocaine but effects last longer than cocaine
• High doses produce paranoid psychotic
  reactions with auditory hallucinations
• Extreme tolerance is observed with
  users able to consume as much as 1.6
  grams of methamphetamine a day
• Use of stimulants to facilitate weight
  loss (amphetamine, fenfluramine,
  phenylpropanolamine) is not associated
  with significant abuse potential
• Mechanism:
• Increase release of dopamine and noradrenaline in brain
  
• Inhibit dopamine and noradrenaline transporters
• Long term use of high doses leads to repetitive
  purposeless (stereotypic) behaviors: aggressiveness, paranoia, psychosis, anorexia and starvation, malnutrition, poor skin circulation, vitamin
  deficiency, skin lesions
  

HD110

Table comparing Meth and Cocaine

HD110

Ecstacy (MDMA)

Hallucinogens

• Increases serotonin, DA and NA release
• Inhibits serotonin transporters
• MDMA is neurotoxic - damaging serotonin
  nerve terminals - most drugs aren't neurotoxic
• Positive effects: empathy, well-being, reduced
  anxiety
• Adverse effects: hyperthermia, dehydration,
  increased blood pressure; depression; risk of
  serotonin syndrome, impotence in males

• LSD, mescaline, psilocybin (magic mushrooms)
• Agonists at serotonin 5HT receptors
• Activate sympathetic nervous system: increased heart rate, dilated pupils, tremor
• Stored in fat -> Fat hippies
• Perceptual distortions, changes in mood, increased introspection, feelings of detachment
• Non-toxic, little dependence
• Panic reactions (“bad trips”), acute psychotic reactions
• Recklessness due to errors in judgement

HD110

 PCP (phencyclidine), Ketamine

Marijuana

• Make you feel nothing (Dissociative Anesthetics)
• All act as noncompetitive blockers of the NMDA
  associated calcium channel
• Produce neurotoxicity in hippocampus
• Effects include emotional withdrawal, concrete thinking and bizarre responses to projective tests, catatonic posturing, hallucinations and hostile or assaultive behaviors, disorientation, perceptual distortions, loss of proprioception, numbness, sweating, rapid heart rate, hypertension
• Withdrawal symptoms include an agitated psychotic state which can be treated with diazepam or haloperidol
• Thought to provide a model for psychotic behavior

• Lipid soluble, sequestered in fat
• Activation of the CB1 receptor is correlated with
  analgesia, hypothermia, catalepsy, decreased
  locomotor activity and memory disturbances
• Actions at the CB2 receptor are responsible for
  impaired immune responses
• Positive effects are relaxation and feelings of well
  being
• Negative effects are impaired cognitive function,
  impaired co-ordination and/or reaction times,
  increased pulse rate, red eyes
• Potential medical uses: appetite stimulation,
  antiemesis, pain relief, anticonvulsant
• “amotivational syndrome”: loss of energy and
  drive to work
• Withdrawal symptoms include: restlessness,
  irritability, mild agitation, insomnia, nausea, cramping, sleep disturbances
• Dronabinol is a synthetic cannabinoid for
  treatment of nausea and vomiting
• Sativex®, oral spray containing THC, for
  multiple sclerosis pain

HD110

Opioids – Heroin (diacylmorphine)

Sedatives & Hypnotics - Alcohol

• IV use -> drug gets to brain very quickly = high addictive potential
• Produces a “rush”, followed by euphoria, feelings of
  tranquility
• Overdose danger-respiratory depression
• Withdrawal - The onset of heroin withdrawal symptoms begin six to eight hours after the last dose is administrated. Major heroin withdrawal symptoms peak between 48 and 72 hours after the last dose of heroin and subdue after about one week. The symptoms of heroin withdrawal produced are similar to a bad case of the flu.
• Speedballs (Heroin + coke)

• Reduces excitation by inhibition of NMDA receptor and enhances inhibition by actions at a modulatory
  site on GABA-A complex and at 5-HT3 receptor located on GABA neurons.
• Cross-tolerance to other sedativehypnotic
  drugs such as benzodiazepines and barbiturates.
• Alcohol poisoning usually in young people
• Bad FX not expected by public:
• Superman syndrome with Meth (leap from tall
  buildings….)
• Psychotic paranoia with angel dust PCP
• Death by vomit aspiration with barbituates
• Causes changes fluidity of normal membranes, all of the above can happen more commonly
• Toxicity includes liver disease, severe depression (often leading to suicide) and alcoholic Korsakoff’s syndrome consisting of a loss of short-term memory and an inability to learn new skills
• Withdrawal symptoms: craving, tremor, irritability, nausea, sleep disturbance, tachycardia, hypertension, sweating and perceptual distortions.
• In severe cases: Delirium Tremens consisting of
  severe agitation, confusion, visual hallucinations, fever, profuse sweating, tachycardia, nausea, diarrhea and dilated pupils, as well as seizures that may occur 12-48 hours after the last drink.
• Treatment for withdrawal symptoms can be obtained
  with short acting benzodiazepines (oxazepam).

HD110

Barbiturates

Solvents

• Block excitatory (glutamate) calcium and enhance inhibitory (GABA) chloride channels
• Tolerance is pharmacokinetic, pharmacodynamic and behavioral - Therapeutic index decreased.
• Physical dependence: get upregulation of NMDA receptor and withdrawal symptoms resemble those seen with benzodiazepines including seizures.
• Treatment for addiction as for benzodiazepines
• NOTE: MUCH more dangerous than benzodiazapines

• Ex. Gasoline, paint thinner, glue, benzene, toluene, freon, butane -> cheap, easily available, fast acting
• Euphoria and a “drunk” feeling are followed by disorientation, uncoordinated movements, slurred speech, reduced sensations and possibly hallucinations
• Loss of consciousness, arrhythmias, asphyxiation
• Liver and kidney damage, peripheral nerve damage, brain damage, demyelination

HD110

Benzodiazepines

• Intentional abuse is rare, but physical dep can occur
• Actions are at the modulatory site on the GABA-A
  complex
• Tolerance and physical dependence are slow in
  developing (several months). Tolerance occurs to
  the sedative effects with little evidence of tolerance
  to the anti-anxiety effects. However effects on short term memory do not demonstrate tolerance (drug induced insomnia)
• Addiction can lead to enormous escalation of dose
  e.g., while 5-20 mg/day of diazepam is typical
  prescribed dose, abusers may take over 1000
  mg/day and not appear grossly sedated.
• Abuse may occur for production of a “high” but also
  may involve use to heighten the effects of other
  drugs (e.g., methadone) or to reduce unwanted side
  effects (e.g., cocaine)
• Both licit and illicit use over extended period produces physical dependence. Withdrawal symptoms can be difficult to differentiate from reemergence of the anxiety symptoms for which the
  drug may have been prescribed.
• Withdrawal symptoms are usually mild and involve
  anxiety, agitation, increased sensitivity to light and
  sound, paresthesia, muscle cramps, myoclonic
  jerks, sleep disturbances and dizziness. Symptoms
  of withdrawal from high dosages include seizures
  and delirium.
• Anticonvulsant medication can be used (e.g., carbamazepine and phenobarbital). Flumazenil can be used for acute toxic overdose.

HD110

Drug use and associated Disorder

HD080 - Mood Disorders IV tutorial -> Imptnt cases, look at them

Anxiety Disorders Epi

Cocaine and Methamphetamine -> Schizophrenia, paranoia, anhedonia, compulsive behavior

Stimulants -> Anxiety, panic attacks, mania and sleep disorders

LSD, Ecstasy & psychedelics -> Delusions and hallucinations

Alcohol, sedatives -> Depression and mood disturbances

PCP & Ketamine -> Antisocial behavior

• 25% of the Population
• Women > Men - Except OCD = 1:1 ratio
• Age of onset (<20 y)

Depression (not anxiety disorder) > Social anxiety disorder > Post-traumatic stress disorder > Generalized anxiety disorder > Panic disorder > Obsessive-compulsive disorder

Comorbidity is the rule rather than the exception

1. Mood Disorder (unipolar, bipolar)
2. Alcohol abuse
3. Anxiety Disorder

HD083

Specific Patient Populations at High

Risk for Anxiety and Depression (7)

Normal vs. Abnormal Anxiety

Diagnostic Issues for Anxiety

1. Chronic fatigue
2. Irritable bowel syndrome
3. Insomnia
4. Persistent pain (abdominal, back, joint or limb)
5. Chest pain (unexplained)
6. Headache
7. Multiple visits(>6 visits in 6 mo. excluding OB)

Bad is when there is Avoidance of the feared situation, person, place, or thought on a repeated basis is what makes it pathological

Important to rule out anxiety disorder due to a general medical condition

• Heart disease, thyroid problem, tumor etc.

Important to rule out substance-induced anxiety disorder

• EtOH (withdrawal), cocaine, etc.

Important to look for comorbid conditions

HD083

PTSD: Definition

GPs Need to screen for PTSD in all patients with...

Trauma and the probability of PTSD

1) Criterion A1: Exposure to Traumatic Events - Actual or threatened death or injury to self or others

2) Criterion A2: Response Involves Intense Fear, Helplessness or Horror********

3) 3 Symptom Clusters:

Criterion B: Re-experiencing = The traumatic event is re-experienced in 1 or more of the following ways:

• Recurrent & intrusive distressing recollectionsand dreams of the event
• Acting or feeling as if the trauma were reoccurring
• Psychological distress and/or physiological reactivity when exposed to cues that resemble an aspect of the traumatic event

Criterion C: Avoidance/Numbing

Avoidance of stimuli associated with trauma and a general numbing of responsiveness as indicated by 3 or more of the following:

• Avoidance of thoughts, feelings or
• Conversation associated with the trauma
• Avoidance of activities that will arouse
• Recollection of the trauma (places or people)
• Inability to recall an important aspect of event
• Markedly diminished interest in significant activities
• Feelings of detachment
• Restricted range of mood
• Sense of foreshortened future

Criterion D: Hyperarousal

Symptoms of increased arousal as indicated by 2 or more of the following:

• Difficulty falling or staying asleep
• Irritability or outbursts of anger
• Difficulty concentrating
• Hypervigilance

4) Criterion E: Symptoms Present >1 Month

5) Criterion F: Clinically Significant Distress or Impaired Functioning

GPs Need to screen for PTSD in all patients with:

• Sleep complaints
• Somatization
• Depression
• Other comorbid anxiety disorders
• Alcohol or chemical use
• Suicidal ideation/ER visits
• High rate of medical service consumption

• 55% of the population (USA) will experience
  a major traumatic event
• Approximately 7–10% will develop PTSD

HD110

Panic Disorders (2)

Panic attack
A discrete period of intense fear/anxiety where onset is abrupt and peaks within 10 minutes
4 or more of the following 13 symptoms

1. Cardiovascular
       Chest pain or discomfort
       Palpitations or tachycardia
2. Respiratory
      Feeling of choking
      Dyspnea or the sensation of being smothered***
3. Gastrointestinal
      Nausea or abdominal upset
4. Neurologic
      Dizziness, feeling of unsteadiness or faintness
      Numbness or tingling sensation
      Trembling or shaking
5. Integument
      Sweating
      Flushes or chills
6. Cognitive:
      Depersonalization (being detached from oneself or
      derealization (feelings of unreality)
      Fear of going crazy or of losing self-control
      Fear of dying

Panic Attacks DOES NOT EQUAL Panic Disorder

Can occur in normal individuals (30%) and can occur in other mental disorders besides Panic Disorder

Panic Disorder

1. Recurrent unexpected panic attacks
2. Anticipatory anxiety: 1 or more of the following
for at least 1 month:

• Persistent concern about having another panic attack
• Worrying about the consequences of an attack (e.g., having a heart attack)
• Significant change in behaviour due to recurrent panic attacks (agoraphobic avoidance)

3. Not due to a Substance or Medical Condition
4. Not better accounted for by another mental disorder
(Specific Phobia, OCD, PTSD, Separation Anxiety)

Note: Agorophobia can occur with or without a Panic Disorder

HD083

Obsessive Compulsive Disorder

1. Obsessions and/or compulsions
2. Time-consuming (>1 hour/day)
3. Marked distress
4. Interference with social and occupational
   functioning

Obsessions: Contamination > Pathological doubt > Somatic > Symmetry > Aggressive > Sexual >
Multiple

Compulsions: Checking > Washing > Counting > Need to ask/confess > Symmetry/precision > Hoarding > Multiple

Particular to OCD:

• Some evidence for infectious etiology  (poststreptococcal) in some childhood onset cases
• Placebo response rate is lower (5-10%) than most other anxiety disorders and other psychiatric llnesses which show 25-30%
• Need higher doses, and longer trials of pharmacotherapy for response
• Most common of the anxiety disorders to be associated with Tic Disorders and Tourette’s

HD083

Social Anxiety Disorder

Generalized Anxiety Disorder

Specific Phobias

• Marked or persistent fear of social or performance situations
• Individuals fear scrutiny, negative evaluation,
  humiliation or embarrassment
• Exposure to (or anticipation of) social/performance situation provokes anxiety
• Avoidance of social/performance situations
• Significant distress or impairment in social and occupational functioning

Difference is that this has Day to Day life issues

Criteria:

Excessive unrealistic anxiety and (uncontrollable) worry
> 6 months about numerous typical events or activities of daily life AND
3 of more the following symptoms:

• Restlessness or feeling keyed up or on edge
• Being easily fatigued
• Difficulty concentrating or mind going blank
• Irritability
• Muscle tension
• Sleep disturbance (difficulty falling asleep or staying asleep, or restless, unsatisfying sleep)

Types of anxiety disorder

Ex Blood, animals, closed spaces

HD083

Treating Anxiety Disorders with Antidepressants

1. Start low
2. Go slow ( titrate up over 4-6 wks )
3. Aim sufficient
4. Wait longer ( 8-12 wks after reaching
   therapeutic dose )

Essentially, ALL antidepressants (except bupropion) are effective for treating ALL anxiety disorders, with THREE exceptions: Usually we use SSRIs

• For OCD - need highly serotonergic antidepressant (SSRI, Clomipramine)
• For SOCIAL PHOBIA, (and atypical depression) TCAs are less effective
• Use CBT
  
• For PANIC DISORDER purely noradrenergic antidepressants are perhaps NOT effective (eg. maprotiline)

Keep Treating:

• 40-90% relapse rates with discontinuation of medication (especially if no CBT) within 6 months
• Many patients require lifelong maintenance treatment

Combining Antidepressants With Benzodiazepines:

• Provides rapid anxiolysis during antidepressant/ antianxiety therapeutic lag ( early relief of suffering )
• Dec early anxiety associated with initiation of antidepressant (decrease S/Es)
• Dec residual anxiety with antidepressant treatment (augmentation)
• Serotonergic antidepressants prevent and treatcomorbid depression / other anxiety disorders

HD082

Lifetime incidence of psychosis

Causes of Psychosis

3-5%

Can be caused by:

• Bipolar mania
• Schizoaffective disorder
• Alzheimer Disease
• Drugs or drug withdrawl
• Medical condition
• Schizophrenia
• ~1% lifetime risk; 11/100,000/yr (USA)
• Males 1.4 times more at risk than females
• Onset in males at 15-24 years
• Onset in females at 25-34 years
• Staggering morbidity - accounts for 2.5% of all health care costs in US – very high!
• Genetic predisposition – greater risk with 1st or 2nd degree relative that has it (10x inc chance with Mom/Dad/Brother/Sister)
  
  

HD082

Psychosis Mechanism - Dopamine Hypothesis

Positive symptoms:

Due to hyperactivity in the mesolimbic dopamine pathway

Negative and cognitive symptoms:

Result from dopaminergic hypoactivity in the mesocortical pathway

VTA = Ventral Tegmental Area

NAcc = Nucleus Accumbens
PFC = Prefrontal Cortex

VTA -> Positive Symptoms (+ Dopamine) via Mesolimbic -> NAcc -> Motivation, Reward, Addiction, Reinforcing behaviour

VTA -> Negative Symptoms (+ Dopamine) via Mesocortical -> PFC -> Cognition, Communication, Social function, Stress response

Support for dopamine hypothesis:

• Most antipsychotics strongly block D2 dopamine receptors
• Drugs that increase dopaminergic activity can produce psychosis
• Ex Cocaine and meth

HD082

Typical antipsychotics

Mechanism:

• Action thought to be antagonism of D2 receptors in mesolimbic pathway
• Blocks VTA -> NAcc pathway and thus stops the + symptoms, but since (-) aren't affected we get people with very flat affect

Examples:

Chlorpromazine (Thorazine), Fluphenazine (Permitil, Prolixin), Haloperidol (Haldol), Thiothixene (Navene)

Adverse effects:

• Receptor non-selectivity = (Extrapyramidal Side Effects (EPS))
  
• Toxic confusional state, dry mouth, urinary retention (Antimuscarnic)
• Orthostatic hypotension, dizziness, tachycardia, impotence
• Weight gain
• Sedation
• Blockade of non-mesolimbic dopaminergic pathways
• Nigrostriatal Pathway (main drawback to these drugs)
• Unintentionally we also block the Substantia niagra to striatum path (via dec Dopamine) and this effects Coordination of Voluntary movement
• Parkinson’s syndrome – tremor and rigidity, stooped posture
• Akathisia - pacing shifting, shuffling
• Acute dystonic reactions – muscle spasm
• Tardive dyskinesia (late onset; can be irreversible) – abnormal, involuntary movements (uncontrollable twisting and jerking). Can’t see it until it is too late
• Tuberoinfundibular Pathway
• Unintentionally we also block the Hyopthalamus to pituitary (via dec Dopamine) and this effects lactate production
  
• Women – lactation, amenorrhea, infertility
• Men – lactation, impotence, decreased libido, gynecomastia

Other adverse effects of typical antipsychotics:

• Pseudodepression related to drowsiness, restlessness and autonomic effects
• Corneal and lens deposits (Chlorpromazine)
• Retinal deposits (Thioridizine)
• Cardiac arrhythmias in overdose (Thioridizine especially)
• Neuroleptic malignant syndrome
• Severe muscle rigidity, impaired sweating, fever, autonomic instability

HD082

Advantages of atypical antipsychotics (SGAs)

SGAs = Second Generation Antipsychotics (clozapine, resperidone)

1. Reduced D2 receptor affinity
• ↓ positive symptoms with fewer EPS
2. Increased serotonin 5-HT2 affinity
• ↓ negative symptoms by increasing mesocortical dopamine
• Thus affecting the VTA -> PFC pathway and decreasing the Negative Symptoms

Adverse Effects:

• Generally, same as typical antipsychotics with lower risk, especially of EPS
• Seizures (2-5%) in patients receiving Clozapine
• Weight gain, hyperlipidemia, hyperglycemia associated with 5-HT2 blockade (Clozapine, Olanzapine)
• Agranulocytosis (1-2%) in patients receiving Clozapine
• Cardiac QT prolongation (Ziprasidone)
• Higher death rate in elderly patients with dementia

EPS replaced by weight gain/hyperglycemia as dominant adverse effect

Drug interactions:

• CYP 3A4 interaction (St. John’s Wort), CYP 1A2 interaction (smoking), CYP 2D6 interaction
• Excess sedation – mood stabilizers, hypnotics, alcohol, antidepressants, antihistamines
• Additive antimuscarinic effects
• Metoclopramide – D2 antagonist, EPS
• SSRI/dopamine interaction

Sedative

• Anxiolytic, calming effects are desired
• CNS depression is often not a desired effect

Hypnotic

• Promotes drowsiness
• Promotes onset and maintenance of sleep

1. Anxiety
2. Insomnia
3. Sedation and amnesia
4. Conscious sedation (brain and neck surgery)
5. Epilepsy and seizure
6. Ethanol withdrawal

HD087

Insomnia

Once Delerium Tremens begin...

Order of choice for prescriptions for Anxiety Treatment

# 1 cause caffeine of insomnia

Types and Treatment:

1) Difficulty falling asleep

Use fast-acting, but shorter duration drug

2) Frequent awakenings – more difficult to treat

Falling asleep is not the issue, so use a drug of medium duration

3) Short duration of sleep

Falling asleep is not the issue, so use a drug of medium duration

4) “Unrefreshing” sleep

Medium duration drug

We want to keep people in stages 3-5 (5 is REM) sleep

• Benzodiazepines decrease stage 3, 4, and 5 sleep, while increasing stage 2 – not ideal

There is no known medical treatment to stop them. Grand mal seizures, heart attacks and stroke can occur during the DT's, all of which can be fatal

1. SSRIs, SNRIs
2. Zopiclone
3. Benzodiazipines

HD087

Onset, Duration and CNS FX to consider with Anxiolytics

Mechanism of Benzodiazipines

Rate of onset (most important) for CNS drugs is determined by transfer to CNS, which is controlled by lipophilicity

• More lipophilic = More rapid onset of action – gets to BBB fast (greater addicition risk)

Duration of effect depends on redistribution of drug out of the brain

• First to highly vascularized tissue (sk. muscle)
• Then, to adipose tissue (LSD)
• Relative level of adipose tissue has a very large effect on duration of effect and metabolite accumulation
• Important for elderly and obese
• Don’t want to use long-acting BZDs b/c of risk of Dizziness, impaired coordination (Falls)

• Work by activating the GABAa receptor (primary inhibitory neurotransmitter in brain)
• Activation of GABAa decreases electrical activity of neurons

HD087

Problems with BZDs

Side FX

Contrainditcations

Physical dependence is an issue with BZDs – can even happen with one dose (Concern with short-duration BZDs)

Long-term use is associated with significant physical dependence and patients MUST be tapered
Sudden discontinuance can cause:

• Convulsions
• Confusion
• Psychosis
• Effects similar to DTs

Potential:

• There is both abuse and addiction potential
• BZDs are among the most widely abused drugs-effects similar to alcohol
• Those with rapid-onset (triazapam, diazepam) give “rush”

Side effects and Overdose:

• Drowsiness, ataxia, confusion,vertigo, impaired judgement – same as alcohol
• Amnesia
• Occasionally (5-10%) have paradoxical effects-increased anxiety, insomnia (“mean drunk”)
• Overdose-commonly occurs with alcohol

Contraindications:

• Myesthenia Gravis
• Narrow-angle glaucoma
• Alcoholism or drug abuse – only for withdrawal and must be done in hospital
• Pregnant or nursing mothers
• Severe sleep apnea

HD087

BZD: Diazepam (Valium) drug properties

Uses

Lorazepam (Ativan) drug properties

Uses

• Highly lipophilic, so rapid onset
• High abuse potential
• Active metabolites
• Very slowly eliminated - 8.5 day half-life   
• Comes in very small dosage levels

Uses:

1. Anxiety (long-acting)
2. Insomnia (Falling asleep and maintenance)
3. Alcohol withdrawal – commonly used
4. Tapering off other BZDs (long action, availability of small doses)

• Not highly lipophilic, (slow onset) – dec addiction potential
• No active metabolites - direct conjugation
• T1/2 approximately 8 hrs – not good for alcohol withdrawal

Uses:

• Anxiety
• Sleep Maintenance
• Not choice for longer term treatment in the elderly due to its stronger amnesic effects
• Good choice for short term treatment of a younger, non-drinking patient as it is relatively less sedating
• Abuse: slow onset, but highly potent

HD087

3 Bad BZDs

Flumazenil

List of Non-BDZ Anxiolytics

Flunitrazepam (Rohypnol):

• Very potent, Colorless, odorless and tasteless
• High doses cause retro and anterograde amnesia

Flurazepam (Dalmane):

• Extremely long plasma T1/2 (40 - 250 hr)
• Multiple potent metabolites, especially in elderly, and those with high fat % -> metabolites can accumulate to very high levels
• Overdose and chronic accumulation can lead to long-term mental effects

Triazolam (Halcion):

• Very rapid onset
• Very short duration of effect (3-6hr)
• Associated strongly with rebound anxiety, withdrawal syndromes, and early waking

• Benzodiazepine competitive antagonist – never use if taking BDZ, alcoholics, seizures
• Used to reverse the CNS depressant effects of benzodiazepine overdose

Common Alternatives

SSRIs, Buspirone, Zopiclone

Rarely used

Barbiturates, Chloral hydrate

HD087

Treatment of Anxiety:

Benzodiazepines vs SSRIs

Effectiveness, Therapeutic index, Drug interactions, Physiological dependence, Amnesic effects, Onset of anxiolytic effects, Mental alertness/motor coordination,Duration of therapy

Effectiveness:

• SSRIs more appropriate for long term anxiety, especially if anxiety may be a symptom of depression
• No abuse risk. But it takes a while, can the patient wait a few weeks?
• SSRIs side effects may mimic anxiety, insomnia also common

Therapeutic index: Both are high

Drug interactions:

• SSRIs:  due to inhibition of liver enzymes
• Benzodiazepines:  CNS depressants, including ethanol and antihistamines

Physiological dependence: More of a problem with benzodiazepines

Amnesic effects: Produced by benzodiazepines, not SSRIs

Onset of anxiolytic effects: Faster with benzodiazepines than SSRIs

Mental alertness, motor coordination: Can be decreased by benzodiazepine treatment

Duration of therapy

• Days or weeks with benzodiazepines
• Months with SSRIs

HD087

Zopiclone

 Buspirone

Chloral hydrate and Thiopental

• Structurally unrelated to benzodiazepines but works in the same way (Enhances GABA-mediated neuronal inhibition)
• Zopiclone is claimed to be slightly specific for a1 GABA (thus the difference in sleep effects)
• Antagonized by flumazenil
• Rapid onset, rapid metabolism - fewer concerns with accumulation
• Used for short-term treatment of insomnia and for anxiety
• More effective than BZDs because tends to increase stage 3 and 4 sleep

• Does not bind GABA receptors (Binds to both dopamine and 5-HT R)
• Very rapid onset - peak levels achieved in under an hour
• Half-life 3-11 hours, active metabolites with longer T1/2
• Anxiolytic effects take about a week to develop
• Not as effective as diazepam
• Relieves anxiety without causing marked sedative or euphoric effects
  
• No effects on mental alertness or motor coordination, e.g. driving
  
• No potentiation of CNS depression caused by other sedative-hypnotics, ethanol, or TCAs
  
• Minimal abuse potential
  
• No withdrawal effects

Bad!

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