Physiology - Pharmacology and Patient Safety Flashcards
Facts about nicotine
Naturally occurring plant alkaloid
Found primarily in solanasceous plants
Principal source was tobacco and replacement therapy
Pure nicotine is a clear liquid w/ characteristic odour, turns brown on exposure to air
Absorption of nicotine
Nicotine is a wek base (pKa = 8.0)
Absorption through mucous membrane is pH dependent and increases as pH increases
Where can nicotine be absorbed through
Oral cavity (absorption poor) Skin Lung Urinary bladder GI tract (poor absorption due to low pH)
Main absorption of nicotine in cigarette smoke
Through funds
pH of alveoli is 7.4 so nicotine from cigar smoke is unchanged and easily crosses alveolar membrane into blood
Exposure to nicotine
Bad breath
Stained teeth
Smoker’s cough
Increased heart rate and bp
Bad breath - exposure to nicotine
Nicotine and other chemicals in tobacco gets deposited in oral cavity
Stained teeth - exposure to nicotine
Sticky substances in the smoke get deposited on teeth and thus causes stains
Smoker’s cough - exposure to nicotine
Coughing is a protective physiological mechanism to remove irritants from the body, esp from the respiratory tract
Increased heart rate and bp - exposure to nicotine
Short term effect
Nicotine metabolism
Occurs in liver within 1-2hrs in humans
70-80% gets oxidised to cotinine by oxidation
50% is excreted in urine
Nicotine can also be excreted via faeces, bile, saliva, sweat
Cotinine
Inactive metabolite of nicotine
Nicotine effects on whole organism
Increased hr Cardiac contractility Increased bp Decreased blood temp Mobilisation of b mood sugar Increase in FFA in blood Increase catecholamines levels in blood Arousal or relaxation
FFA
Free fatty acids
Catecholamines
Adrenaline
Noradrenaline
Nicotine effects on cellular level
Increased synthesis and release of hormones
Activation of tyrosine hydroxylase
Activation of several transcription factors
Induction of heath shock proteins
Effects of apoptosis
Induction of chromosome aberrations
Induction of sister chromatid exchange
Effects of nicotine on the autonomic nervous system
Reduces/ inhibits effects of parasympathetic activation
Tends to increase/ activate sympathetic activation
Why does nicotine effect the autonomic nervous system in the way it does
Parasympathetic endings release Ach and sympathetic endings relate NA (NE)
Ach
Acetylcholine
NA
Noradrenaline
NE
Norepinephrine
Cholinergic receptors
Receptors on the surface of cells that get activated when they bind to a type of acetylcholine
AChR
Ligand-gated ion channels and are present at the neuromuscular junction and signal muscular contraction with stimulation
Structure of nAChR
Composed of 5 subunits, 2 alpha, and one each of beta, delta and gamma subunits
All subunits arranges in barrel or cylindrical shape around a central pore
Each alpha subunit has a Ach binding site
How do nAChR’s work
Each of two alpha subunits have to be bound to Ach to allow influx of Ca2+ and Na+ intracellularly and efflux of K out of cell
Types of cholinergic receptors
Nicotinic (nAChR)
Muscarinic (mAChR)
Named after drugs that work on them
Nicotinic acetylcholine receptors
Pentameric ligand-gated ion channels
Muscarinic acetylcholine receptors
Seven-helix G-protein coupled membrane protein
Peripheral effects of nicotinic receptor activation
Increase in heart rate (HR), cardiac output (CO) and arterial pressure
Reduction in GI motility
Sweating
What does the peripheral effects of nicotinic receptor activation result from
Stimulation of autonomic ganglia and peripheral sensory receptors mainly in heart and lungs
What does nicotine act on
Nn receptors
(alpha4) 2(beta2)3 - brain cortex & hippocampus - role in cognitive function
(alpha3) 2(beta4)3 – ganglion
(alpha1) 2beta1deltaepsilon - muscle
What does smoking increase the risk of
Coronary heart disease (Myocardial Infarct)
Peripheral vascular disease (hypertension)
Lung cancer (carcinogens, tar & CO)
Chronic Obstructive Pulmonary Disease
Abnormal foetal development (low birth weight
COPD
Chronic obstructive Pulmonary Disease
Incl chronic bronchitis and emphysema
What conc do we see minimal effects of ethanol at
10mmol/L (46mg/ 100ml)
What conc leads to severe intoxication
150mg/ 100ml
What conc of ethanol is lethal
500mg/ 100ml - respiratory failure
1 unit
8g ethanol (amount in ½ pint, 1 measure of spirit, 1 glass wine) Strength (ABV) x volume (ml) / 1000 = units
UK recommendation for alcohol intake
14 units a week for men and women
Where does ethanol metabolic occur
Liver
Ethanol absorption
Ethan ol is rapidly absorbed via stomach
90% of ethanol is metabolised,
5-10% is excreted unchanged in expired air and urine, basis of police breath & urine tests
Ethanol effects on body
Cardiovascular system Endocrine system GI tract Liver - most serious long term consequence Foetal development
Ethanol effects on cardiovascular system
Cutaneous vasodilation, causes warm feeling but actually increases heat loss
Ethanol effects on endocrine system
Diuresis – caused by inhibition of release of ADH (hormone) from the pituitary
Ethanol effects on GI tract
Increased salivary and gastric excretion
Ethanol effects on liver
Increased fat accumulation —> hepatitis and finally hepatic necrosis and fibrosis
Effects on lipid metabolism, platelet function & atherosclerosis
Ethanol effects on foetal development
Foetal alcohol syndrome (FAS)
Alcohol-related neurodevelopmental disorder (ARND)
Ethanol effects on CNS - acute ethanol intoxication
Slurred speech
Motor incoordination
Increased self confidence
Euphoria
Effect on mood can vary, loud and outgoing or morose and withdrawn
Intellectual and motor performance and sensory discrimination all show uniform impairment
Ethanol effects of CNS - chronic ethanol intoxication
Irreversible neurological effects (e.g. dementia, peripheral neuropathy)
May be due to ethanol, but also its metabolites (e.g. acetaldehyde, FA esters)
Some effects are due to thiamine deficiency (Wernicke’s-Korsakoff syndrome)
Mechanism of action of alcohol on CNS
Enhancement of GABA-mediated inhibition, similar to action to benzodiazepines
Effect smaller and less consistent though
Inhibits transmitter release in response to nerve terminal depolarisation by inhibiting opening of voltage dependent calcium channels in neurons
Flumazenil
Benzodiazepine antagonist
Reverses central depressant effects of ethanol
Not used in alcohol dependence - side effect is to increase seizures
What does alcohol increase the risk of
CNS atrophy Cardiomyopathy Peptic ulcers Pancreatitis Liver damage Varices Testicular atrophy
Tolerance
Decrease in pharmacological effect on repeated administration of drug – dose has to be increased to get same effect
Dependence
State when drug-taking becomes compulsive (taking precedence over other needs
Withdrawal (abstinence) syndrome
Adverse effects, both physical and psychological, occurring after stopping taking drug
Craving
Intense desire for a drug that long outlasts the withdrawal (abstinence) syndrome
Reward pathway
Mesolimbic/ mesocortical dopaminergic pathway
Activated by virtually all dependence-producing drug
Nicotine and dopamine
Nicotine enhances synthesis and release of dopamine
Acts on cholinergic receptors on dopamine cell bodies in the ventral tegmental area (VTA)
What does alcohol decreases the activity of
GABAergic interneurons
Alcoholics have hypofunction of mesolimbic system
Severity is dependent on amount consumed
Mesocortical pathway
Starts in VTA and travels to prefrontal cortex, passes through nucleus accumbens
Mesolimbic pathway
Begins in VTA and passes through nucleus accumbens and ends at hippocampus nucleus and amygdaloid
Abstinence Syndrome in response to nicotine withdrawal
Increased irritability, impaired psychomotor tasks, aggressiveness, sleep disturbance
Last 2-3 weeks, although craving for cigarettes lasts much longer
Main dopaminergic pathways
Mesolimbic
Mesocrtical
Nigrostriatal
Tubero-hypophyseal
Abstinence syndrome in repose to ethanol withdrawal
Has 3 stages
1st stage of absence syndrome (ethanol)
Main symptoms are tremor, nausea, sweating, fever & sometimes hallucinations
Lasts about 24hrs
2nd stage of absence syndrome (ethanol)
Epilepsy-like seizures
3rd stage of absence syndrome (ethanol)
‘Delirium tremens’ – results in confusion, agitation, aggression & more severe hallucinations
Develops over a few days
Mechansims for treating drug dependence
Substitution, to alleviate withdrawal symptoms Long-term substitution Blocking response Aversive therapies Modification of cravings
Examples of substitution to alleviate withdrawal symptoms
Benzodiazepines, to blunt alcohol withdrawal
Examples of long-term substitution
Nicotine patches, chewing gum, spray, inhaler, lozenge
Examples of blocking response
Varenicline spp antagonist for nAChR
Examples of aversive therapies
Disulfiram to induce unpleasant response to alcohol
Examples of modification of craving
Bupropion (antidepressant)
Effects of smoking and drinking relating to having an operation
Increased risk of DVT
Withdrawal symptoms
Chest infections
